Program for the Assessment of Clinical Cancer Tests (PACCT-1): Trial Assigning Individualized Options for Treatment:The TAILORx Trial
Phase: PHASE3
Conditions: Breast Adenocarcinoma, Hormone Receptor Positive, Stage IA Breast Cancer AJCC v7, Stage IB Breast Cancer AJCC v7, Stage IIA Breast Cancer AJCC v6 and v7, Stage IIB Breast Cancer AJCC v6 and v7, Stage IIIB Breast Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

PACCT-1 
 
1 
ECOG-ACRIN Cancer Research Group 
and 
The Breast Cancer Intergroup 
Program for the Assessment of Clinical Cancer Tests 
(PACCT-1): Trial Assigning Individualized Options for 
Treatment: The TAILORx Trial 
STUDY CHAIR: 
Joseph A. Sparano, M.D. 
STUDY CO-CHAIR: 
Della F. Makower, M.D. 
STUDY STATISTICIAN: 
Robert Gray, Ph.D. 
PATHOLOGY CO-CHAIR: 
Sunil S. Badve, M.D. 
COMMUNITY CO-CHAIR: 
Thomas Saphner, M.D. 
BREAST COMMITTEE CHAIR: 
George Sledge, M.D 
NCCTG CO-CHAIR: 
Edith A. Perez, M.D. 
SWOG CO-CHAIR: 
Daniel F. Hayes, M.D. 
CALGB CO-CHAIR: 
Elizabeth Claire Dees, M.D. 
ACOSOG CO-CHAIR: 
John Olson, M.D., Ph.D. 
NCIC CTG CO-CHAIR: 
Kathleen Pritchard, M.D. 
NSABP CO-CHAIR: 
Charles E. Geyer, M.D. 
QOL CO-CHAIR 
Lynne I. Wagner, Ph.D. 
Version Date:  April 25, 2014 
NCI Update Date:  December 16, 2014 
STUDY PARTICIPANTS 
ACTIVATION DATE 
ALLIANCE / Alliance for Clinical Trials in Oncology 
SWOG / SWOG 
NCIC-CTG / NCIC Clinical Trials Group  
NRG / NRG Oncology Foundation, Inc  
Institutions aligned with ECOG-ACRIN will enroll 
patients via ECOG-ACRIN. Institutions not aligned with 
ECOG-ACRIN will enroll patients via the NCI Cancer 
Trials Support Unit (CTSU). 
Data management activities will be performed by the 
Cancer Trials Support Unit (CTSU). All non-RDC sites 
will fax hard-copy case report forms and query 
responses to 301-545-0406. 
NOTE: 
This does not include Expedited Adverse 
Event Reporting; please follow instructions 
in Section 5.3 for submission of AE data. 
The CTSU will use the PACCT-1 number as required for 
reporting to ECOG-ACRIN and the NCI and when 
registering patients through ECOG-ACRIN. 
CTSU participants and institutions will be instructed to 
use the PACCT-1 study number on all data forms, 
reports, and communications. 
April 7, 2006 
Update #1 – Incorporated Prior to Activation 
Addendum #1 – 9/06 
Update #2 – 9/06 
Addendum #2 – 9/07 
Update #3 – 11/07 
Addendum #3 – 8/08 
Addendum #4 – 3/09 
Update #4 – 3/09 
Addendum #5 – 1/10 
Update #5 – 7/10 
Update #6 – 9/11 
Addendum #6 – 2/12 
Addendum #7 – 2/13 
Update #7 – 3/13  
Update #8 – 10/13 
Update #9 – 11/13  
Addendum #8 – 6/14  
Update #10 – 12/14 
Rev. 1/10 
Rev. 9/06 
Rev. 6/14 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
 
 
Rev. 9/06, 
        8/08 
 
 
 
Rev. 9/06 
Rev. 6/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
2 
Table of Contents 
Schema ...................................................................................................................... 9 
1. Introduction ...................................................................................................... 10 
1.1 Background ............................................................................................. 10 
1.2 Axillary Lymph Node Negative Breast Cancer and Indications for 
Chemotherapy ........................................................................................ 11 
1.3 Genomic Profiling in Breast Cancer ........................................................ 12 
1.4 Rationale for the Proposed Study ........................................................... 21 
1.5 Correlative Science .................................................................................. 24 
1.6 Quality of Life Component ...................................................................... 24 
1.7 Gender and Ethnicity .............................................................................. 36 
2. Objectives ......................................................................................................... 37 
2.1 Primary .................................................................................................... 37 
2.2 Secondary: ............................................................................................... 37 
2.3 Quality of Life Objectives: ....................................................................... 38 
2.4 Determinants of Late Relapse Ancillary Study (EL112LAB) ..................... 38 
3. Selection of Patients ......................................................................................... 39 
3.1 Pre-Registration ...................................................................................... 40 
3.2 Registration/randomization (24 to 72 hours after submission of the 
Oncotype DX Assay report to the ECOG-ACRIN Operations Office – 
Boston) .................................................................................................... 44 
3.3 Registration to Ancillary Study EL112LAB (Step 3).................................. 45 
4. Pre-registration and Registration/Randomization Procedures ........................ 46 
4.1 Pre-Registration ...................................................................................... 47 
4.2 Registration/Randomization ................................................................... 50 
4.3 Instructions for Patients Who Do Not Start Assigned Protocol Treatment52 
4.4 STEP 3: Registration to Ancillary Study EL112LAB .................................. 53 
5. Treatment Plan ................................................................................................. 54 
5.1 Treatment Arms ...................................................................................... 54 
5.2 Radiotherapy ........................................................................................... 55 
5.3 Quality of Life Assessments .................................................................... 55 
5.4 Adverse Event Reporting Requirements ................................................. 58 
6. Measurement of Effect ..................................................................................... 60 
6.1 Ipsilateral Breast Tumor Recurrence (IBTR) ............................................ 60 
6.2 Local/Regional Recurrence (LRR) ............................................................ 60 
6.3 Distant Recurrence (DR) .......................................................................... 60 
6.4 Second Primary Breast Cancer ................................................................ 60 
6.5 Second Primary Cancer (non-breast) ...................................................... 60 
6.6 Disease-Free Survival (DFS) ..................................................................... 61 
6.7 Distant Recurrence-Free Interval (DRFI) ................................................. 61 
6.8 Recurrence-Free Interval (RFI) ................................................................ 61 
6.9 Overall Survival ....................................................................................... 61 
Rev. 3/13 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
3 
6.10 Cause-specific Survival ............................................................................ 61 
6.11 Quality of Life .......................................................................................... 61 
7. Study Parameters .............................................................................................. 62 
7.1 Therapeutic Parameters.......................................................................... 62 
7.2 [Submission of Biological Materials Removed in Addendum #2] ........... 63 
7.3 Timepoints for QOL Assessments1,2 ...................................................... 63 
7.4 Requirements for Ancillary Study EL112LAB (Step 3 registration) ......... 63 
8. Drug Formulation and Procurement ................................................................. 65 
8.1 Cyclophosphamide .................................................................................. 65 
8.2 Methotrexate .......................................................................................... 69 
8.3 Fluorouracil (Infusional) .......................................................................... 72 
8.4 Doxorubucin ............................................................................................ 74 
8.5 Paclitaxel ................................................................................................. 76 
8.6 Epirubicin ................................................................................................ 79 
8.7 Docetaxel ................................................................................................ 81 
8.8 Tamoxifen ............................................................................................... 83 
8.9 Exemestane ............................................................................................. 85 
8.10 Anastrozole ............................................................................................. 86 
8.11 Letrozole.................................................................................................. 88 
9. Statistical Considerations .................................................................................. 90 
10. Tissue and Blood Specimens ............................................................................. 99 
10.1 Pre-Registration Submissions.................................................................. 99 
10.2 Submitting the RS to the ECOG-ACRIN Operations Office – Boston ..... 101 
10.3 Registration/Randomization Submissions (All Patients) ....................... 101 
10.4 ECOG-ACRIN Sample Tracking System .................................................. 106 
10.5 [“Processing of Specimen in ECOG-ACRIN Central Biorepository and 
Pathology Facility” Deleted in Addendum #2] ...................................... 107 
10.6 Banking .................................................................................................. 107 
10.7 Lab Data Transfer Guidelines ................................................................ 107 
10.8 Sample Inventory Submission Guidelines ............................................. 107 
11. Records to Be Kept .......................................................................................... 109 
11.1 Records Retention ................................................................................. 109 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
4 
12. Patient Consent and Peer Judgment .............................................................. 110 
13. References ...................................................................................................... 110 
Appendix I  Informed Consent Template [Deleted in Update #7]......................... 119 
Appendix I-A  EL112LAB: North American Breast Cancer Groups Biospecimen  Bank 
for Determinants of Late Relapse in Operable Breast Cancer Suggested Patient 
Consent Form [Deleted in Update #7] ............................................................ 120 
Appendix II  Chemotherapy Regimens .................................................................. 121 
Appendix III  Hormonal Therapy Regimens ........................................................... 123 
Appendix IV  Submission of Biological Materials and Related Documents ........... 125 
Appendix V  Pathology Submission Guidelines ..................................................... 126 
Appendix VI   PACCT-1 and EL112LAB Peripheral Blood Collection and Shipping Kit 
Order Form ..................................................................................................... 136 
Appendix VII   PACCT-1 Shipment Notification Form - REMOVED ........................ 137 
Appendix- VIII   Correlative Science for the PACCT-1 Trial .................................... 138 
Appendix IX  Patient Thank You Letter .................................................................. 141 
Appendix X  Oncotype DX Assay Information ....................................................... 142 
Appendix XI  Cancer Trials Support Unit (CTSU) Participation Procedures ........... 148 
Appendix XII Ancillary Study EL112LAB ................................................................. 154 
 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
5 
 
ECOG-ACRIN STUDY CHAIR 
ECOG-ACRIN BREAST COMMITTEE CHAIR 
 
Joseph A. Sparano, MD 
Albert Einstein Cancer Center 
Montefiore Medical Center 
Weiler Division 
1825 Eastchester Road, 2S, Rm. 47 
Bronx, NY 10461 
Phone: 718-904-2555 
Fax: 718- 904-2892 
Email: ecog.tailorx@jimmy.harvard.edu 
 
George W. Sledge, Jr, MD  
Indiana Cancer Pavilion 
Room 473 
535 Barnhill Drive 
Indianapolis, IN 46202 
Phone: 317-274-0920 
Fax: 317-274-3646 
Email: gsledge@iupui.edu 
 
 
CORRELATIVE SCIENCE COMMITTEE CHAIR 
ECOG-ACRIN STUDY CO-CHAIR 
 
Matthew Ellis, MD, PhD 
Washington University 
660 S. Euclid, Campus Box 8056 
St. Louis, MO 63110 
Phone: 314-362-8866 
Fax: 314-362-7086 
Email: mellis@im.wustl.edu 
 
Della F. Makower, MD 
North Division of Montefiore Medical Center 
600 East 233rd Street 
Bronx, NY 10466 
Phone: 718-920-9900 
Fax: 718-798-7474 
Email: dmakower@montefiore.org 
 
TISSUE BANKING COMMITTEE CHAIR 
ADJUVANT ON-LINE CO-CHAIR 
 
Soonmyung Paik, MD 
4 Allegheny Center, 5th Floor 
East Commons Professional Building 
Pittsburgh, PA 15212 
Phone: 412-359-5013 
Fax: 412-359-3239 
Email: soon.paik@NSABP.org 
 
Peter Ravdin, MD, PhD 
University of Texas at San Antonio  
19931 Encino Royale 
San Antonio, TX 78299 
Phone: 210-215-9799 
Fax: 210-497-7952 
Email: pmravdin@aol.com 
 
 
ECOG-ACRIN STATISTICIAN 
ECOG-ACRIN COMMUNITY CO-CHAIR 
 
Robert Gray, PhD 
ECOG-ACRIN Operations Office – Boston 
900 Commonwealth Ave. 
Boston, MA 02215 
Phone: 617-632-3610 
Fax: 617-632-2990 
Email: gray@jimmy.harvard.edu 
 
Thomas Saphner, MD 
Green Bay Oncology 
1726 Shawano Ave. 
Green Bay WI 54303 
Phone: 920-884-3135 
Fax 920-884-3144 
Email: tsaphner@gboncology.com 
 
ECOG-ACRIN PATHOLOGY CO-CHAIR 
STUDY CHAIR LIAISON 
 
Sunil S. Badve, MBBS,MD  
Division of Surgical Pathology 
Indiana University School of Medicine 
550 North University Blvd, UH - 3465 
Indianapolis, IN 46202-5280 
Phone: 317-274-1823 
Fax: 317-274-5346 
Email: sbadve@iupui.edu 
 
Una Hopkins, RN 
Montefiore Medical Center 
Weiler Division 
1695 Eastchester Road, 1st Floor 
Bronx, NY 10461 
Phone: 718-904-2555 
Fax: 718-405-8526 
E-mail: ecog.tailorx@jimmy.harvard.edu 
 
Rev. 9/07 
Rev. 9/07 
Rev. 1/10 
6/14 
Rev. 3/09 
Rev. 9/07 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
6 
 
 
ECOG-ACRIN QOL CO-CHAIR 
 
SWOG CO-CHAIR, SPECIAL POPULATIONS 
 
Lynne I. Wagner, Ph.D. 
Northwestern University 
676 N. St. Clair #1200 
Chicago, IL 60611 
Phone: 312-695-6946 
Fax: 312-695-1328 
Email: Iwagner@northwestern.edu 
 
Kathy S. Albain, MD 
Loyola University Medical Center 
2160 S. 1st Ave., Rm 109 
Maywood, IL 60153 
Phone: 708-327-3102 
Fax: 708-327-2210 
Email: kalbain@lumc.edu 
 
TBCI CHAIR 
ACOSOG STUDY CO-CHAIR 
 
William C. Wood, MD 
Winship Cancer Institute 
Emory University 
1364 Clifton Rd NE B206 
Atlanta, GA 30322-1059 
Phone: 404-727-5800 
Fax 404-727-4716 
Email: Wood1@emoryhealthcare.org 
 
John Olson, MD, PhD 
Duke University Medical Center 
Department of Surgery, Box 2945 
Durham, NC 27110 
Phone 919-668-1767 
Fax 919-684-6810 
Email: jaomd@duke.edu 
 
 
NCIC CTG STUDY CO-CHAIR 
CALGB STUDY CO-CHAIR 
 
Kathleen Pritchard, MD 
Toronto-Sunnybrooke Cancer Center 
2075 Bayview Ave. 
Toronto, ON M4N 3M5 Canada 
Phone: 416-480-4616 
Fax: 416-480-6002 
Email: kathy.pritchard@sw.ca 
 
Elizabeth Claire Dees, MD 
University of North Carolina 
3009 Old Clinic Bldg CB 7305 
Chapel Hill, NC 27599-7305 
Phone: 919-966-4431 
Fax 919-966-6735 
Email: claire_dees@med.unc.edu 
 
 
SWOG STUDY CO-CHAIR 
NSABP STUDY CO-CHAIR 
 
Daniel F. Hayes, MD 
University of Michigan Medical Center 
6312 CCGC 
1500 E. Medical Center, Dr.  
Ann Arbor, MI 48109-0942 
Phone: 734-615-6725 
Fax: 734-615-3947 
Email: hayesdf@umich.edu 
Charles E. Geyer, MD  
Allegheny Cancer Center 
320 East North Ave, 5thf Fl. 
Pittsburgh, PA 15212 
Phone 412-359-8353 
Fax 412-359-6263 
Email: charles.geyer@NSABP.org 
 
 
NCCTG STUDY CO-CHAIR 
 
 
Edith A. Perez, MD 
Mayo Clinic 
4500 San Pablo Road 
Jacksonville, FL  32224-9980 
Tel: (904)953-7080 
Fax: (904) 953-2315 
Email: perez.edith@mayo.edu 
 
 
Rev. 9/06 
Rev. 1/10 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
7 
Cancer Trials Support Unit (CTSU) Address and Contact Information 
Data management activities for the study will be performed by CTSU with the exception 
of the Quality of Life component. 
All sites, ECOG-ACRIN and non-ECOG-ACRIN alike, will submit data via the CTSU. For this 
reason, investigators and study support staff involved in the collection and reporting of study 
data must be registered members of the CTSU. QOL data, for ECOG-ACRIN and non-ECOG-
ACRIN sites, will be submitted to the ECOG-ACRIN Operations Office – Boston. 
 
To submit site registration documents: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone - 1-888-823-5923 
Fax – 215-569-0206  
Email: CTSURegulatory@ctsu.coccg.org (for submitting regulatory documents only) 
 
Rev. 9/07, 
       7/10 
Rev. 12/14 
For patient enrollments: 
Please refer to patient enrollment section for instructions on using the OPEN system, which 
can be accessed at https://www/ctsu.org/OPEN_SYSTEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any OPEN-related questions at ctsucontact@westat.com. 
NOTE: 
No exemptions or waivers will be granted for patients who do not meet the 
eligibility criteria. 
Rev. 8/08 
Rev. 1/10 
For data submission: 
Data management activities for PACCT-1 (TAILORx) will be performed by the CTSU for 
ECOG-ACRIN and non-ECOG-ACRIN sites alike. Sites pre-selected by ECOG-ACRIN will 
submit case report forms and manage discrepancies via CTSU’s Remote Data Capture 
(RDC) system. All non-RDC sites will fax CRFs, clinical reports and responses to query and 
delinquency letters to 301-545-0406. 
Data management activities for the QOL study will be performed by the ECOG-ACRIN 
Operations Office – Boston for both ECOG-ACRIN and non-ECOG-ACRIN sites. 
Rev. 9/06 
NOTE: 
This does not include Expedited Adverse Event Reporting; please follow 
instructions in Section 5.3 for submission of AE data. 
Rev.12/14 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org. Access to the CTSU members’ websiteis managed through the Cancer 
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) 
registration system and requires user log on with CTEP-IAM username and password. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
8 
Rev. 9/06, 
       9/07 
Rev. 1/10 
For patient eligibility or treatment-related questions: 
Questions regarding eligibility or treatment should be directed to the ECOG-ACRIN Study 
Chair (Joseph Sparano, M.D.) and/or Study Chair Liaison (Una Hopkins, R.N.) or the CTSU 
Help Desk at 1-888-823-5923. An email to the following email address is PREFERRED, and 
will be reviewed by the Study Chair and Study Chair Liaison (and other study team 
members); a response will be provided within 24 hours (ecog.tailorx@jimmy.harvard.edu). 
For questions regarding patients who have been pre-registered or registered, please provide 
the sequence number in the subject heading and/or content of the email. 
For QOL questions: 
For questions regarding the quality of life portion of the study, please contact Dr. Lynne 
Wagner at: (312) 695-6946 or lwagner@northeastern.edu. 
All other questions (including forms-specific questions) should be communicated by 
phone or e-mail to the CTSU Help Desk at:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. 
All calls and correspondence will be triaged to the appropriate CTSU representative.  
Rev. 12/14 For detailed information on the regulatory and monitoring procedures for CTSU sites: 
Please review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU 
members’ website   https://www.ctsu.org> education and resources tab > CTSU Operations 
Information >CTSU Regulatory and Monitoring Policy 
The CTSU Public Web site is located at: www.ctsu.org  
The CTSU Registered Member Web site is located at http://members.ctsu.org 
 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
9 
Schema 
ER-Positive and/or PR-Positive Breast Cancer
Axillary Node-Negative 
Candidate for Adjuvant Cytotoxic Therapy
in Addition to Hormonal Therapy
Registration5/Randomization5,7 
Secondary Study Group - 1
Recurrence Score < 11
(~29% of Population)
Patients = Registered
Primary Study Group  
Recurrence Score 11-25
(~44% of Population)
Patients = Randomized
Secondary Study Group - 2 
Recurrence Score > 25
(~27% of Population)
Patients = Registered
Arm A
Hormonal Therapy2
QOL Assessment7
Arm D
Chemotherapy Plus 
Hormonal Therapy 3,6
QOL Assessment7
Arm B
Hormonal Therapy2
QOL Assessment7
Arm C
Chemotherapy Plus 
Hormonal Therapy 3
QOL Assessment7
Pre-Registration 
Accrual Goal =11,248 patients
Patients who have had breast conservation surgery will also be treated with radiotherapy.
Refer to Section 5.2 for RT guidelines
1. A tumor specimen MUST be sent to Genomic Health for the Oncotype DX assay (see Section 10 and Appendix V for details). Residual tumor tissue and RNA 
    
will be forwarded to the ECOG PCO-RL by Genomic Health, and will be retained by the ECOG PCO-RL for individuals who have consented to use of tissue for 
    
future research (or returned to the site if consent was not granted).  Patients who have had the Oncotype 
DX assay performed prior to pre-registration may also 
    enroll if the RS was 11-25, the patient has signed consent, and all eligibility criteria are met.  In this case, tumor specimen must be sent directly to the 
ECOG 
    PCO-RL.
2. Patients will receive hormonal therapy of the treating physician’s choice (see Appendix  III for details).
3. Patients will receive chemotherapy plus hormonal therapy of the treating physician’s choice (see Appendices II & III for details).
4. See Appendix III for status definitions
5. See Section 10.2 for submission of samples to the ECOG PCO-RL.
6  For patients with a RS > 26 who do not register on another CTSU study, the enrolling site is asked to provide baseline and follow-up information on a voluntary     
basis. Requested information will include the following: (1) a baseline case report form, (2) a report of disease relapse event (as defined in Section 6), and/or 
    
second primary cancer, and/or death (if any of these events occur), (3) and a report of disease and survival status 5 years after registration. 
7. QOL assessments should be completed for all patients registered/randomized to the TAILORx trial at baseline, 3 months, 6 months, 12 months, 24 months, and 
    36 months. See Section 7.3 for additional scheduling information.
8. Patients become potentially eligible for EL112LAB if disease free and were registered to step 1 (Arm A,B,C or D) at least 4.5 years (54 months) and no more 
    
than 7.5 years (90 months) prior to registration to step 3. To assist sites, ECOG will provide a list of patients with date ranges of their potential eligibility.
9. Following registration to EL112LAB: blood samples are submitted at registration and upon recurrence; recurrence tumor tissue upon recurrence; and health  
    
information at registration and yearly for 5 years.
Stratify
• 
Tumor Size: < 2.0 cm vs. > 2.1cm
• 
Post-menopausal vs. Pre- or Peri-menopausal 4
• 
Planned chemotherapy: Taxane-containing (i.e. paclitaxel, docetaxel) vs. 
Non-taxane-containing
• 
Planned radiation therapy: whole breast, no boost planned vs. whole 
breast, boost planned vs. partial breast irradiation planned vs. no planned 
radiation therapy (for patients who have had a mastectomy)
• 
Oncotype DX Recurrence Score (11-15, 16-20 or 21-25)
Submit tumor specimen to Genomic Health for 
ONCOTYPE DX Assay1
Rev. 9/06
Rev. 9/06, 9/07
Rev. 9/06
Rev. 9/06
Rev. 9/06
Rev. 9/06
Rev. 3/09
Rev. 3/09
Rev. 1/10
Rev. 1/10
Rev. 1/10
Rev. 1/10
Rev. 1/10
Rev. 1/10
Registration8 
EL112LAB Ancillary: Submission of 
specimens and health information 
x 5 years and at recurrence9
Rev. 2/13
Rev. 2/13
Rev. 2/13
Rev. 2/13
 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
10 
1. 
Introduction 
1.1 
Background 
In 2004, it is projected that there will be 215,900 new cases of female breast 
cancer and 40,110 deaths due to the disease in the United States (1). Cancer is 
the leading cause of death in women between the ages of 40-79, with breast 
cancer being the most common cancer in this group, and the second leading 
cause of cancer death. Breast cancer mortality has declined over the past 10 
years due largely to the earlier detection of cancer by mammographic screening, 
but also in part due to the increasing use of adjuvant hormonal therapy and 
chemotherapy (2,3). The selection of adjuvant hormonal therapy based upon 
expression of the estrogen receptor (ER) and/or progesterone receptor (PR) has 
remained consistent (about two-thirds of all cancers) over the past 30 years. 
However, indications for adjuvant chemotherapy have expanded considerably to 
now include even women at very low risk of systemic recurrence. For example, 
the addition of adjuvant chemotherapy to tamoxifen reduces the risk of relapse in 
patients with axillary node negative, estrogen receptor (ER)-positive disease by 
approximately 30% (4-7). Indeed, attention has now begun to focus on who 
should not rather than who should receive chemotherapy (8). Models have been 
developed that can assist physicians in estimating the absolute benefit for an 
individual patient, although such models are based purely on clinical data and 
have inherent limitations (9,10). An International Expert Consensus Panel (11) 
defined “minimal risk” and “average-risk” groups for “endocrine-responsive” 
disease, and suggested that adjuvant chemotherapy be considered for women in 
the “average risk” group (Table 1) who are less than 70 years of age; by 
definition, “average risk” does not include patients with pure tubular or colloid 
histology, histologic patterns associated with a very favorable prognosis. A 
limitation of these guidelines is their reliance on histologic and/or nuclear grade 
for risk classification, which some have reported to have great interobserver 
variability, even amongst expert pathologists (12). Another limitation is that a 
relatively small proportion of patients with axillary node-negative, ER-positive 
disease are classified as “minimal risk”.  Evidence-based practice guidelines 
issued by the National Comprehensive Cancer Center Network (www.nccn.org) 
use a lower threshold for recommending adjuvant chemotherapy in addition to 
hormonal therapy (Table 1). Although the NCCN guidelines do not use the terms 
“minimal risk” or “average risk”, these terms have been used in Table 1 to draw 
comparisons between the two guidelines for groups who are advised to receive 
or not to receive adjuvant chemotherapy. Finally, the United States National 
Institute of Health Consensus Development Panel concluded, “On the basis of 
available data, it is accepted practice to offer cytotoxic chemotherapy to most 
women with lymph node metastases or with primary breast cancers larger than 1 
cm in diameter (both lymph node-negative and lymph node-positive). For women 
with lymph node-negative cancers smaller than 1 cm in diameter, the decision to 
consider chemotherapy should be individualized. Similarly, in patients with small 
lymph node-negative breast cancers with favorable histologic subtypes, such as 
tubular and mucinous cancers, retrospective data support long-term survival 
following primary therapy without the need for adjuvant chemotherapy.” With 
regard to age, the panel concluded, “There are limited data to define the optimal 
use of adjuvant chemotherapy for women more than 70 years of age…. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
11 
Increased participation of women over the age of 70 years in randomized clinical 
trials and studies specifically addressing the value and tolerance of adjuvant 
chemotherapy in these women are urgently needed” (13). 
Table 1 - Recommendations for Adjuvant Therapy of Axillary Lymph Node-
Negative, Endocrine Responsive Disease 
 
Definition 
Premenopausal 
Postmenopausa
l 
International 
Consensus 
Guidelines 
(Goldhirsch, 
2003) 
Minimal Risk (*): 
Tubular or colloid histology  
OR 
All of the following features 
(*): 
pT<2 cm, and Grade 1, 
and Age ≥ 35 years 
Hormonal 
Therapy 
OR None 
Hormonal 
Therapy 
OR None 
NCCN 
Guidelines 
(www.nccn.org) 
 
Tubular or colloid histology 
OR 
pT < 1 cm and no 
unfavorable features 
Hormonal 
Therapy 
OR None 
Hormonal 
Therapy 
OR None 
International 
Consensus 
Guidelines 
(Goldhirsch, 
2003) 
Average Risk: 
ER and/or PR expressed, 
and at least one of the 
following features: 
pT > 2 cm, or  
Grade 2 or 3, or  
Age < 35 years 
 
Chemotherapy ⇒  
Hormonal 
Therapy 
OR 
Hormonal 
Therapy 
Hormonal 
Therapy 
OR 
Chemotherapy ⇒ 
 Hormonal 
Therapy 
NCCN 
Guidelines 
(www.nccn.org) 
 
pT > 1cm, AND 
Histology ductal (NOS), 
lobular, mixed, or 
metaplastic 
OR 
Tumor 0.6-1.0 cm with 
unfavorable features+ 
 
Chemotherapy ⇒  
Hormonal 
Therapy 
Chemotherapy ⇒ 
Hormonal 
Therapy OR 
Hormonal 
Therapy (if > 60 
years of age) 
 
Abbreviations and/or definitions: pT – pathologic tumor size, defined as size of 
invasive component of tumor; Grade – histologic and/or nuclear grade; ER – 
estrogen receptor; PR – progesterone receptor; unfavorable features (+) – for 
NCCN guidelines, defined as angiolymphatic invasion, poor nuclear grade, poor 
histologic grade, or Her2 overexpression 
Minimal Risk (*) – some panel members recognize lymphatic and/or vascular 
invasion as a factor indicating greater risk than minimal risk 
1.2 
Axillary Lymph Node Negative Breast Cancer and Indications for Chemotherapy 
According to Surveillance and Epidemiology and End Results (SEER) data, 
approximately 25% of women present with “average risk” node-negative disease 
in the United States, accounting for about 54,000 women diagnosed with breast 
cancer each year (14). Although adjuvant chemotherapy is of clear benefit even 
in “average risk” populations, the majority of women are treated unnecessarily to 
benefit a few. Assuming a relative risk reduction of 30% from the addition of 

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adjuvant chemotherapy to hormonal therapy, the absolute benefit derived from 
the addition of chemotherapy is low, even in individuals at higher risk for relapse. 
For example, using the ADJUVANT! decision analysis model, approximately 100 
women must be treated in order to benefit only 3 or 4 patients (Table 2).  A 
recent report indicated that this decision tool performed remarkably well when 
validated using an independent population based dataset including 4083 women 
with pT1-2, pN0-1 breast cancer, including patients with lymph node negative 
disease (15). The decision aid did overestimate prognosis, however, for ER-
positive disease (10 year breast cancer specific survival projected 84.9% with 
ADJUVANT! vs. 83.0% in validation dataset) and for the benefit for adjuvant 
chemotherapy (projected 75.2% vs. actual 70.6%). Although such decision aids 
may be useful in estimating the benefit of chemotherapy, they are not sufficiently 
reliable to distinguish individuals who will not derive benefit from adjuvant 
chemotherapy. 
Table 2 - Absolute Improvement in 10-Year Disease Free Survival in Node-
Negative Breast Cancer Treated by Addition of Chemotherapy to Tamoxifen 
(tam) 
St. Gallen 
Risk Group 
Grade 
Tumor 
size (cm) 
Tam 
x 5 years 
Tam x 5 
years 
plus chemo 
Absolute risk 
reduction by 
addition of 
chemo to tam 
Minimal Risk 
1 
1.1-2.0  
93% 
94% 
1% 
Average Risk 
2 
1.1-2.0  
81% 
83% 
2% 
Average Risk 
3 
1.1-2.0  
78% 
81% 
3% 
Average Risk 
1 
2.1-3.0  
75% 
78% 
3% 
Average Risk 
2 
2.1-3.0  
73% 
76% 
3% 
Average Risk 
3 
2.1-3.0  
68% 
72% 
4% 
Calculations based upon Adjuvant Online model (www.adjuvantonline.com) (10).  
Calculation based upon women age 55 in perfect health, ER-positive tumor, 
negative axillary lymph nodes; chemotherapy regimen is AC (doxorubicin 60 
mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks x 4 cycles) 
1.3 
Genomic Profiling in Breast Cancer 
Gene expression profiling of human breast cancer has been shown to be 
potentially useful in identifying breast tumor subtypes associated with distinct 
phenotypic characteristics that may have clinical implications. A series of studies 
have been reported over the past few years that have utilized expression profiling 
for the following purposes: (1) identifying distinct molecular subtypes of breast 
cancer, (2) identifying molecular signatures associated with a good vs. poor 
prognosis (i.e., prognostic factor), and (3) identifying molecular signatures that 
predict benefit from specific therapies (ie, predictive factor). 
1.3.1 
Identifying Molecular Subtypes of Breast Cancer 
Perou initially reported variations in gene expression patterns in 40 
breast tumors analyzed by cDNA microarrays and hierarchical 
clustering that classified tumors into a basal epithelial-like group, a 
luminal group, an ERBB2-overexpressing group, and a normal breast-
like group (16). A subsequent report by the same group that included 

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78 cancers, 3 fibroadenomas, and 4 normal breast tissues indicated 
that the previously characterized luminal epithelial/ER-positive group 
could be divided into at least two subgroups with distinctive 
expression profiles, and that these subtypes were associated with 
differing prognoses when analyzed in a uniformly treated group of 
patients (17). Another report by the same group provided additional 
evidence supporting their original findings in two different data sets 
that included 115 patients with breast cancer treated with neoadjuvant 
chemotherapy; a favorable prognosis noted for the luminal A 
subgroup, unfavorable prognosis for the basal and Her2 group, and 
an intermediate prognosis was noted for the luminal B group (18). It is 
noteworthy that routine immunohistochemical markers for hormone 
receptor expression and Her2/neu expression may be used to 
approximate these genomic subtypes, with the basal type 
characterized by absence of ER/PR and Her2/neu expression, luminal 
types characterized by ER and/or PR expression without Her2/neu 
expression, and Her2 type characterized by presence of Her2/neu 
expression irrespective of ER/PR expression status 
1.3.2 
Identifying Molecular Signatures Associated with Prognosis (ie, 
Prognostic Factor) 
Other groups have evaluated gene expression profiles by performing 
supervised clustering analyses on the basis of clinical outcome 
(relapsers vs. non-relapsers) in order to identify specific gene 
expression profiles associated with prognosis. Some of these studies 
are summarized in Table 3, and discussed in further detail below. For 
the purposes of this discussion, the techniques may be broadly 
categorized as those that utilize routinely processed tissue (e.g., 
formalin-fixed, paraffin embedded tissue) and those that require 
specialized processing not routinely performed in clinical pathology 
laboratories (e.g., snap frozen fresh tissue).

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Table 3 – Characteristics and Performance of Selected Molecular Profiling 
Techniques 
 
Van de Vijver, 
2002 
Piccart, 2004 
Wang V, Klijn 
JG, Zhang Y, et 
al., 2005 
Paik, 2003 
Esteva, 2003 
Tissue 
Fresh frozen 
Fresh frozen 
Fresh frozen 
Paraffin-
embedded  
Paraffin-
embedded 
Molecular 
technique 
Rosetta 
Inpharmatics 
RNA expression  
Rosetta 
Inpharmatics 
RNA 
expression 
Affymetrix human 
U133a GeneChip 
RNA expression 
Genomic Health 
RT-PCR 
RNA expression 
Genomic Health 
RT-PCR 
RNA expression 
Tissue processing 
Thirty 30 micron 
sections  
Thirty 30 
micron sections 
Thirty 30 micron 
sections 
Three 10 micron 
sections 
Three 10 micron 
sections 
No. genes in 
panel 
70 genes 
70 genes 
76 genes 
16 genes (plus 
5 reference 
genes) 
16 genes (plus 
5 reference 
genes) 
Training/Validation 
Validation 
Validation 
Training & 
validation 
Training & 
 validation 
Validation 
No. 
selected/evaluable 
295/295 
301/291 
286/286 
2167/675 
220/149 
ER Expression 
77% 
67% 
70% 
100% 
70% 
Axillary Nodes 
Positive 
Negative 
 
51% 
49% 
 
0% 
100% 
 
0% 
100% 
 
0% 
100% 
 
0% 
100% 
Adjuvant therapy 
Tamoxifen 
Chemotherapy 
Both 
 
7% 
31% 
7% 
 
0% 
0% 
0% 
 
0% 
0% 
0% 
 
100% 
0% 
0% 
 
0% 
0% 
0% 
Median followup 
6.7 years  
10 years 
8.4 years 
10.9 years 
Minimum of 5 
years 
Genetic signature 
Good 
Intermediate 
Poor 
 
61% 
Not applicable 
39% 
 
63% 
Not applicable 
37% 
 
34% 
Not applicable 
64% 
 
51% 
22% 
27% 
 
32% 
14% 
54% 
1.3.2.1 
Frozen Tissue Specimens 
A group from the Netherlands Cancer Institute in 
Amsterdam identified a 70 gene panel that was evaluated 
in a training set of 78 breast cancers measuring less than 5 
cm in size associated with negative axillary nodes in 
patients less than 55 years of age, by characterizing the 
molecular signature of patients who did and did not have 
systemic relapse within five years (19). The “good” and 
“poor” signature profiles outperformed established clinical 
criteria. The technology involved use of an RNA 
expression profile in fresh frozen tissue (Rosetta 
Inpharmatics; 25,000 transcripts). This methodology was 
subsequently evaluated in a validation set of 295 
consecutive patients with stage I or II breast cancer 
younger than 53 years old, of whom 151 had lymph-node–
negative disease and 144 had lymph-–positive disease 

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(Table 3) (20). Adjuvant therapy was given to 44% of all 
patients, including 6% of the lymph node negative group 
and 83% of the lymph node positive group; adjuvant 
therapy included chemotherapy in 31%, hormonal therapy 
in 7%, and both in 7%. Among the 295 patients, 180 had a 
good-prognosis signature (61%) and 115 had a poor-
prognosis signature (39%).  At 10 years, the probability of 
remaining free of distant metastases was 51% (±5%) in the 
group with a poor-prognosis signature and 85% (±4%) in 
the group with a good-prognosis signature. Multivariate 
Cox regression analysis showed that prognosis profile was 
a strong independent factor predicting disease outcome. 
For the lymph node negative group, the estimated 5-year 
distant disease free survival was 95% (+3%) for the good 
signature group and 66% (+5%) for the poor signature 
group. When comparing the expression profiling with 
established clinical criteria in lymph node negative disease, 
the expression profile assigned many more to the low-risk 
group (good-prognosis signature) than did the clinical 
criteria (40% vs. 15% for St. Gallen criteria and 7% for NIH 
criteria). In addition, low-risk patients identified by gene-
expression profiling had a higher likelihood of metastasis-
free survival than those classified according to the St. 
Gallen or NIH criteria, and high-risk patients identified by 
gene-expression profiling tended to have a higher rate of 
distant metastases than did the high-risk patients identified 
by the St. Gallen or NIH criteria. This result indicates that 
both sets of the currently used clinical criteria misclassify a 
substantial number of patients. Indeed, the high-risk group 
defined according to the NIH criteria included many 
patients who had a good-prognosis signature and a good 
outcome. Conversely, the low-risk group identified by the 
NIH criteria included patients with a poor-prognosis 
signature and poor outcome. Similar subgroups were 
identified within the high-risk and low-risk groups identified 
according to the St. Gallen criteria. Since both the St. 
Gallen and the NIH subgroups contain misclassified 
patients (who can be better identified through the 
prognosis signature), these patients would be either 
overtreated or undertreated in current clinical practice. An 
external validation study of the 70 gene profile was 
subsequently performed by the TRANSBIG Network, and a 
preliminary analysis of this study has been presented (21). 
This study included frozen tumor specimens from 301 
patients with node-negative breast cancer who had primary 
treatment rendered at six non-Dutch centers in the United 
States and Europe, and who received no systemic 
adjuvant therapy. Sixty-three percent had high-risk profile 
(consistent with the 60% incidence for the original Dutch 
report), and this signature was associated with a 1.8-fold 
increased risk of systemic recurrence and 2.5-fold 

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increased risk of death. However, there was significant 
heterogeneity between original Amsterdam and external 
validation samples, and the overall performance of the 
prognostic signature was inferior in the external validation 
set.  Another group from the Erasmus Medical Center in 
Rotterdam reported their experience with RNA expression 
profiling using a different platform (Affymetrix Human 
U133a GeneChip; 23,000 transcripts), which included 286 
node-negative breast cancer patients who received no 
adjuvant systemic therapy (including 115 patients in the 
training set and 171 in the validation set) (22). In the 
training group of 115 patients (80 ER-positive), a 76-gene 
signature (60 for ER-positive and 16 for ER-negative) was 
identified that was predictive of distance metastases within 
5 years. A high-risk gene signature was associated with a 
significantly increased risk of distant metastases within 5 
years when adjusted for known prognostic variables 
(hazard ratio [HR] 5.78; p< 0.00003), including in 
subgroups of patients with tumors between 1-2 cm in size 
(N=79; HR 14.1, p< 0.00003), premenopausal women 
(n=84; HR 9.6; p<0.0002), and postmenopausal women 
(N=87; HR 4.04, p=0.0017). In the subgroup of 42 ER-
negative patients in the validation set, a 16 gene profile 
had strong predictive value (HR 8.74, p=0.012). 
1.3.2.2 
Formalin-Fixed Paraffin Embedded Specimens 
Another technique that utilizes a 21-gene panel RT-PCR 
assay that can be performed on formalin-fixed paraffin 
embedded tissue (FPET). The RT-PCR assay is capable 
of quantifying up to 400 genes from small RNA fragments 
(50–250 bp) extracted from three 10-micron FPET 
sections.  The assay machine measures mRNA 
abundance by recording real-time fluorescence and time to 
a certain amplification threshold.  It uses three specific 
reagents for each gene results in high specificity. The 
assay (Oncotype DX Breast Cancer Assay, Genomic 
Health, Redwood, CA; 
http://www.genomichealth.com/oncotype) is performed 
within 10-14 days, and has received CLIA approval in the 
United States. The training set that was used to develop 
this assay consisted of three studies involving 449 patients 
from three groups, including 224 patients treated with 
node-negative, ER-positive disease treated with tamoxifen 
(23), 79 patients with 10 or more positive axillary nodes 
(24), and 146 additional patients with operable breast 
cancer (25). Two hundred fifty candidate genes were 
selected from the literature for study in this training set. 
Univariate analysis of 185 cancer related genes indicated 
that 41 genes were associated with relapse free survival (p 
< 0.05), including 22 with p < 0.01, 10 with p< 0.001. 
Expression of many genes were tightly correlated.  A 

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“Recurrence Score” (RS) was calculated using a weighted 
algorithm based upon gene expression profiles of groups 
of genes (e.g., proliferation, ER, Her2, and invasion-
associated genes) and some individual genes that 
emerged as predictive in the training set (e.g., CD69, BAG-
1, GSTM-1) (Table 4). Each group of genes receives a RS 
of up to 15, with each unit of RS equivalent to a two-fold 
increase in RNA expression level. The score for each gene 
group is weighted toward the proliferation, Her2, and ER-
associated genes using the adjustment outlined in Table 4. 
In the training set, groups were identified that had a high 
(RS ≥ 31), low (RS <18), or intermediate (RS 18-30) risk of 
systemic recurrence. 
Table 4: Genomic Health Recurrence Score (RS) 
Algorithm (Oncotype DX) 
Group 
 
Genes 
Adjustment 
Proliferation 
Ki67, STK15, survivin, cyclin B1, MYB2 
+1.04 
Her2 
Her2, Grb7 
+0.47 
ER 
ER, PR, BCL-2, SCUBE2 
-0.34 
Invasion 
Stromelysin-3, CAT 
+0.10 
CD68 
CD68 
+0.05 
BAG- 
BAG-1 
-0.07 
GSTM-1 
GSTM-1 
-0.08 
The Genomic Health RS was subsequently evaluated in a 
validation set that consisted of a subset of patients with 
ER-positive, node negative breast cancer enrolled on 
NSABP trial B-14 (23, 26). Of the 2167 patients enrolled on 
this trial who were either randomized or registered to 
receive tamoxifen, tumor blocks were available for 675 
cases with at least 5% invasive cancer; there was no 
difference in patient characteristics or outcome for those 
who did or did not have blocks available for study. The 
mean age of the study population was 52.4 years, mean 
tumor size was 2 cm, and median follow up was 10.9 
years. The results of the analysis are contrasted with other 
studies in Table 3, and outlined in greater detail in Table 5. 
The primary study endpoint was distant recurrence free 
survival (DRFS) at 10 years; for the primary endpoint, 
patients were censored at the time of development of 
contralateral breast cancer, second non-breast cancer, or 
death without breast cancer recurrence.

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Table 5. Genomic Health Recurrence Score in B-14 
Trial (N=668) 
Recurrence 
Score  
(1–100) 
Risk group 
No. 
(%) 
10-year distant 
recurrence rate 
(95% C.I.) 
5-year distant 
recurrence rate 
(95% C.I.) 
< 18 
 
Low 
338 
(51%) 
6.8 % (4–9.6%) 
2.1% (0.6-3.7%) 
18 –30 
 
Intermediate 
149 
(22%) 
14.3% 
(8.3–
20.3%) 
9.2% (4.4-14%) 
>/= 31 
 
High 
181 
(27%) 
30.5% 
(23.6–
37.4%) 
22.1%  
(15.9-28.2%) 
Approximately 50% of patients were classified as having a 
low risk RS (<18), a group that experienced only a 6.8% 
distant recurrence rate at 10 years. There was a 
significantly inferior 10-year DRFS rate for those with a 
high RS compared to those with a low RS (p<0.00001). 
Cox proportional hazard model indicated that the only 
factor that emerged as significant variable at 10 years was 
the RS (hazard ratio [H.R.] 3.21, 95% confidence intervals 
[C.I.] 2.23, 4.61; p< 0.00001). A continuous model was 
also developed that plots RS (X-axis) vs. 10-yr DRFS (Y-
axis), and allows estimation of 10-year distant recurrence 
rate for specific RS. Information regarding 5-year distant 
recurrence rate is also provided in Table 5. These data 
illustrate that about one-third of distant relapses occurred 
between year 5 and 10 for patients with an intermediate or 
high RS tumor; in contrast, about two-thirds of relapses in 
the low RS group occurred between years 5 and 10.

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Figure 1. Genomic Health Recurrence Score as a Continuous Variable. 
Although the arbitrarily defined cut points as defined in 
Table 5 identified groups with disparate and substantially 
different risks of relapse that are clinically relevant, other 
analysis indicates that the RS also predicts relapse as a 
continuous variable (Figure 1). This point has relevance for 
the risk groups defined in this trial as described in Section 
1.4. 
The Genomic Health RS was also evaluated in 149 
evaluable patients with node-negative breast cancer who 
were referred to MD Anderson Cancer Center over a 20-
year period and who did not receive adjuvant 
chemotherapy (27). Tumor blocks were available for only 
149 of the 220 patients who met these criteria during this 
time period. The characteristics of the study population are 
contrasted with the B-14 validation set in Table 3. In this 
study, RS was not predictive of distant relapse. An unusual 
feature of this study was that patients with good nuclear 
grade had a worse outcome compared with patients with 
intermediate or high nuclear grade. This study points out 
that the distinct assays may need to be developed for ER-
positive and ER-negative cancers. The Oncotype DX 
assay is CLIA-approved only for patients with ER-positive, 
node negative breast cancer. 
0%
5%
10%
15%
20%
25%
30%
35%
40%
0
5
10
15
20
25
30
35
40
45
50
Recurrence Score
 Distant Recurrence at 10 Years
Low Risk Group 
High Risk Group 
Intermediate
Risk Group  

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Finally, the reliability of the Genomic Health RS was also 
validated in a population-based case-control study (28). 
The study included patients with node-negative breast 
cancer treated at 19 Kaiser Permanent hospitals between 
1985 and 1995 who were less than 75 years of age and 
received no adjuvant chemotherapy. Of the 4964 patients 
identified, there were 227 eligible cases who died of breast 
cancer and 446 eligible controls who did not die of breast 
cancer and were matched for clinical characteristics. The 
results indicated that RS score was the strongest predictor 
of breast cancer death in multivariate analysis (odds ratio 
for death 6.5, p=0.002), that RS significantly predicted 
breast cancer death in patients treated with or without 
tamoxifen, and that the risk of breast cancer death at 10 
years was similar in this population as in the B-14 
population. 
1.3.3 
Identifying Molecular Signatures Associated with Response to 
Treatment (ie, Predictive Factor) 
A follow up report by the NSABP and Genomic Health provided 
further information regarding the predictive value the 21 gene 
Oncotype DX panel. The study included 357 of 373 patients with ER-
positive node negative breast cancer in the placebo arm of the B-14 
trial, and 424 of 430 patients treated with tamoxifen plus CMF (or MF 
in trial B-20) (29). In the B-20 trial, the addition of CMF chemotherapy 
to tamoxifen significantly improved 5-year disease free survival (DFS; 
89% vs. 85%; p=0.001) and distant recurrence-free survival (DRFS; 
91% vs. 87%; p=0.006). Similar results were evident for MF 
chemotherapy. Overall, the addition of CMF to tamoxifen reduced the 
event rate by 35% for DFS, and 33% for DRFS (4). When the data 
were analyzed by RS risk group, there was a significant interaction 
between RS and benefit from chemotherapy (interaction p=0.0368); 
chemotherapy significantly reduced the risk of distant recurrence in 
the high RS group (hazard ratio 0.258), but not in the intermediate or 
low risk groups. In addition, when evaluating the effect of tamoxifen by 
RS group in patients treated with tamoxifen only or a placebo, there 
was a significant interaction between tamoxifen benefit and RS 
(p<0.001); RS was found to be an independent prognostic factor in 
the placebo arm, and tamoxifen reduced the risk of recurrence only in 
patients with a low or intermediate recurrence score. 
The predictive accuracy of the RS in the tamoxifen alone arm of this 
analysis does not provide an independent validation set and must be 
interpreted with caution, as the tamoxifen arm of the B20 trial was 
used as the training set for development of the RS. Nevertheless, the 
analysis suggests that RS may be used to identify individuals who are 
more likely to derive benefit from chemotherapy.
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Table 6. Genomic Health Recurrence Score and Response to Chemotherapy in B-
20 Trial (N=651) 
 
Risk 
group 
(RS 
ranges) 
No. 
Patients 
10-year DRFS 
Tam 
10-year DRFS 
Tam + 
Chemotherapy 
Hazard Rate (and 95% C.I.) 
for Distant Recurrence in 
Patients Treated with 
Chemotherapy 
P-Value 
Low (< 
18) 
353 
(54%) 
97% 
96% 
1.312 (0.456, 3.777) 
0.76 
Intermedi
ate (18-
30) 
134 
(21%) 
91% 
89% 
0.613 (0.236, 1.59) 
0.71 
High (> 
30) 
164 
(25%) 
61% 
88% 
0.258 (0.126, 0.528) 
0.001 
1.4 
Rationale for the Proposed Study 
Clinical breast cancer research over the past 30 years has focused on expanding 
indications for adjuvant chemotherapy, and has been successful in establishing 
that even patients expected to have a very good prognosis with hormonal 
therapy alone derive some small absolute benefit from adjuvant chemotherapy 
(13). Previous attempts to refine prognostic and predictive factors using standard 
histopathologic criteria (e.g., tumor grade), indices of proliferation (S-phase 
fraction, Ki-67) or genomic instability (e.g., DNA ploidy), or single gene/protein 
expression profiles (e.g., Her2/neu, p53 expression) have not been sufficiently 
reliable to merit routine clinical use in patients with low to moderate-risk disease 
(12, 30). 
Although several distinct molecular signatures identified by differing 
methodologies have been developed that may serve as useful prognostic 
markers, we have chosen to utilize Oncotype DX Breast Cancer Assay in this 
trial for the following reasons: (1) It is a standardized, multi-gene RT-PCR-based 
molecular technique performed in a single laboratory, (2) It may be applied to 
tissue specimens routinely processed in clinical pathology laboratories, (3) It has 
received CLIA approval in the United States to “…assess the likelihood that a 
women’s breast cancer will…recur…” (www.genomichealth.com), (4) It more 
reliably predicts prognosis than standard clinical criteria in patients with ER-
positive, node-negative disease than standard clinical criteria, including tumor 
size, histologic grade, and age, (5) Its performance has been validated in a large 
population-based study, (6) Preliminary data indicates that it predicts benefit from 
adjuvant chemotherapy. Patients with ER-positive, axillary node negative breast 
cancer account for nearly one-half of all breast cancer diagnosed in the United 
States, and is the group in which more patients unnecessarily receive adjuvant 
chemotherapy. 
Patients with ER and/or PR-positive, axillary lymph node negative breast cancer 
who meet standard clinical criteria for adjuvant chemotherapy, who are medically 
suitable candidates for chemotherapy, will be eligible to participate in this trial. 
Although these patients meet established clinical criteria for chemotherapy, the 
typical patient may be expected on average to derive a 3% improvement in 10-
year DFS from such treatment. In this trial, the Oncotype DX Breast Cancer 
Assay will be utilized to prospectively guide treatment decisions for low risk and 
high risk tumors. In addition, the trial will attempt to refine the precision of the test 
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in individuals who have intermediate risk tumors where the assay result is 
indeterminate in its ability to identify whether chemotherapy is beneficial. Patients 
will be assigned to treatment according to the schema indicated below. The 
definitions of low, intermediate, and high risk utilized in this trial are slightly 
different than those previously defined. 
• 
“Secondary Study Group-1” (RS ≤ 10): Patients will be assigned to 
receive hormonal therapy alone. A RS of ≤ 10 was selected as the 
threshold for low risk because it is associated with a 10 year distant 
recurrence rate on average of ≤ 5% if treated with tamoxifen alone, and 
because no benefit from chemotherapy has been demonstrated in this 
group.  
• 
“Primary Study Group” (RS 11-25) Patients will be randomly assigned 
to receive chemohormonal therapy vs. hormonal therapy alone. The risk 
of distant recurrence if treated with tamoxifen alone is sufficiently high to 
recommend chemotherapy (approximately 10% for the entire group), but 
chemotherapy has not been established to be clearly beneficial in this 
specific group. 
• 
“Secondary Study Group-2” (RS ≥ 26):  Patients will be assigned to 
receive chemotherapy plus hormonal therapy. A RS of ≥ 26 was selected 
as the threshold for high risk because it is associated with a 10 year 
distant recurrence rate of on average of 20% or more, and because 
chemotherapy has been shown to be beneficial in this group. 
The primary clinical endpoint will be disease-free survival in patients in the 
“Primary Study Group.” Co-primary endpoints will include distant relapse-free 
interval, relapse free interval, and overall survival (as defined in Section 6). The 
trial will be adequately powered to determine whether hormonal therapy is not 
inferior to chemotherapy plus hormonal therapy in patients in the “Primary Study 
Group.”  Should hormonal therapy be shown not to be inferior to chemohormonal 
therapy, it will spare the need for chemotherapy in up to 40% of women with ER-
positive, axillary node negative breast cancer. In addition, all patients identified to 
have a non-elevated RS in this trial will be spared the need for adjuvant 
chemotherapy.  
This study will include only patients with Her2/neu negative disease. Only 8% of 
patients enrolled in the B14 validation study had Her2/neu positive disease, and 
< 1% with a RS of < 26 demonstrated Her2/neu amplification. The outcomes for 
the recurrence score categories used in the PACCT trial for distant recurrence-
free survival (DRFS) and disease free survival (DFS) are shown in Table 7 (10-
year outcomes) and Table 8 (5 year outcomes) (29).  For the analyses described 
in Tables 6-8, the following definitions are used: (1) disease-free survival (DFS) - 
time to first local, regional, or distant recurrence, second primary cancer, or death 
due to any cause, and (2) distant recurrence free survival (DRFS) - time to first 
distant recurrence or death from cancer (contralateral breast cancers, other 
second primary cancers, and deaths due to other cancers were censored; local 
and regional recurrences were ignored). 
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Table 7:  
Genomic Health Recurrence Score and Response to Chemotherapy in B20 Trial (N=651) by RS Distribution in PACCT Trial (10 year 
outcomes) 
RS 
No. 
Patients 
Tam  
10-year DRFS 
Tam + 
Chemo 
10-year 
DRFS 
H.R. (& 95% CI)  
For DRFS Event by 
Addition of Chemo 
P- 
Value 
Tam 
10 –year 
DFS 
Tam + 
Chemo 
10-year 
DFS 
H.R. (& 95% CI)  
For DFS Event by 
Addition of Chemo 
P- 
Value 
< 11 
177 (27%) 
98% 
95% 
1.788 (0.360, 8.868) 
0.471 
77% 
85% 
0.605 (0.317,1.153) 
0.124 
11-25 
279 (43%) 
95% 
94% 
0.755 (0.313, 1.824) 
0.531 
81% 
76% 
1.106 (0.671,1.823) 
0.691 
> 25 
195 (30%) 
63% 
88% 
0.285 (0.148, 0.551) 
<0.0001 
53% 
75% 
0.446 (0.270, 0.738) 
0.0012 
Abbreviations: H.R. - hazard ratio; CI - confidence intervals; DRFS - distant recurrence-free survival; DFS - disease free survival; 
Tam - tamoxifen; chemo - chemotherapy (which included cyclophosphamide, methotrexate, 5-fluorouracil or methotrexate/5-
flurourucil. 
Table 8: 
Genomic Health Recurrence Score and Response to Chemotherapy in B20 Trial (N=651) by RS Distribution in PACCT Trial (5-year 
outcomes) 
RS 
No. 
Patients 
Tam 
5-year DRFS 
Tam + 
Chemo 
5-year 
DRFS 
H.R. (& 95% CI)  
For DRFS Event by 
Addition of Chemo 
P- 
Value 
Tam 
5 –year 
DFS 
Tam + 
Chemo 
5-year 
DFS 
H.R. (& 95% CI)  
For DFS Event by 
Addition of Chemo 
P- 
Value 
< 11 
177 (27%) 
98% 
99% 
1.788 (0.360, 8.868) 
0.471 
92% 
95% 
0.605 (0.317,1.153) 
0.124 
11-25 
279 (43%) 
97% 
97% 
0.755 (0.313, 1.824) 
0.531 
94% 
91% 
1.106 (0.671,1.823) 
0.691 
> 25 
195 (30%) 
69% 
94% 
0.285 (0.148, 0.551) 
<0.0001 
63% 
85% 
0.446 (0.270, 0.738) 
0.0012 
NSABP data indicates the following incidence of Her2/neu amplification in 668 patients evaluated in the B14 validation study: positive 
55 (8%), missing 8 (1%), negative 605 (91%). The proportion of patients with Her2/neu amplification by RS as categorized in the B14 
validation study is as follows: RS < 18 - 0/334; RS 18-31 – 5/147 (3%); RS > 31 – 50/179 (28%). The distribution for the RS groups 
as defined in the PACCT trial for the B14 validation study is as follows: RS < 11 – 0/159, RS 11-25 – 2/283 (<1%); RS > 25 – 53/218 
(24%). For this reason, we have altered eligibility to include only patients with Her2/neu negative disease, which will serve to reduce 
the number of patients screened in order to identify patients with a RS of 11-25 from 11,553 to10,046. 
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1.5 
Correlative Science 
Although the purpose of PACCT-1 is to validate the utility of the Genomic Health 
Recurrence Score, tumor RNA will be banked in addition to FPET tissue 
microarrays, plasma, and germ-line DNA. By virtue of the chemotherapy vs. no 
chemotherapy comparison in patients in the primary study group, we will be able 
to assess the utility of other “Clinical Cancer Tests” as they evolve (e.g., other 
genomic and/or epigenomic technologies, tumor and/or serum proteomic 
patterns, single nucleotide polymorphisms in drug and/or estrogen metabolizing 
enzymes, etc). Toward this end, all patients participating in this trial will be asked 
to donate specimens of tumor, lymphocytes, and serum for banking. As previous 
experience indicates that about 90% of patients who donate biological specimens 
consent to unspecified future research, it is anticipated that a number of 
additional studies will be planned in the future as technology evolves and as the 
trial matures. The background and rationale for selecting these biological 
specimens for long-term storage is provided in Appendix- VIII, as well as the 
process required for utilizing these specimens for future research. 
1.6 
Quality of Life Component 
The quality of life component for PACCT-1 proposes to evaluate differences 
between women with breast cancer receiving hormonal treatment alone (Arm B) 
versus women receiving chemotherapy followed by hormonal treatment (Arm C) 
on the following domains: (1) cognitive impairments, (2) fatigue, (3) fear of 
recurrence, (4) endocrine symptoms and (5) overall health-related quality of life 
(HRQL). Our primary question of interest is the extent to which chemotherapy 
plays a causal role in the development of cognitive impairments. PACCT-1 offers 
a unique and previously unavailable opportunity to assess breast cancer patients 
from the study group who are randomized to receive hormonal therapy alone 
versus chemotherapy + hormonal therapy. Prior to the availability of genetic 
testing to determine risk of recurrence as is used in TAILORx, randomization to 
chemotherapy versus no chemotherapy would not be ethical. Given the 
randomized design, the assessment of women enrolled on this trial will allow us 
to more definitively evaluate the extent to which chemotherapy contributes to the 
development of perceived cognitive dysfunction. A significant weakness of 
research on chemotherapy-related cognitive function to date has been the lack of 
an adequate control group, leading to results that are confounded by systematic 
differences in disease status (95). Women participating on TAILORx who are 
randomized to hormonal treatment alone will provide a comparison group that is 
comparable with regard to disease, sociodemographic characteristics, 
educational level, symptoms of mood disorders and other characteristics that 
may affect cognitive function. Previous studies in this area have been 
confounded by systematic differences in disease status, and so the TAILORx 
design will allow us to draw definitive conclusions regarding the impact of 
chemotherapy on cognitive impairment.  
As secondary endpoints, we are interested in the contribution chemotherapy 
makes to the severity of fatigue and endocrine symptoms. We seek to evaluate 
the extent to which chemotherapy exacerbates or attenuates fear of recurrence. 
We are also interested in the long-term trajectory of these symptoms throughout 
and following treatment. Last, we seek to evaluate the trajectory of HRQL as 
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women transition from treatment to survivorship status and to asses the overall 
effect of these symptoms on HRQL post-treatment. 
The TAILORx trial includes a correlative science component that holds the 
potential to advance our understanding of genetic markers for susceptibility to 
disease- and treatment-related symptom burden. TAILORx participants bank 
tumor RNA, FPET tissue microarrays, plasma, and germline DNA.  Banked 
biological specimens can be evaluated in future studies as “Clinical Cancer 
Tests” evolve (e.g. other genomic and/or epigenomic technologies, tumor and/or 
serum proteomic patterns, single nucleotide polymorphisms in drug and/or 
estrogen metabolizing enzymes, etc.) to identify genetic predictors of cognitive 
impairments associated with cancer and cancer treatments. At the ASCO 2004 
Annual Meeting Plenary session, Sloan presented compelling data from a 
Gastrointestinal Cancer Intergroup phase III trial for metastatic colorectal cancer 
that demonstrated differences in quality of life among patient groups that differed 
based on the presence of genetic variants. Specifically, Sloan and colleagues 
(90) demonstrated a link between genetic structure and fatigue. Ahles (2007) has 
postulated that genes associated with brain function, neural or vascular repair in 
the central nervous system, drug metabolism, or blood-brain transporter systems 
might be important for predicting which patients will be more vulnerable to 
chemotherapy-related cognitive impairments. The prospective collection of 
cognitive function among TAILORx participants simultaneously with the collection 
of baseline plasma and genomic material offers the exciting opportunity for future 
research projects to identify genetic predictors for cognitive impairment among 
individuals with cancer. The identification of genetic predictors for cognitive 
impairment would significantly advance the science in this area and could lead to 
more targeted interventions for individuals at greatest risk for long-term cognitive 
deficits following anti-cancer treatment. 
1.6.1 
Evidence for the Clinical Significance of Chemotherapy-Related 
Cognitive Impairment 
Many cross-sectional studies have demonstrated impairments in 
cognitive function among adults who have received chemotherapy in 
comparison to adults with cancer who did not undergo chemotherapy. 
Schagen et al. (84) found that women with breast cancer who 
received adjuvant chemotherapy were more likely to report difficulties 
with concentration and memory compared to breast cancer patients 
who did not. When patients’ underwent neuropsychological 
assessment, those receiving chemotherapy were significantly more 
likely to demonstrate cognitive impairment compared to those who did 
not receive chemotherapy. Neuropsychological impairment was not 
affected by mood, fatigue, or time since diagnosis (84). Brezden and 
colleagues (42) found that breast cancer patients receiving adjuvant 
chemotherapy had worse memory and language functioning 
compared to healthy controls, even after statistically controlling for 
age, education, and menopausal status. Between-groups differences 
were not found on a measure of mood, suggesting that the cognitive 
differences were not related to a mood disturbance.  In the same 
study, a group of patients who had completed chemotherapy at least 
one year earlier had cognitive tests scores that were between scores 
from the current chemotherapy and healthy control groups suggesting 

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that these impairments may last for months following treatment 
completion (42). Ahles et al. (37) examined breast cancer and 
lymphoma survivors who were a minimum of 5 years post-treatment 
and disease free and found that survivors treated with systemic 
chemotherapy scored significantly lower on neuropsychological 
testing than survivors who received local therapy only (p < 0.04). 
Ahles and colleagues’ findings indicated that a subgroup of survivors 
experience long-term cognitive deficits, which tend to be subtle in 
nature. Despite this growing body of evidence, findings from cross-
sectional studies are difficult to interpret because patients receiving 
chemotherapy vary systematically from those receiving local therapy 
alone in terms of disease-related factors. Thus, the role of 
chemotherapy in the development of cognitive dysfunction cannot be 
teased apart from confounding factors. 
As more research has been conducted in this area, meta-analyses 
have aggregated research findings to obtain a better understanding of 
chemotherapy-related cognitive impairment. Anderson-Hanley and 
colleagues (38) conducted a meta-analysis of the neuropsychological 
effects of systemic therapies for cancer and found significant negative 
effect sizes for patients compared to normative data and control 
patient data on several cognitive domains, including executive 
function, verbal memory, and motor function. Even when samples 
were limited to those with “less severe” diagnoses and treatments, the 
effect sizes remained significant. However, when they calculated 
effect sizes for the limited number of studies that included a pre-
treatment assessment of cognitive function they did not find evidence 
of changes in cognitive function. Falletti and colleagues (52) 
conducted a meta-analysis based on 6 studies that examined 
cognitive function among breast cancer patients receiving adjuvant 
chemotherapy. Results from cross-sectional studies indicated a 
negative effect size in each cognitive domain examined with a 
significant relationship between effect size and time since completing 
chemotherapy. However, findings from prospective studies indicated a 
positive effect size, or improvement in cognitive function, from pre-
chemotherapy to 3 weeks and one year post-chemotherapy. These 
findings support the need for prospectively designed studies to fully 
understand the trajectory of cognitive function throughout treatment 
for cancer. 
Wefel and colleagues (110) conducted the first prospective study 
among 18 breast cancer patients who were planning to undergo 
chemotherapy. In their sample, 33% of participants demonstrated 
cognitive impairments prior to starting treatment, 61% demonstrated a 
decline in their cognitive function relative to their baseline 
performance 3 weeks post-chemotherapy, and at 1 year post-
chemotherapy 50% of patients who declined demonstrated 
improvement. This finding that one-third of participants had evidence 
of cognitive impairment prior to chemotherapy was surprising to 
clinicians, researchers, and patient advocates who had operated on 
the assumption that cognitive impairments during cancer treatment 
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which has evolved from patient advocacy groups. Upon the 
presentation of Wefel and colleagues’ results, we examined data 
collected from our own larger prospective trial of breast cancer 
patients receiving adjuvant chemotherapy and found similar results. 
We administered a 90-minute neuropsychological assessment and 
patient-reported outcomes assessment prior to chemotherapy, at 
Cycle 4 Day 1, and at a 6 month follow-up (107). Among our sample 
of 57 breast cancer patients, prior to chemotherapy 17-29% 
demonstrated cognitive impairments depending on the criteria used to 
classify participants as impaired (51). These findings underscore the 
importance of utilizing a prospective, longitudinal design to 
understand the extent of impairment due to chemotherapy versus 
disease burden and other contributing factors, particularly since the 
pathophysiology is unknown (37,81,85). While prospectively designed 
studies offer a more solid evidence base for an association between 
chemotherapy and cognitive impairment, methodological challenges 
such as the lack of a comparable control group with the same disease 
characteristics and, therefore the same disease-related symptom 
trajectory, limit assumptions about causality. The proposed trial 
complies with recommendations for advancing our scientific 
knowledge base in the area of chemotherapy-related cognitive 
impairments by employing a prospective design that includes a pre-
treatment assessment and utilizing a comparison group (98).  
The primary hypothesis for this study is that women randomly 
assigned to receive chemotherapy + hormonal therapy will have a 
higher level of self-reported cognitive impairments than women 
randomized assigned to receive hormonal therapy alone. 
Chemotherapy-induced menopause has been suggested as a 
possible etiology for cognitive decline, however, to date the extent of 
impairment between pre- and post-menopausal breast cancer patients 
has been found to be similar (97). The inclusion of pre- and post-
menopausal women in our sample will allow us to examine 
differences in the extent of decline based on menopausal status 
among women assigned to receive chemotherapy. 
The relationship between estrogen and cognitive function is complex 
and has warranted numerous studies, as discussed in a literature 
review published by Shilling et al. (88). Few studies have examined 
the effect of hormone therapy for breast cancer on cognition. Schagen 
and colleagues (84) did not find differences between breast cancer 
patients who received tamoxifen and those who did not. Jenkins and 
colleagues (61) examined 94 women from the Anastrozole, Tamoxifen 
or Combined (ATAC) trial in comparison to 35 women without breast 
cancer. ATAC participants demonstrated mild impairments on a 
processing speed task and a measure of immediate verbal memory. 
The proposed trial will allow us to prospectively evaluate the trajectory 
of perceived cognitive function among women randomized to receive 
hormonal therapy alone. We acknowledge that women assigned to 
receive hormonal therapy may experience changes in cognitive 
function associated with hormonal treatment, which will be taken into 

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consideration in interpreting any differences observed between 
participants treated on Arm B versus Arm C. 
1.6.2 
Evidence for the Clinical Significance of Cancer-Related Fatigue 
Cancer-related fatigue is perhaps one of the most common symptoms 
associated with cancer and has been associated with significant 
decrements in quality of life (76). Fatigue among individuals with 
cancer can be related to the disease itself and metabolic changes 
associated with cancer, as well as from the effects of treatment (94). 
Some investigators have conceptualized cognitive impairments as a 
component of fatigue, labeling this symptom “attentional fatigue” (46). 
Vogelzang and colleagues (101) found that among patients treated 
with chemotherapy or radiotherapy, more than one-third reported that 
fatigue interfered with their ability to work, relationships with others, 
and physical and emotional well-being. Many cancer survivors may 
experience fatigue for months or even years post-treatment, even 
those who remain disease-free (87).  
The collection of genetic material as part of the TAILORx trial design 
will allow future research to potentially identify genetic predictors of 
treatment-related fatigue. Because fatigue is commonly a symptom of 
cancer and a side effect of cancer treatment, it is virtually impossible 
to tease apart the extent to which fatigue is a disease-related versus 
treatment-related (for review see Wagner, Cella & Peterman, 2003). 
This is an important distinction when weighing the risks versus 
benefits of undergoing chemotherapy, particularly when 
chemotherapy may only provide marginal survival benefit.  Given the 
randomized assignment to treatment, this trial offers a unique 
opportunity to quantify the extent to which chemotherapy contributes 
to fatigue among individuals with breast cancer.   
Research on cognitive impairments among individuals with cancer 
has consistently demonstrated an association between fatigue 
severity and cognitive function (37,60). Among our own sample of 
breast cancer patients undergoing chemotherapy, we found modest 
correlations between perceived cognitive function and fatigue (.51 - 
.62; unpublished data). Based on this association, it is important to 
include fatigue as a secondary endpoint in the proposed trial. We 
hypothesize that women assigned to receive chemotherapy plus 
hormonal therapy will report a greater level of fatigue than those 
assigned to only receive hormonal treatment. 
1.6.3 
Evidence for the Clinical Significance of Fear of Recurrence 
Approximately 60-99% of women with breast cancer report ongoing 
fears regarding the possibility of a breast cancer recurrence, even 
among samples up to 5 years post-treatment (71,78,92,100,103). 
Previous studies have indicated that more physically and 
psychologically aversive treatment protocols, such as chemotherapy 
or mastectomy, may be associated with a higher fear of recurrence 
(62,86), however other studies have not replicated this finding (48,71). 
It seems plausible that the measured increase in fear of recurrence 
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to a more generalized increase in overall distress associated with 
more aggressive disease in comparison to those receiving less 
aversive treatment. Evidence for increased distress at the completion 
of chemotherapy in the “re-entry” literature suggests that women with 
breast cancer perceive a protective benefit from chemotherapy, which 
reduces fear of recurrence (75). Distress at treatment termination has 
been so well-documented that the end of chemotherapy has become 
a common entry point for introducing coping and stress management 
interventions. 
The ECOG protocol E2Z04 (Study Chair: V. Champion) is a currently 
active study which is examining psychosocial characteristics of 
women with breast cancer who were previously treated on a 
cooperative group protocol. Preliminary results from this protocol have 
demonstrated that women who were younger at diagnosis (≥ 45 years 
of age) have a higher fear of recurrence than women who were 55-70 
years of age at diagnosis (112). 
The proposed trial offers a unique opportunity to evaluate whether 
chemotherapy exacerbates or attenuates fear of recurrence, without 
confounding disease characteristics and other factors which may 
directly influence fear of recurrence. Based on existing literature and 
what we have learned thus far from E2Z04, we hypothesize that pre-
menopausal women randomly assigned to hormone therapy will 
experience a higher fear of recurrence than pre-menopausal women 
assigned to chemotherapy + hormonal treatment. We also 
hypothesize that younger age will be associated with a higher fear of 
recurrence. In addition, women with cancer may perceive that their 
cognitive function is compromised by a preoccupation with health-
related concerns. The inclusion of this secondary endpoint will allow 
us to explore whether an association exists between perceived 
cognitive impairments and fear of recurrence. If an association is 
demonstrated, future clinical research could evaluate whether 
interventions for fear of recurrence lead to an improvement in 
perceived cognitive function. 
1.6.4 
Evidence for the Clinical Significance of Endocrine Symptoms and 
Health-Related Quality of Life 
Few randomized trials have evaluated the long-term impact of 
hormonal treatment on quality of life and the extent to which adjuvant 
chemotherapy exacerbates symptom burden from subsequent 
hormonal therapy. Fallowfield and colleagues (53) examined the 
quality of life of postmenopausal women on the ATAC trial. The 
investigators found an increase in patient-reported endocrine 
symptoms from baseline to the 3 month assessment, after which 
endocrine symptoms stabilized at follow-up assessments. The sample 
of participants examined by Fallowfield and colleagues did not receive 
adjuvant chemotherapy prior to hormonal treatment. Previous trials of 
adjuvant chemotherapy have failed to measure the impact of 
treatment on endocrine-related symptoms. In the recent Adjuvant 
Breast Cancer (ABC) chemotherapy trial, women who received 
adjuvant tamoxifen were randomized to standardized chemotherapy 

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(87% received CMF) versus none. Of the 199 women who 
participated in the quality of life sub-study, women who received 
chemotherapy reported more problems with chronic effects in 
particular those relating to vasomotor symptoms (e.g. night sweats 
that continued for up to 30 months; Adjuvant Breast Cancer Trials 
Collaborative Group, 2007). These results suggest that an 
assessment of endocrine-related symptoms among our study sample 
may provide important data pertaining to differences in symptom 
burden among women assigned to hormonal therapy alone or 
chemotherapy + hormonal therapy. 
While it is recognized that the majority of the acute effects of 
chemotherapy (e.g., nausea, vomiting, diarrhea, stomatitis, alopecia, 
and neutropenia) will resolve, there is increasing concern that the sub-
acute effects and long-term sequelae of chemotherapy may have a 
lasting impact on the quality of life of the breast cancer survivors.  
Modern day adjuvant chemotherapy is associated with premature 
menopause, weight gain, arthritic complaints, mood disorders, fatigue, 
and cognitive effects that may potentially impair the quality of life of 
women.  Some women who are < 40 years of age (estimates between 
13-38%) and the vast majority of women over the age of 40 
(estimates between 57-96%) will experience premature menopause 
following adjuvant chemotherapy (53,77).  Premature menopause is 
associated with increased menopausal symptoms, such as hot 
flashes, genitourinary problems, and sexual dysfunction.  Additionally, 
women following premature menopause will have accelerated bone 
mineral density loss (43,59). Weight gain has been reported in more 
than 50% of women receiving adjuvant chemotherapy with mean 
gains of 2.5-5 kilos (50,57).  Weight gain appears to be more common 
in pre-menopausal women who experience menopause secondary to 
chemotherapy.  This type of weight gain is likely to have an influence 
on a women’s physical health.  With increasing use of dose-intensive 
and taxane-based regimens, previously unobserved sequelae such as 
neuropathy and myalgias are increasingly common.  Many of these 
symptoms are very slow to resolve and may have long-term 
consequences for women.  Additionally, moderate to long-term effects 
of fatigue are also increasingly recognized (41,68).  Such fatigue has 
been associated with a decrease in daily functioning.  Cognitive 
impairments discussed above may also have a lasting impact on 
women’s functional ability. 
Ganz et al. (56) demonstrated the potential negative effect of 
chemotherapy on long-term quality of life of breast cancer survivors.  
In a single arm observational study, investigators identified 1,336 
survivors between 5-10 years following their initial diagnosis of breast 
cancer (55,56). Of these 763 (57%) disease-free survivors completed 
a quality of life assessment with a mean follow-up of 6.3 years from 
diagnosis.  Survivors who had received adjuvant chemotherapy or 
tamoxifen or both had a worse quality of life compared to those who 
had not received adjuvant systemic therapy with respect to physical 
functioning (p = 0.03), bodily pain (p = 0.01), social functioning 
(p=0.02) and general health (p = 0.03). 

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Few randomized trials have evaluated long-term impact of adjuvant 
chemotherapy on quality of life (35,40,47).  While these studies have 
shown limited effects, they are problematic from several aspects: i) 
many of these trials evaluated uncommon types of chemotherapy for 
short duration (e.g., CMF x 3 months); ii) compliance with quality of 
life assessments was poor (< 80%); iii) quality of life was evaluated 
using instruments that have not been widely validated and are not 
currently used; and iv) specific symptoms – fatigue, vasomotor and 
sexual symptoms were not routinely evaluated.  Recent trials 
comparing anthracycline-based chemotherapy regimens to 6 cycles of 
CMF or taxane-based regimens to anthracycline-based regimens 
report increasingly worse quality of life with more intensive regimens 
that are now widely used (65,66,69,70). 
While the main hypothesis of TAILORx is that chemotherapy is 
unlikely to have an effect on disease-free survival in this intermediate 
risk group,  there is a possibility that such women may achieve small 
benefits in reduction in recurrence, so that the impact of 
chemotherapy on long-term symptomatology and in particular on 
HRQL is relevant.  Such information would be important to women 
and their physicians considering whether small benefits in adjuvant 
chemotherapy are worth any observed long-term impact on quality of 
life outcomes. We hypothesize that women who receive 
chemotherapy prior to hormonal treatment will report more endocrine 
symptoms and sexual dysfunction and poorer HRQL than women 
receiving hormonal treatment alone. 
1.6.5 
Clinical Significance and Rationale for the Quality of Life Study Design 
The PACCT-1 trial offers a unique and previously unavailable 
opportunity to assess patient-reported outcomes among breast cancer 
patients who are randomized to receive hormonal therapy alone 
versus chemotherapy + hormonal therapy. The randomized design 
will allow us to isolate and quantify the effects of chemotherapy on 
symptoms of interest, given equivalence between groups on disease, 
sociodemographic, and other characteristics which have historically 
confounded the interpretation of study findings. Previous studies 
examining breast cancer patients who received chemotherapy to 
those who did not were confounded by systematic differences in 
disease status. The use of a randomized design is methodologically 
superior to previous studies using cross-sectional and prospective 
designs, which will allow us to draw definitive conclusions regarding 
the role of chemotherapy in contributing to cognitive impairment. This 
is an important area of investigation because data on the extent to 
which chemotherapy compromises cognitive function may assist 
patients and health-care providers in their decision-making related to 
treatment and evaluating potential benefits versus the potential risks. 
Longitudinal data on the trajectory of cognitive function, fatigue, and 
endocrine symptoms among women who undergo chemotherapy and 
hormonal therapy versus those who undergo hormonal therapy alone 
can help to inform women with breast cancer of what to expect during 
and following treatment and will allow us to evaluate target symptoms 

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as women undergo active treatment and transition into survivorship. 
Longitudinal data on the trajectory of fear of recurrence can assist 
with determining when to best deliver interventions to address this 
common concern among breast cancer survivors. The collection and 
banking of biological specimens from TAILORx participants will allow 
the future investigation of genetic predictors for cognitive impairments, 
fatigue, and endocrine symptoms. 
1.6.6 
Measures selected 
1.6.6.1 
Rationale for Quality of Life Measure Selection 
Cognitive function is the primary endpoint for the PACCT-1 
quality of life component. Cognitive function can be 
assessed using multiple approaches, including 
neuropsychological assessment, neuroimaging, and 
patient self-report. Historically, neuropsychological 
assessment has been viewed as the “gold standard” for 
detecting and localizing neuropathology among individuals 
with traumatic brain injury or neurologic disease. However, 
this approach has been criticized for the lack of ecological 
validity (i.e. the “functional and predictive relationship 
between the patient's performance on a set of 
neuropsychological tests and the patient's behavior in a 
variety of real world settings,(83) particularly among 
individuals with intact neurological function such as 
individuals with breast cancer who are receiving adjuvant 
chemotherapy (45,93). The interpretation of 
neuropsychological test scores in a longitudinal design is 
also complicated by practice effects, or the improvement in 
performance over time due to increasing familiarity with the 
demands of the test (72). In addition, neuropsychological 
assessment imposes significant participant burden and 
due to the stringent requirements for assessment 
administration procedures this method is not feasible in the 
context of a large, multi-site clinical trial. While 
neuroimaging techniques have demonstrated differences 
between cancer patients who have received chemotherapy 
and oncology patients who have not received 
chemotherapy, as well as healthy controls, these 
assessment techniques are not practical for a multi-site 
trial given the expense of conducting imaging studies, the 
participant burden imposed by the length of imaging 
studies, and the complications inherent to ensuring 
comparability of imaging data and combining data 
collected from different imaging equipment and multiple 
institutions. 
A number of recent studies have highlighted the utility of 
self-report in the assessment of individuals’ perceived 
cognitive changes related to chemotherapy (60,63). Kohli 
et al. used the EORTC Cognitive Function scale to 
examine a sample of oncology patients undergoing 

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chemotherapy through participating in a cooperative group 
clinical trial. Participants reported more cognitive problems 
during and after chemotherapy in comparison to pre-
chemotherapy self-report. While self-reported cognitive 
function has been criticized because it has tended not to 
be associated with actual neuropsychological performance 
(60,84,98), recent provocative findings suggest that in the 
case of mild cognitive impairment patient self-report may 
be more sensitive than neuropsychological testing 
(49,54,82). 
Most research to date examining the association of 
chemotherapy and cognitive function has utilized 
neuropsychological testing to evaluate cognitive function. 
The use of neuropsychological testing to assess mild 
cognitive impairment does pose methodological limitations 
(e.g. ecological validity, practice effects) and numerous 
recent studies have demonstrated that patient self-report 
may be more sensitive than neuropsychological testing in 
detecting early cognitive decline. Neuropsychological 
testing is costly to administer and imposes significant 
participant burden. In consideration of these factors, we 
have selected perceived cognitive function as the primary 
endpoint for the quality of life study component. Given the 
unique opportunity to assess women with breast cancer 
randomized to receive chemotherapy versus no 
chemotherapy, this trial provides the only opportunity to 
date to collect comparison group data. This data will help 
to interpret previous research results and can also be used 
as comparison group data in future research. 
1.6.6.2 
Measures to be Administered 
Perceived cognitive function will be assessed using the 
Functional Assessment of Cancer Therapy – Cognitive 
Function Version 3. The FACT-Cog is the only patient-
reported outcome measure to be developed based on 
direct input from oncology patients and expert clinicians 
(105,108).  
The Quality of Life Co-Chair, Dr. Lynne Wagner, 
developed the FACT-Cog Version 3, the primary endpoint 
for this trial. Items for the FACT-Cog were developed 
based on themes that emerged from qualitative interviews 
with experienced oncology providers and interviews and 
focus groups with patients who reported cognitive 
impairments from chemotherapy (105,108). Within the 
scope of an NCI R01 project (PI: Cella), the initial version 
of the FACT-Cog was administered to a sample of 204 
general oncology patients, which provided preliminary 
validation data and scale refinement (104). The FACT-Cog 
has been used by several investigators to assess 
perceived cognitive function among colorectal cancer 

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patients, patients undergoing bone marrow transplant, and 
among patients with breast and testicular cancer (99,60). 
FACT-Cog data from multiple institutions was combined 
with our own locally collected data to evaluate the 
dimensionality of perceived cognitive function as measured 
by the FACT-Cog. Those analyses supported the presence 
of two factors: perceived cognitive impairment and 
perceived cognitive abilities (64).  Accordingly, the FACT-
Cog Version 3 includes Perceived cognitive impairments 
and Perceived cognitive abilities as two distinct subscales. 
The FACT-Cog is currently being validated using data 
collected from a sample of breast cancer patients 
undergoing chemotherapy.  The 20-item FACT-Cog 
Perceived cognitive impairments subscale demonstrated 
excellent internal consistency at all assessment time 
points, including pre-, during and post-treatment 
(Cronbach’s alpha ranged .93 - .95; unpublished data). 
The FACT-Cog Perceived cognitive impairments subscale 
was highly correlated (.75 - .87; unpublished data) with the 
Cognitive Difficulties Scale (CDS; 73), a 39-item self-report 
measure of perceived cognitive function. The Perceived 
cognitive impairments subscale was moderately correlated 
with the Hospital Anxiety and Depression Scale (HADS) 
Anxiety scale (.33 - .46), HADS Depression scale (.39 - 
.53), and the FACT-Fatigue subscale (.51-.62; unpublished 
data) at pre-, mid-, and post-treatment assessments.  
Previous research using the FACT-Cog (Version 2) among 
individuals undergoing bone marrow transplant 
demonstrated a significant correlation with the EORTC 
Cognitive Function (EORTC-CF) scale and similar 
psychometric properties (Jacobs et al. 2007). Because the 
EORTC-CF scale only includes 2 items, the FACT-Cog 
provided greater information about the types of cognitive 
deficits patients were experiencing. 
Secondary quality of life endpoints, specifically fatigue, fear 
of recurrence, endocrine symptoms and HRQL are by 
nature subjective experiences. Accordingly, these domains 
will be assessed using patient self-report measures. 
Fatigue will be assessed using the Functional Assessment 
of Cancer Therapy – Fatigue subscale (FACT-F) (111) and 
the Patient Reported Outcomes Measurement Information 
System (PROMIS) Fatigue 7-item Short Form. The 
inclusion of the PROMIS Fatigue Short Form will allow us 
to contribute to the validation of this tool, which will require 
the concurrent administration of the FACT-Fatigue 
subscale. Once validated, the PROMIS Fatigue Short 
Form will allow us to link our data with other oncology and 
non-oncology samples. Endocrine symptoms will be 
assessed using the FACT-Endocrine Symptoms subscale 

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(FACT-ES). The FACT-ES includes questions on 
vasomotor symptoms, mood, and sexual function. This 
scale was selected base on its previous use to evaluate 
the side effects of hormonal treatment in other large clinical 
trials (ATAC trial; Fallowfield et al. 2004). Fear of 
recurrence will be evaluated using the 5-item Assessment 
of Survivor Concerns (58). This instrument was selected 
because it was validated with a sample of short- and long-
term cancer survivors and despite its brevity, exhibits 
excellent psychometric properties. The FACT-General (44) 
will be administered at three key time points to assess 
overall HRQL. 
1.6.6.3 
Assessment Schedule 
Our primary question of interest is the extent to which 
chemotherapy plays a causal role in the development of 
perceived cognitive impairments. We are interested in the 
causal role chemotherapy plays in fatigue and the extent to 
which chemotherapy contributes to endocrine symptoms 
associated with hormonal treatment. We seek to evaluate 
the extent to which chemotherapy exacerbates or 
attenuates fear of recurrence. We are also interested in the 
long-term trajectory of these symptoms throughout and 
following treatment among women in the Primary Study 
Group (Arms B and C) and women in the Secondary Study 
Group who receive hormonal treatment alone (Arm A) or 
chemotherapy followed by hormonal treatment (Arm D). 
Based on these goals, the study assessment will be 
administered at the time of TAILORx randomization and at 
3, 6, 12, 24, and 36 months post-randomization. To 
evaluate the effect of chemotherapy on domains of 
interest, the best time for an assessment is at maximal 
exposure to chemotherapy (ie. at the time of or 
immediately following the last cycle). The TAILORx 
protocol allows participants to receive 1 of 9 chemotherapy 
regimens which range in length from 8 to 24 weeks. To 
date, the majority of TAILORx participants enrolled are 
receiving 4 cycles of treatment and the most common 
regimens include AC 3 week cycles (29%), TC 3 week 
cycles (22%), and AC dose dense 2 week cycles (16%).  
Data collected at the 3 month assessment will be used for 
the primary analysis to capture most participants when 
they have recently completed chemotherapy or are 
approaching the end of their regimen. 
The 6-month and 12-month assessments may provide the 
most clinically relevant data, because many clinicians and 
patients are aware of acute symptoms during 
chemotherapy and they are primarily interested in learning 
when they will return to normal or pre-treatment function. 
Many studies have documented that cognitive dysfunction 

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and fatigue can last for months or years following 
treatment completion. The follow-up assessments (24 and 
36 months post-randomization) will provide data on long-
term function and will allow us to determine whether any 
differences between treatment groups that emerge resolve 
over time. The FACT-G will only be administered pre-
treatment and at 12 and 36 month follow-up assessments 
to minimize participant burden, while providing data on the 
long-term trajectory of HRQL and the effects of symptom 
burden on HRQL. 
1.7 
Gender and Ethnicity 
Entry to this study is restricted to female patients. Study entry is open to patients 
of all ethnic backgrounds. Historically, approximately 15% of patients enrolled on 
ECOG-ACRIN breast cancer studies are members of minority ethnic groups. It is 
anticipated that a similar proportion of patients on this study will be members of 
ethnic minorities. Based on current data, ECOG-ACRIN believes that interactions 
between ethnicity and genomic profiling are not expected, and accrual will not be 
increased to meet subgroup targets.

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2. 
Objectives 
In women with ER-positive and/or PR-positive, axillary node-negative breast cancer who 
meet standard clinical criteria for adjuvant chemotherapy in addition to hormonal 
therapy, the objectives of this trial are: 
2.1 
Primary 
2.1.1 
To determine whether adjuvant hormonal therapy is not inferior to 
adjuvant chemohormonal in women whose tumors meet established 
clinical guidelines for adjuvant chemotherapy and fall in the “primary 
study group” category (Oncotype DX Recurrence Score 11-25). The 
primary study endpoint is disease-free survival; other co-primary 
endpoints include distant recurrence free interval, recurrence free 
interval, and overall survival as defined in Section 6. 
2.1.2 
To create a tissue and specimen bank for patients enrolled in this trial, 
including formalin fixed paraffin embedded tumor specimens, tissue 
microarrays, plasma, and DNA obtained from peripheral blood. This 
resource will be critical for evaluating emerging Clinical Cancer Tests. 
2.2 
Secondary: 
2.2.1 
To determine whether adjuvant hormonal therapy is sufficient 
treatment (i.e. 10 year distant disease-free survival of at least 95%) 
for women whose tumors meet established clinical guidelines for 
adjuvant chemotherapy and who fall into the "Secondary Study 
Group-1" category (Oncotype DX Recurrence Score ≤ 10). The 
primary study endpoint is disease-free survival; other co-primary 
endpoints include distant recurrence free interval, recurrence free 
interval, and overall survival as defined in Section 6. 
2.2.2 
To compare the outcomes projected at 10 years by Adjuvant! (with 
outcomes  projected using classical pathologic information including 
tumor size, hormone receptor status, and histologic grade) with those  
made by the Genomic Health Oncotype DX  test.  Classical pathologic 
information and outcome results will also be used to create and refine 
models that would use classical information instead of or in 
combination with genomic tests.   
2.2.3 
To estimate failure rates as a function of RS separately in the 
chemotherapy (arms C, D) and no chemotherapy (arms A, B) groups. 
The purpose of the analysis is to develop more precise estimates of 
the relationship between recurrence score and chemotherapy 
treatment effect, if any, at the upper range of the RS 11 – 25 group. 
2.2.4 
To determine the prognostic significance of the Oncotype DX 
recurrence score and of the individual RS gene groups (proliferation 
gene group, HER2 gene group, ER gene group, invasion gene group, 
and other genes). 

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2.3 
Quality of Life Objectives: 
2.3.1 
To evaluate the effects of chemotherapy + hormonal therapy vs. 
hormonal alone on: 
(a) perceived cognitive impairment  
(b) fatigue 
(c) fear of recurrence among pre-menopausal patients 
(d) endocrine symptoms and sexual dysfunction 
(e) overall HRQL 
2.3.2 
To determine whether perceived cognitive impairment, fatigue, fear of 
recurrence, endocrine symptoms and overall HRQL are similar for 
patients receiving chemotherapy plus hormonal therapy in secondary 
study group 2 as for those in the primary study group (arms D vs. C). 
2.3.3 
To determine whether perceived cognitive impairment, fatigue, fear of 
recurrence, endocrine symptoms and overall HRQL are similar for 
patients receiving hormonal therapy alone in secondary study group 1 
as for those in the primary study group (arms A vs. B). 
2.3.4 
To determine whether age will be inversely associated with a fear of 
recurrence, independent of treatment assignment. 
2.3.5 
Among participants receiving hormonal treatment alone on Arm A and 
Arm B, to determine whether Oncotype DX Recurrence score will be 
inversely correlated with fear of recurrence. 
2.4 
Determinants of Late Relapse Ancillary Study (EL112LAB) 
2.4.1 
To create a biospecimen repository including plasma, serum and 
CellSearch™ cassettes containing circulating tumor cells (CTC) for 
evaluating determinants of late relapse, including candidate 
biomarkers reflecting occult tumor burden (e.g., CTCs and plasma 
tumor DNA) and host factors  (e.g., estrogen, insulin-IGF axis, 
inflammation, etc).  
2.4.2 
To create a biorepository of metastatic tumor samples in patients who 
have had a late relapse.  
2.4.3 
To determine body mass index (BMI) and comorbidity burden in 
patients with operable breast cancer five or more years after 
diagnosis.  
2.4.4 
To determine whether there is a relationship between late relapse and 
BMI at diagnosis and at 5 years after diagnosis, and whether BMI-
associated inflammatory and/or metabolic biomarkers are associated 
with early and late recurrence
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3. 
Selection of Patients 
Each of the criteria in the following section must be met in order for a patient to be 
considered eligible for this study. Use the spaces provided to confirm a patient’s 
eligibility. For each patient, this section should be photocopied, completed and 
maintained in the patient’s chart.  
NOTE: 
This study involves a pre-registration and a registration/randomization (see 
Section 4).  All time frames for prestudy scan and lab values and other 
requirements will be based on the date of pre-registration. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician. 
NOTE: 
Questions regarding eligibility or treatment should be directed to the ECOG-
ACRIN Study Chair  (Joseph Sparano, M.D.) and/or Study Chair Liaison (Una 
Hopkins, R.N.) or the CTSU Help Desk at 1-888-823-5923. An email to the 
following email address is PREFERRED, and will be reviewed by the Study 
Chair and Study Chair Liaison (and other study team members); a response 
will be provided within 24 hours (ecog.tailorx@jimmy.harvard.edu). For 
questions regarding patients who have been pre-registered or registered, 
please provide the sequence number in the subject heading and/or content of 
the email. 
NOTE: 
Patients enrolled on the PACCT-1 trial may be enrolled on other CTSU trials 
under the following conditions: (1) the treatment options in the other trials are 
consistent with PACCT-1-specified treatment assignment (ie, 
chemohormonal therapy or hormonal therapy alone) and (2) although 
registration on the PACCT-1 trial is required prior to registration on any other 
CTSU trial requiring chemotherapy, it is preferred (but not necessarily 
required) prior to registration on another CTSU trial not involving 
chemotherapy (eg, hormonal therapy, bisphosphonate therapy).  
NOTE: 
Pre-registration requires a previously determined Recurrence Score (from 
GHI) or tissue available for submission for Oncotype DX assay.  See section 
7.2 for submission of forms and samples associated with Recurrence Score 
status. 
NOTE: 
If the Oncotype DX Recurrence Score was previously performed by 
Genomic Health and the RS is 11-25, eligible patients may proceed from 
the pre-registration process to randomization within 24 to 72 hours after 
submission of the Oncotype DX Assay report to the ECOG-ACRIN 
Operations Office – Boston (see sections 3.1.3, 3.1.10 and 4.2).   Pre-
registration may NOT be bypassed. 
ECOG-ACRIN Patient No. 
 
Patient’s Initials (Last, First, Middle) 
 
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Rev. 9/06 
Rev. 9/06 
Rev. 9/07 
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3.1 
Pre-Registration 
3.1.1 
Patients with operable histologically confirmed adenocarcinoma of the 
female breast who have completed primary surgical treatment and 
meet the following criteria 
3.1.1.1 
ER and/or PR-positive: 
Estrogen and/or progesterone receptor positive disease 
(as defined by local pathology laboratory). 
ER Status: Positive / Negative / Indeterminate Date______ 
(please circle one) 
PR Status: Positive / Negative / Indeterminate Date______ 
(please circle one) 
3.1.1.2 
Negative axillary nodes: 
As assessed by a sentinel lymph node biopsy, an axillary 
dissection, or both, and as defined by the Sixth Edition of 
the AJCC staging criteria (check definition that applies): 
_____ pN0:  
No regional lymph node metastases 
histologically, no additional examination 
for isolated tumor cells (NOTE: Isolated 
tumor cells (ITC) are defined as single 
tumor cells or small cell clusters not 
great than 0.2 mm, usually detected 
only by immunohistochemical (IHC) or 
molecular methods but which may be 
verified on H& E stain. ITCs do not 
usually show evidence of malignant 
activity [eg, proliferation or stromal 
reaction]).  
____ pN0 (i-):  
No regional lymph node metastases 
histologically; negative IHC 
____ pN0 (i+):  
No regional lymph node metastases 
histologically; positive IHC, no IHC 
cluster greater than 0.2 mm 
____ pN0 (mol-):  No regional lymph node metastases 
histologically; negative molecular 
findings (RT-PCR [reverse transcriptase 
polymerase chain reaction]) 
____ pN0 (mol+):  No regional lymph node metastases 
histologically; positive molecular findings 
(RT-PCR) 
Rev. 9/07 
Rev. 9/07 
Rev. 9/07 
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3.1.1.3 
Tumor size 1.1–5.0cm (or 5 mm-1.0 cm plus 
unfavorable histological features): 
Unfavorable features defined as intermediate or poor 
nuclear and/or histologic grade, or lymphovascular 
invasion. 
NOTE: 
Definition of tumor size: The tumor size used for 
determination of eligibility is the pathologic 
tumor size, which is usually determined by the 
size of the tumor as measured by inspection of 
the gross specimen. If the tumor size is 
measured microscopically and the tumor 
includes ductal carcinoma in-situ, the 
measurement should include only the invasive 
component of the tumor. 
3.1.1.4 
The tumor must be Her2/neu negative by either fluorescent 
in-situ hybridization (FISH) or immunohistochemistry (e.g. 
0 or 1+ by DAKO Herceptest). 
3.1.2 
The patient and physician must be agreeable to initiate standard 
chemotherapy and hormonal therapy as adjuvant therapy. The 
standard chemotherapy and hormonal therapy options permitted are 
described in Appendix II and Appendix III. 
3.1.3 
A tissue specimen from the primary breast cancer has been located 
and is ready to be shipped to the appropriate laboratory after consent 
is obtained and within 3 days following pre-registration as indicated in 
Section 10. 
NOTE: 
For determination of the Oncotype Recurrence Score, 
tissue must be shipped to Genomic Health. If the Oncotype 
DX Recurrence Score was previously performed by 
Genomic Health (prior to pre-registration), tissue must be 
submitted to the ECOG-ACRIN Central Biorepository and 
Pathology Facility upon randomization. 
3.1.4 
Patients must be ≥ 18 years and ≤ 75 years. Patients must be less 
than 76 years of age because patients will be followed for up to 20 
years, and because the primary study endpoints are based upon a 10 
year endpoint. 
3.1.5 
Patients must have adequate organ function, including the following 
within 4 weeks prior to pre-registration:  
• 
Leukocyte count ≥ 3500/ mm3 and platelets ≥ 100,000/mm3. 
Leukocyte count: ______ 
Date of test: ______ 
Platelet Count: ______ 
Date of test: ______ 
• 
Serum creatinine ≤ 1.5mg/dL.  
Creatinine: ______ 
 
Date of test: _______ 
• 
Serum aspartate transaminase (AST) that is ≤ 3-fold the upper 
institutional limits of normal.  
AST: _______  
Date of test: _______ 
Institutional limits of normal __________________ 
Rev. 8/08 
Rev. 9/06 
 
Rev. 9/06 
Rev. 12/14 
_______
Rev. 9/06 
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3.1.6 
Patients must be disease-free of prior invasive malignancies for ≥ 5 
years with the exception of curatively-treated basal cell or squamous 
cell carcinoma of the skin or carcinoma in situ of the cervix. Patients 
with a previous ipsilateral or contralateral invasive breast cancer, or 
with bilateral synchronous cancers, are not eligible. Patients with 
previous ipsilateral or contralateral DCIS are not eligible.   
3.1.7 
Prior Treatment 
3.1.7.1 
Mandatory prior surgery criteria: 
3.1.7.1.1 
Patient must pre-register within 84 days 
from the final surgical procedure required to 
adequately treat the primary tumor. (Please 
note that if margins are not clear and a 
resection has to be conducted after pre-
registration but before randomization, the 
patient will be deemed to be within the 84 
day window allowed by protocol and 
therefore eligible). 
3.1.7.1.2 
All tumors should be removed by either a 
mastectomy or local excision plus an 
acceptable axillary procedure (i.e., sentinel 
lymph node biopsy, axillary dissection, or 
both).  There must be adequate (at least 1 
mm if margin width specified) tumor-free 
margins of resection (for invasive and ductal 
carcinoma in-situ) in order for the patients to 
be eligible.  Patients with lobular carcinoma 
in-situ involving the resection margins are 
eligible. 
3.1.7.2 
Criteria re: other prior treatments: 
3.1.7.2.1 
No prior chemotherapy for this malignancy. 
3.1.7.2.2 
No prior radiation therapy for this 
malignancy.  This includes no prior 
MammoSite Brachytherapy RT. 
3.1.7.2.3 
Hormonal therapy: Patients who develop 
breast cancer while receiving a selective 
estrogen-receptor modulator (SERM; e.g., 
tamoxifen, toremifene, raloxifene) or an 
aromatase inhibitor (e.g., anastrazole, 
letrozole, exemestane) for breast cancer 
prevention or a SERM for other indications 
(e.g., raloxifene for osteoporosis) are not 
eligible. However, patients may have 
received up to 8 weeks of a SERM or 
aromatase inhibitor for this malignancy and 
still be eligible for study entry. 
_______
_______
_______
_______
_______
_______
_______
_______
_______
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Rev. 9/06 
Rev. 9/07 
Rev. 9/07 
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3.1.8 
Patients must have an anticipated life expectancy of at least 10 years. 
Patients with the following medical conditions should not be enrolled 
on the study: 
3.1.8.1 
Chronic obstructive pulmonary disease requiring treatment. 
3.1.8.2 
Chronic liver disease (e.g., cirrhosis, chronic active 
hepatitis) 
3.1.8.3 
Previous history of a cerebrovascular accident. 
3.1.8.4 
History of congestive heart failure or other cardiac disease 
that would represent a contraindication to the use of an 
anthracycline (e.g., doxorubicin or epirubicin). 
3.1.8.5 
Chronic psychiatric condition or other condition that would 
impair compliance with the treatment regimen. 
3.1.9 
Women must not be pregnant or breast-feeding due to the potential 
use of cytotoxic chemotherapy for patients participating in this trial, 
which is contraindicated due to the potential for chemotherapy to 
cause harm to the fetus or infant. All females of childbearing potential 
must have a blood test or urine study within 2 weeks prior to pre-
registration to rule out pregnancy. (See Section 7.1.) 
Female of childbearing potential?______ (Yes or No)  
Date of negative blood or urine pregnancy test: _________ 
3.1.9.1 
Women of childbearing potential must be strongly advised 
to utilize an accepted and effective form of non-hormonal 
contraception (e.g. intrauterine device, condoms, 
diaphragm, abstinence). 
3.1.10 
Patients must not have previously had the Oncotype DX Assay 
performed, with the exception of patients who have had the assay 
performed and have a Recurrence Score of 11-25. 
NOTE:  
A copy of the “Oncotype DX Patient Report” is to be faxed 
to the ECOG-ACRIN Operations Office – Boston (Fax: 
617-582-8578, Attn: Pre-registration/PACCT-1) upon 
receipt of the report, or, if Oncotype DX Assay was 
previously performed, immediately following pre-
registration. The protocol number (PACCT-1), and pre-
registration sequence number MUST be indicated on the 
report. 
Physician’s Signature: _________________________________ Date: __________ 
_______
_______
_______
_______
_______
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3.2 
Registration/randomization (24 to 72 hours after submission of the Oncotype DX 
Assay report to the ECOG-ACRIN Operations Office – Boston) 
3.2.1 
At the time of registration/randomization, information that will be 
required for proper stratification (as indicated in Section 4.2.5) will 
include:  
• 
Tumor Size (≤ 2. 0 cm vs. ≥ 2.1 cm): 
_________________________ 
• 
Menopausal Status [Post-menopausal vs. Pre- or peri-
menopausal (see Appendix III for status definitions)]: 
______________________ 
• 
Planned Chemotherapy (Taxane-Containing vs. Non-Taxane 
Containing): 
____________________________________________ 
• 
Planned Radiation Therapy [Whole breast, no boost planned vs. 
Whole breast, boost planned vs. Partial breast irradiation planned 
vs. No planned radiation therapy (for patients who have had a 
mastectomy)]: 
___________________________________________ 
NOTE: 
Research associates may need to contact the treating 
physician prior to registration regarding what type of 
adjuvant chemotherapy is planned if that information is 
not available in the medical record. 
3.2.2 
Oncotype DX Assay result: 
Pre-registration #: ________________ 
RS score:  ________________ 
 
Physician’s Signature: __________________________________ 
Date: _______ 
_______
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3.3 
Registration to Ancillary Study EL112LAB (Step 3) 
All patients who meet the following criteria are eligible to participate in 
the ancillary study: 
3.3.1 
Patient was registered/randomized to treatment (Step 2 - Arms A, B, 
C, or D) at least 4.5 years (54 months) and no more than 7.5 years 
(90 months) prior to registration to step 3. It is preferable for patients 
to be registered to step 3 at 5 years (60 months +/- 6 months) after 
registration to step 2. 
3.3.2 
Patient is disease free, with no prior recurrence, at time of registration 
to Step 3. 
3.3.3 
The primary tumor tissue and peripheral blood sample were 
previously submitted for research studies just prior to or following 
registration/randomization to treatment as outlined in 
PACT1/TAILORx Section 10. 
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4. 
Pre-registration and Registration/Randomization Procedures 
Data management activities for the PACCT-1 study will be performed jointly by the 
Cancer Trials Support Unit (CTSU) and the ECOG-ACRIN Cancer Research Group 
(ECOG-ACRIN). All sites (ECOG-ACRIN and non-ECOG-ACRIN alike) will submit study 
data to the CTSU (with the exception of Expedited Adverse Event Reporting; please 
follow instructions in section 5.3 for submission of AE data), therefore, all PACCT-1 
investigators and support staff (ECOG-ACRIN and non-ECOG-ACRIN alike) must 
be registered members of the CTSU. Please see the CTSU website (www.ctsu.org) for 
details on registering as a CTSU member. 
NOTE: 
This study involves both a pre-registration and a 
registration/randomization.  Please read these instructions carefully. 
NOTE:  
Pre-registration is required for low risk patients and for high risk 
patients who will be followed in the voluntary registry. 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific 
regulatory documents must be submitted to the CTSU Regulatory Office at the 
following address: 
CTSU Regulatory Office 
Coalition of National Cancer Cooperative Groups 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
FAX: (215) 569-0206  
E-mail: CTSURegulatory@ctsu.coccg.org  
(for regulatory document submission only) 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A.  
CTSU IRB Certification Form. 
 
Or 
B.  
Signed HHS OMB No. 0990-0263 (Replace Form 310). 
 
Or 
 
C.  
IRB Approval Letter 
NOTE: 
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
Rev. 9/07 
Rev. 9/06 
Rev. 7/10 
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• 
Date of review. 
• 
Signature of IRB official 
The CTSU encourages you to link to the following RSS2.0 webpage so that more 
information on RSS2.0 as well as the submission forms can be accessed 
http://www.ctsu.org/rss2_page.asp. If you have questions regarding regulatory 
document submission, please telephone the CTSU Help Desk at 1-888-823-5923 or E-
mail CTSUContact@westat.com. 
Checking Your Site’s Registration Status: 
Check the status of your site’s registration packets by querying the RSS site registration 
status page of the members’ section of the CTSU website.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
• 
Enter your 5-character CTEP Institution Code and click on Go 
Patients must not start protocol treatment prior to pre-registration and 
registration/randomization. 
4.1 
Pre-Registration 
Each investigator must have an NCI investigator number and must maintain an 
“active” investigator registration status through the annual submission of a 
complete investigator registration packet (FDA Form 1572 with original signature, 
current CV, Supplemental Investigator Data Form with signature, and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI. These forms are available on the CTSU Web site 
(enter credentials at https://www.ctsu.org; then click on the Register tab) or by 
calling the PMB at 240-276-6575 Monday through Friday between 8:30 a.m. and 
4:30 p.m. Eastern time. 
Patient registration can occur only after pre-treatment evaluation is complete, 
eligibility criteria have been met, and the study site is listed as ‘approved’ in the 
CTSU RSS. Patients must have signed and dated all applicable consents and 
authorization forms.   
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to 
this study. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following:  
• 
All eligibility criteria have been met within the protocol stated timeframes. 
Site staff should use the registration forms provided on the group or 
CTSU web site as a tool to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
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Rev. 12/14 
Rev. 8/08, 
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Access requirements for OPEN: 
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) 
used for the CTSU members' web site.  
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the relevant Group or CTSU roster.  
• 
To perform registrations on protocols for which you are a member of the 
Lead Group, you must have an equivalent 'Registrar' role on the Lead 
Group roster. Role assignments are handled through the Groups in which 
you are a member. 
• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., 
non-Lead Group registrations) you must have the role of Registrar on the 
CTSU roster. Site and/or Data Administrators can manage CTSU roster 
roles via the new Site Roles maintenance feature under RSS on the 
CTSU members' web site. This will allow them to assign staff the 
"Registrar" role.  
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation 
for your records. 
Further instructional information is provided on the OPEN tab of the 
CTSU members’ side of the CTSU website at https://www.ctsu.org or 
at https://open.ctsu.org. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com 
The following information will be requested for pre-registration: 
4.1.1 
Protocol Number 
4.1.2 
Investigator Identification  
4.1.2.1 
Institution and affiliate name 
4.1.2.2 
Investigator’s name 
4.1.3 
Patient Identification  
4.1.3.1 
Patient’s initials (Last, First, Middle) and chart number 
4.1.3.2 
Patient’s Social Security number 
4.1.3.3 
Patient demographics 
4.1.3.3.1 
Sex 
4.1.3.3.2 
Birth date (mm/yyyy) 
4.1.3.3.3 
Race 
4.1.3.3.4 
Ethnicity 
4.1.3.3.5 
Nine-digit ZIP code 
4.1.3.3.6 
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4.1.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 
3.1. An eligibility worksheet has been appended to the protocol. A 
confirmation of pre-registration will be forwarded by the ECOG-ACRIN 
Operations Office – Boston. 
4.1.5 
Additional Requirements 
4.1.5.1 
Patients must provide a signed and dated, written informed 
consent form. 
4.1.5.2 
Pathology blocks are to be submitted as follows: 
• 
For determination of Oncotype DX Recurrence 
Score, materials must be submitted no later than 3 
days after pre-registration as outlined in section 
10.1. Kits for tissue submission may be ordered 
prior to pre-registration. 
NOTE: 
If slides, rather than blocks, are 
submitted for the RS assessment, 
additional materials are required for 
central review of ER/PR status as 
indicated in section 10.3. 
• 
If the Oncotype DX Recurrence Score was 
previously determined by Genomic Health and the 
score is 11-25, blocks are to be submitted for 
central review after randomization as indicated in 
Section 10.3. 
NOTE: 
Beginning June 2007, ECOG-ACRIN requires 
that all samples from patients participating in 
PACCT-1 be entered and tracked via the online 
ECOG-ACRIN Sample Tracking System (STS). 
See section 10.4. 
4.1.5.3 
Prior to registration/randomization, the institution must FAX 
a redacted copy of the first page of the “Oncotype DX 
Patient Report” to the ECOG-ACRIN Operations Office – 
Boston (617-582-8578, ATTN: Pre-Registration/PACCT-1). 
Indicate on the report the protocol number (PACCT-1), the 
patient’s initials and patient’s ECOG-ACRIN pre-
registration sequence number. 
• 
If patient is having an Oncotype DX Assay 
performed by Genomic Health, Genomic Health will 
notify the submitting institution of the results of the 
Oncotype DX Assay within 14 working days of 
receipt of the sample. 
• 
If patient has previously had an Oncotype DX 
Recurrence Score performed by Genomic Health, 
and the RS is 11-25, the “Oncotype DX Patient 
Report” should be FAXed to the ECOG-ACRIN 
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Operations Office – Boston within 24 hours 
following pre-registration. 
• 
24 hours (72 hours if a weekend or holiday) after 
submission of the Oncotype DX Patient Report to 
ECOG-ACRIN, the institution may proceed to 
registering/randomizing the patient as outlined in 
Section 4.2. 
4.2 
Registration/Randomization 
Patients must not start protocol treatment prior to 
registration/randomization.   
Treatments should begin within 14 days after registration/randomization. 
Each investigator must have an NCI investigator number and must maintain an 
“active” investigator registration status through the annual submission of a 
complete investigator registration packet (FDA Form 1572 with original signature, 
current CV, Supplemental Investigator Data Form with signature, and Financial 
Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI. These forms are available on the CTSU Web site 
(enter credentials at https://www.ctsu.org; then click on the Register tab) or by 
calling the PMB at 240-276-6575 Monday through Friday between 8:30 a.m. and 
4:30 p.m. Eastern time. 
Patient registration can occur only after pre-treatment evaluation is complete, 
eligibility criteria have been met, and the study site is listed as ‘approved’ in the 
CTSU RSS. Patients must have signed and dated all applicable consents and 
authorization forms. 
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to 
this study. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
Site staff should use the registration forms provided on the group or 
CTSU web site as a tool to verify eligibility. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
Access requirements for OPEN: 
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) 
used for the CTSU members' web site.  
• 
To perform registrations, the site user must have been assigned the 
'Registrar' role on the relevant Group or CTSU roster.  
• 
To perform registrations on protocols for which you are a member of the 
Lead Group, you must have an equivalent 'Registrar' role on the Lead 
Group roster. Role assignments are handled through the Groups in which 
you are a member. 
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• 
To perform registrations to trials accessed via the CTSU mechanism (i.e., 
non-Lead Group registrations) you must have the role of Registrar on the 
CTSU roster. Site and/or Data Administrators can manage CTSU roster 
roles via the new Site Roles maintenance feature under RSS on the 
CTSU members' web site. This will allow them to assign staff the 
"Registrar" role.  
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation 
for your records.  
Further instructional information is provided on the OPEN tab of the CTSU 
members’ side of the CTSU website at https://www.ctsu.org or at 
https://open.ctsu.org. For any additional questions contact the CTSU Help Desk 
at 1-888-823-5923 or ctsucontact@westat.com. 
Institutions may register eligible patients to this study 24 hours (72 hours if 
weekend or holiday) after institution has Faxed a redacted copy of the first page 
of the “Oncotype DX Patient Report” to the ECOG-ACRIN Operations Office – 
Boston (617-582-8578, ATTN: Pre-Registration/PACCT-1) as outlined in Section 
4.1.5.3. 
The following information will be requested: 
4.2.1 
Protocol Number  
4.2.2 
Investigator Identification  
4.2.2.1 
Institution and affiliate name 
4.2.2.2 
Investigator’s name 
4.2.3 
Patient Identification  
4.2.3.1 
Patient’s initials (Last, First, Middle) and chart number 
4.2.3.2 
Patient’s Social Security number 
4.2.3.3 
Patient demographics 
4.2.3.3.1 
Sex 
4.2.3.3.2 
Birth date (mm/yyyy) 
4.2.3.3.3 
Race 
4.2.3.3.4 
Ethnicity 
4.2.3.3.5 
Nine-digit ZIP code 
4.2.3.3.6 
Method of payment 
4.2.3.4 
Patient’s sequence number from pre-registration (Step 1). 
4.2.4 
Classification factor 
Recurrence Score (RS) 
4.2.5 
Stratification factors 
4.2.5.1 
Tumor Size 
≤ 2. 0 cm 
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≥ 2.1 cm 
4.2.5.2 
Menopausal Status 
Post-menopausal 
Pre- or peri-menopausal 
(See Appendix III for status definitions) 
4.2.5.3 
Planned Chemotherapy 
Taxane-containing (i.e., paclitaxel, docetaxel) 
Non-taxane containing 
4.2.5.4 
Planned radiation therapy 
Whole breast, no boost planned 
Whole breast, boost planned  
Partial breast irradiation planned 
No planned radiation therapy (for patients who have had a 
mastectomy) 
4.2.5.5 
OncoType DX Recurrence Score 
11-15 
16-20 
21-25 
4.2.6 
Additional Requirements 
4.2.6.1 
Tumor tissue must be submitted for correlative studies and 
banking as outlined in Section 10. 
NOTE: 
If tissue was submitted at pre-registration for 
Oncotype DX RS assessment, additional 
materials are requested for correlative studies 
and banking. 
4.2.6.2 
Peripheral blood to be retained for possible future use 
should be submitted as outlined in Section 10. 
NOTE: 
Institutions outside the United States and 
Canada are not required to submit fresh 
samples because of the costs and problems 
associated with international shipping. 
NOTE: 
Beginning June 2007, ECOG-ACRIN requires 
that all samples from patients participating in 
PACCT-1 be entered and tracked via the online 
ECOG-ACRIN Sample Tracking System (STS). 
See section 10.4. 
4.3 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, all data will still be 
collected and submitted according to the instructions in the PACCT-1 Forms 
Packet. 
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4.4 
STEP 3: Registration to Ancillary Study EL112LAB 
All patients participating PACCT-1 are eligible to participate in this the 
EL112LAB. Requirements for the ancillary study are outlined in Appendix XII. 
NOTE: 
The ECOG-ACRIN Operations Office – Boston will provide sites a list 
of patients who have been identified as potential candidates for 
EL112LAB. The information provided will include the date range for 
which the patients would be eligible to participate which is dependent 
on the date of registration/randomization to treatment (Step 2).  
Routine notifiers will also be utililized to serve as reminders to sites 
regarding the timeline of a patient’s potential eligibility. 
The following information will be collected at time of registration to step 3 
4.4.1 
Protocol Number  
4.4.2 
Investigator Identification  
• 
Institution and affiliate name 
• 
Investigator’s name 
• 
NCI investigator ID 
4.4.3 
Patient Identification  
4.4.3.1 
Patient’s initials and chart number 
4.4.3.2 
Patient’s Social Security number 
4.4.3.3 
Patient demographics 
• 
Sex 
• 
Birth date (mm/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
4.4.4 
Additional Requirements  
4.4.4.1 
Patients must provide a signed and dated, written informed 
consent form to participate in EL112LAB.  The model 
consent for this ancillary study is provided in Appendix I-A 
4.4.4.2 
Forms and biological materials are to be submitted as 
outlined in Appendix XII. A summary is provided in Section 
7.4.  
NOTE: 
ECOG-ACRIN requires all samples submitted 
to be entered and tracked via the online ECOG-
ACRIN Sample Tracking System (STS). See 
section 10.4. 
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5. 
Treatment Plan 
NOTE: 
All questions regarding treatment or dose modifications should be directed to 
the ECOG-ACRIN Study Chair. 
NOTE: 
Systemic treatment (chemotherapy or hormonal therapy) should be initiated 
within 14 days after registration/randomization. For patients randomized or 
assigned to receive chemotherapy, chemotherapy should be administered 
first; hormonal therapy should begin within 4 weeks after the last dose of 
chemotherapy, and should not be given concurrently with chemotherapy. 
Hormonal therapy may be initiated more than 4 weeks after completion of 
chemotherapy (or more than 2 weeks after registration if receiving hormonal 
therapy alone) if the treating physician elects to begin hormonal therapy after 
completion of radiation therapy. It is recommended that hormonal therapy be 
given concurrently with radiation therapy, but may be delayed until after 
completion of irradiation at the discretion of the treating physician (and should 
begin within 4 weeks of completing irradiation). 
5.1 
Treatment Arms 
NOTE: 
Patients enrolled on the PACCT-1 trial may be enrolled on other 
CTSU trials under the following conditions: (1) the treatment options in 
the other trials are consistent with PACCT-1-specified treatment 
assignment (ie, chemohormonal therapy or hormonal therapy alone) 
and (2) although registration on the PACCT-1 trial is required prior to 
registration on any other CTSU trial requiring chemotherapy, it is 
preferred (but not necessarily required) prior to registration on another 
CTSU trial not involving chemotherapy (eg, hormonal therapy, 
bisphosphonate therapy). 
Secondary Study Group-1 (RS ≤ 10):  Patients will receive hormonal 
therapy of the treating physician’s choice (see Appendix III for 
guidelines) 
5.1.1 
Primary Study Group (RS 11-25): Patients will be randomized at the 
time of registration to receive chemotherapy plus hormonal therapy or 
hormonal therapy alone (see Appendix II and Appendix III for 
guidelines). 
5.1.2 
Secondary Study Group-2 (RS ≥ 26): Patients will receive 
chemotherapy (see Appendix II) and hormonal therapy (see Appendix 
III) of the treating physician’s choice. 
For patients with a RS ≥ 26 who do not register on another CTSU 
study, the enrolling site is asked to provide baseline and follow-up 
information on a voluntary basis. Requested information will include 
the following: (1) a baseline case report form, (2) a report of disease 
relapse event (as defined in Section 6), and/or second primary 
cancer, and/or death (if any of these events occur), (3) and a report of 
disease and survival status 5 years after registration. 
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5.2 
Radiotherapy 
Patients who have had breast conservation surgery will be treated with 
radiotherapy.  Guidelines for radiation therapy are as follows: 
Radiation should begin within 4-8 weeks of registration for patients receiving 
hormonal therapy alone or within 4-8 weeks after completion of chemotherapy (or 
sooner if the patient has adequately recovered from chemotherapy-associated 
toxicity). 
Radiation treatment should be delivered using one of the following: 
(a) 
External beam irradiation to the whole breast to a dose of 45-50 Gy using 
daily fractions of 1.8-2.0 Gy, 5 days per week. A boost dose to the 
primary tumor bed is recommended to bring the total dose to 60-66 Gy. 
(b) 
External beam irradiation to the whole breast using accelerated 
fractionation of 42.56 Gy in 16 daily fractions, 5 days per week.  A boost 
dose to the primary tumor bed is recommended. 
(c) 
Patients may receive accelerated partial breast irradiation (APBI), if they 
are participating in the randomized NSABP/RTOG APBI trial or the 
randomized RAPID APBI trial. Accelerated partial breast irradiation 
(APBI), including Mammosite brachytherapy, is otherwise not permitted, 
either before or after pre-registration, if not on a randomized radiation 
study.  APBI on study may be given before chemotherapy if indicated. 
• 
Breast radiation should not be given concurrently with 
chemotherapy.  It is recommended that hormonal therapy be 
given concurrently with radiation therapy, but may be delayed until 
after completion of irradiation at the discretion of the treating 
physician (and should begin within 4 weeks of completing 
irradiation). 
5.3 
Quality of Life Assessments 
All PACCT-1 participants will be eligible to participate in the QOL assessment. 
The primary QOL objectives pertain to participants in the Primary Study Group 
and those randomly assigned to Arms B and C. Secondary analyses will also 
examine women in the Secondary Study Group (1 and 2) and treated on Arms A 
or D. 
5.3.1 
Assessment Instruments 
Study participants will complete the following patient-reported 
outcomes measures: 
Scale 
Number 
of items 
Estimated 
administration time 
FACT-Cog Version 3 
37 
10 minutes 
FACT-Fatigue subscale 
13 
3 minutes 
PROMIS Fatigue 7-item Short Form 
7 
2 minutes 
Assessment of Survivor Concerns 
5 
2 minutes 
FACT-Endocrine subscale 
19 
4 minutes 
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TOTAL 
81 
21 minutes 
FACT-General* 
27 
7 minutes 
TOTAL: 12 and 36 month assessments 
108 
28 minutes 
*The FACT-G will only be administered at baseline, 12 and 36 months 
in an attempt to minimize participant burden. 
The FACT-Cog Version 3 consists of four subscales: Perceived 
cognitive impairments (20 items), Perceived cognitive abilities (9 
items), Comments from others (4 items) and Impact on quality of life 
(4 items).Subscales are scored and interpreted independently and are 
not combined to create a single score. The Perceived cognitive 
impairment subscale will be used for the primary analysis. 
Demographic and medical characteristics will also be obtained from 
participants, including comorbid illnesses, current medications 
(including treatments for menopausal symptoms), height and weight, 
and level of physical activity. This information is not currently being 
collected from TAILORx participants. We will develop a brief set of 
questions to capture this data. 
5.3.2 
Assessment Schedule 
Participants will be assessed according to the following schedule: 
1) Baseline* (at the time they are assigned to the Primary or 
Secondary Study Groups) 
2) 3 months 
3) 6 months 
4) 12 months* 
5) 24 months 
6) 36 months* 
*The FACT-G will only be administered at baseline, 12 and 36 months 
The proposed assessment time points correspond to TAILORx study 
visits and the probable timing of routine care clinic visits to minimize 
participant burden. The table below displays the length (in months) of 
all 9 chemotherapy regimens allowable per the TAILORx protocol. 
The majority of participants are receiving treatment on Arms 3, 4 and 
9. As indicated in the table, these regimens are completed at 3 
months. The 3 month assessment will be used for the primary 
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Length of chemotherapy regimens for each treatment arm 
0
1
2
3
4
5
6
Months
Arm 4
Arm 3
Arm 9
Arm 6
Arm 7 
Arm 8
Arm 1
Arm 2
Arm 5
Study Arm
 
*Study arm numbers refer to the Regimen code, 
see table in Appendix II 
5.3.3 
QOL Instrument Administration Instructions 
5.3.3.1 
The questionnaires must be administered at the timepoints 
listed above. The patient should be instructed to respond 
to the questionnaires in terms of his/her experience during 
the time frame specified on each questionnaire. 
5.3.3.2 
The CRN/CRA should read the instructions printed on the 
questionnaire to the patient and ensure the patient 
understands the instructions. It is important to assure the 
patient that all material on the questionnaire is confidential 
and will not be shared with the health care team and that it 
will not become part of the medical record. It is permissible 
to assist the patient with the completion of the 
questionnaires as long as the staff person does not 
influence the patient’s responses. 
5.3.3.3 
Whenever possible, the HRQL assessment should be 
administered at the clinic visit before the patient is seen by 
the physician, before evaluations are performed and 
before test results are shared with the patient. In the event 
that the questionnaires are not administered at the clinic 
visit, the HRQL data can be collected by telephone or mail 
as backup methods provided that HRQL data is captured 
prior to initiation of treatment. 
5.3.3.4 
Assistance in reading the questionnaire is permitted if the 
patient is unable to complete the questionnaire on his/her 
own (e.g. difficulty in reading, elderly). It is important not to 
influence the response of the patient. Note why the patient 
required assistance and the type of assistance given. 
5.3.3.5 
Patients should be instructed to answer all the questions 
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about are related to the cancer or cancer treatment. 
Discourage family members from being present during 
questionnaire completion or from influencing the patient’s 
responses. 
5.3.3.6 
The questionnaires must be reviewed by the protocol 
nurse or research coordinator as soon as the patient 
completes them to ensure all items were marked 
appropriately. If the patient has marked more than one 
answer per question, ask the patient which answer best 
reflects how they are feeling. If the patient has skipped a 
question or questions, the patient should be asked if 
he/she would like to answer it. If the patient refuses, it 
should be indicated on the questionnaire that he/she 
declined to answer the item.  
5.3.3.7 
If the patient refuses or cannot complete the questionnaire 
at any time point, he or she should be asked to do so at 
the next scheduled HRQL assessment. 
5.3.3.8 
The patient may decline to complete the HRQL 
assessment for any reason. The reason must be 
documented on the Assessment Compliance Form. 
5.3.3.9 
If a patient misses an appointment on the scheduled date, 
the questionnaires may be completed by telephone on the 
appointed date or they may be completed at the time the 
appointment is rescheduled. If the missed scheduled date 
is on a treatment date, the quality of life assessment will be 
done when the patient comes for the rescheduled 
treatment. 
5.3.3.10 
If a patient cannot complete the quality of life 
questionnaires because he/she is too sick, this should be 
documented on the Assessment Compliance Form. 
5.4 
Adverse Event Reporting Requirements 
Identify the type of event and grade using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.0. 
5.4.1 
Reporting procedure 
Arms A, B, C and D - This study requires that expedited adverse 
event reporting use CTEP's Adverse Event Reporting System (CTEP-
AERS). CTEP's guidelines for CTEP-AERS can be found at 
http://ctep.cancer.gov.  A CTEP-AERS report must be submitted 
electronically to ECOG-ACRIN and the appropriate regulatory 
agencies via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (617-632-3610) 
• 
the NCI (301-897-7497)  
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An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617 632 2990), 
Attention: AE within 48-72 hours.  In addition, supporting or follow up 
documentation must be faxed to the NCI (301- 230-0159) in the same 
timeframe.  
NCI Technical Help Desk:  For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457 or 301-840-8202. 
5.4.2 
Other recipients of adverse event reports 
ECOG-ACRIN will forward CTEP-AERS reports to the appropriate 
regulatory agencies and pharmaceutical company, if applicable. 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 
5.4.3 
Expedited reporting for PACCT-1 protocol 
Attribution 
 
Grade 5a 
 
 
 
Unexpected 
Expected 
 
Possible,  
Probable,  
Definite 
 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: 
Indicates a full CTEP-AERS report is to be submitted within 7 calendar 
days of learning of the event. 
a This includes all deaths within 30 days of the last dose of treatment regardless of 
attribution.  
NOTE: 
Any death that occurs > 30 days after the last dose of treatment and is 
attributed possibly, probably, or definitely to the treatment must be reported 
within 7 calendar days of learning of the event.   
5.4.4 
Reporting second primary cancers 
All cases of second and secondary malignancies [including acute 
myeloid leukemia (AML) and myelodysplastic syndrome (MDS)], 
regardless of attribution, that occurs following treatment on NCI-
sponsored trials must be reported as follows:   
1. Fax a completed TAILORx Second Primary Form within 30 days 
to the CTSU by fax at 301-545-0406.  
NOTE: 
A TAILORx CTSU Data Transmittal Form should 
accompany all forms and reports submitted to the CTSU. 
NOTE: 
The TAILORx Second Primary Form should not be used to 
report recurrence or development of metastatic disease.  
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted by the TAILORx Second Primary Form. 
Rev. 10/13, 11/13 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
60 
6. 
Measurement of Effect 
NOTE: 
Recurrence must be documented by biopsy and/or evidence of disease on 
radiologic studies. Abnormal blood studies alone (e.g., elevated 
transaminases or alkaline phosphatase) are not sufficient evidence of 
relapse.  Whenever possible, histologic proof of recurrence should be 
obtained. 
6.1 
Ipsilateral Breast Tumor Recurrence (IBTR) 
Recurrence occurring within the ipsilateral breast in a patient who has had prior 
breast conserving therapy (ie, lumpectomy). Patients who develop an IBTR must 
continue to be followed for other sites of recurrence, which must be reported if 
they occur.  Development of invasive disease in the ipsilateral breast should be 
reported as IBTR, not as a new primary cancer.  New sites of ductal carcinoma in 
situ (DCIS) should be reported, but will not be considered an IBTR and follow-up 
for IBTR should continue. 
6.2 
Local/Regional Recurrence (LRR) 
One or both of the following: (a) nodal relapse: recurrence in regional lymph 
nodes (e.g., ipsilateral axillary, supraclavicular, or internal mammary lymph 
nodes), and/or (b) recurrence in the skin and/or chest wall in a patient who has 
had a prior mastectomy or breast conserving surgery. Patients who develop an 
LRR must continue to be followed for other sites of recurrence, which must be 
reported if they occur.  
6.3 
Distant Recurrence (DR) 
The development of a distant recurrence of breast cancer, including distant 
organs (eg, brain, liver, lungs, bone, etc) and/or non-regional lymph nodes (eg, 
mediastinal, cervical, contralateral axilla, etc). Patients who develop a distant 
recurrence must continue to be followed for survival; other sites of 
recurrence/progression do not need to be reported. 
6.4 
Second Primary Breast Cancer 
Evidence of invasive breast cancer in the contralateral breast.  Histologic 
confirmation of second primary breast cancers is required.  New sites of DCIS 
should be reported, but are not to be considered an event for purposes of 
analysis, and patients with DCIS should continue to be followed for development 
of invasive disease.  Patients who develop a second primary breast cancer must 
continue to be followed for other sites of breast cancer recurrence, which must 
be reported if it occurs.  
6.5 
Second Primary Cancer (non-breast) 
Any non-breast invasive cancer except squamous or basal cell carcinoma of the 
skin.  New in situ cancers at any site (except breast) should not be reported.  
Patients who develop a second primary cancer must continue to be followed for 
breast cancer recurrence, which must be reported if it occurs. 
Rev. 3/09

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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
61 
6.6 
Disease-Free Survival (DFS) 
Date of randomization or registration to the date of ipsilateral breast tumor 
recurrence, local/regional recurrence, distant recurrence, second primary cancer 
(breast or non-breast), or death from any cause.  
6.7 
Distant Recurrence-Free Interval (DRFI) 
Date of randomization or registration to the date of distant recurrence of breast 
cancer, as defined in Section 6.3, or of death with distant recurrence, if death is 
the first manifestation of distant recurrence. 
6.8 
Recurrence-Free Interval (RFI) 
Date of randomization or registration to the date of first recurrence of breast 
cancer (IBTR, LRR, or DR) or to the date of death with recurrence, if death is the 
first manifestation of recurrence.  
6.9 
Overall Survival 
Date of randomization or registration to date of death from any cause. 
6.10 
Cause-specific Survival 
Date of randomization or registration to date of death from breast cancer. 
6.11 
Quality of Life 
Quality of life endpoints will be measured using patient-reported outcomes 
questionnaires. Domains to be assessed and instruments to be administered 
include perceived cognitive impairments (FACT-Cog), fatigue (FACT-Fatigue and 
PROMIS Fatigue SF), fear of recurrence (Assessment of Survivor Concerns), 
endocrine symptoms (FACT-ES) and HRQL (FACT-General).
Rev. 1/10

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
62 
7. 
Study Parameters 
7.1 
Therapeutic Parameters  
Prestudy CBC (with differential and platelet count) and all required prestudy 
chemistries (as outlined in Section 3) should be done ≤ 4 weeks before pre-
registration. 
[Deleted NOTE in Addendum #2] 
 
Rev. 9/07 
 
Pre-Registration 
Registration/ 
Randomization 
Follow-up4 
 
History & Physical Examination 
X 
 
Between every 3- 6 
months x 5 years, then 
annually thereafter 
 
Disease and survival status 
 
 
X1  
 
Height 
X 
 
 
 
Weight 
X 
 
 
 
Complete Blood Count 
(including leukocyte and platelet count) 
 X2 
 
 
 
Serum creatinine and AST (aspartate transaminase) 
 X2 
 
 
Rev. 9/07 
Mammography and/or Breast MRI9 
 X3 
 
Annual 
 
Oncotype DX assay (RS score)5 
X 
 
 
Rev. 9/07, 
7/10 
BIOLOGICAL MATERIAL SUBMISSIONS and related documents: See section 10 
Rev. 9/07 
Tumor tissue, fixed paraffin-embedded 
 X6 
X7 
 
Rev. 9/07 
Frozen Tumor Tissue 
 
X8 
 
Rev. 9/07  Blood Samples 
 
X7 
 
Rev. 3/09 
Pregnancy Test 
  X10 
 
 
Rev. 1/10 
QOL Assessments 
See Section 7.3 
1 
The following events must be reported to ECOG-ACRIN within 30 days that they are known to have 
occurred: death from any cause, recurrence (ipsilateral breast tumor recurrence, local/regional recurrence, 
or distant recurrence, as defined in Section 6), or second primary cancer; if these events have not occurred, 
follow-up at the time points indicated for history and physical exam is required to confirm that they have not 
occurred.  
2 
Obtained within 4 weeks prior to pre-registration 
3 
Mammogram and/or Breast MRI obtained as part of the original diagnosis, biopsy and surgical treatment 
will suffice and need not be repeated.   
4 
Follow-up for up to 20 years 
5 
Oncotype DX assay (RS score) is performed by Genomic Health (see Sections 4 and 10 and Appendix V). 
Fax a redacted copy of the first page of the “Oncotype DX Patient Report” to the ECOG-ACRIN Operations 
Office 
– 
Boston  
(617-582-8578, ATTN: Pre-Registration/PACCT-1).  Registration/randomization may proceed 24 hours and 
up to 72 hours (if weekend or holiday) after submission of the Oncotype DX Patient Report to ECOG-
ACRIN. 
6 
MANDATORY from patients with no RS score determined prior to pre-registration.  Samples must be 
submitted to Genomic Health, Inc for Oncotype Dx assessment.  See section 10.1. 
7 
Required for central review and, if patient consents, banking for future research.  See section 10.3. 
8 
For patients who consent to future use.  See section 10.3. 
9 
Bilateral breast MRI alone is acceptable if mammography could not be performed. 
10 
All females of childbearing potential must have a blood test or urine study within 2 weeks prior to pre-
registration to rule out pregnancy. 
Rev. 9/07 
Rev. 9/06 
Rev. 9/06 
Rev. 9/07 
Rev. 9/07, 
        7/10 
Rev. 9/07 
Rev. 9/07 
Rev. 9/07 
Rev. 9/07 
Rev. 3/09 

ECOG-ACRIN 
PACCT-1 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
63 
7.2 
[Submission of Biological Materials Removed in Addendum #2]  
All sample submission information can be found in section 10. 
7.3 
Timepoints for QOL Assessments1,2 
Scale3 
Baseline 
(Randomization) 
3 
months. 
6 
months 
12 
months 
24 
months 
36 
months 
FACT-Cog Version 3 
X 
X 
X 
X 
X 
X 
FACT-Fatigue subscale 
X 
X 
X 
X 
X 
X 
PROMIS Fatigue 7-item 
short form 
X 
X 
X 
X 
X 
X 
Assessment of Survivor 
Concerns 
X 
X 
X 
X 
X 
X 
FACT-Endocrine 
Subscale 
X 
X 
X 
X 
X 
X 
FACT-General 
X 
 
 
X 
 
X 
1. 
Assessment at randomization must be completed before treatment is 
initiated. All follow-up assessments should be completed on the target 
date or as close to the target date as possible. For follow-up 
assessments, QOL should be administered + two weeks of the target 
date. 
2. 
All assessments are to be administered by the site and mailed back to the 
ECOG-ACRIN Operations Office – Boston at: 
ECOG-ACRIN Operations Office – Boston 
Attn: Data 
900 Commonwealth Avenue 
Boston, MA 02215 
 
3. 
Please see PACCT-1 forms packet for QOL assessment forms. 
7.4 
Requirements for Ancillary Study EL112LAB (Step 3 registration)  
For all patients who have registered to Step 3, forms and samples are to be 
submitted as outlined in Appendix XII. A schedule summary is provided below. 
Kits for sample collection and shipment are available for sites in the United 
Stated and Canada.  Complete the KIT ORDER FORM (Appendix XIV) and fax 
to Zemotak-International at (800) 815-4675. Institutions outside the United States 
Rev. 9/07 
Rev. 1/10 
Rev. 2/13 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
64 
and Canada who wish participate in this ancillary study are to contact the ECOG-
ACRIN CBPF to discuss the logistics of specimen submissions. 
NOTE: 
ECOG-ACRIN requires all samples submitted to be entered and 
tracked via the online ECOG-ACRIN Sample Tracking System (STS). 
See section 10.4. 
 
 
Registration to 
EL112LAB 
At 1, 2, 3, 4, & 5 years 
after registration to EL112LAB 
Tumor recurrence 
 
Health 
Questionnaires 
X 
X 
 
Rev.10/13 
 FASTING Blood 
samples1 
X 
 
X 
 
Tumor sample 
 
 
X 
1.  Fasting draws are strongly encouraged.  Provide time of last caloric intake in 
STS.
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
65 
8. 
Drug Formulation and Procurement 
8.1 
Cyclophosphamide 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.1.1 
Other Names 
Cytoxan, Neosar, CTX, CPM, NSC #261037. 
8.1.2 
Classification 
Cyclophosphamide is a prodrug biotransformed to active alkylating 
metabolites by a mixed function microsomal oxidase system. 
8.1.3 
Mode of Action 
Cyclophosphamide metabolites are thought to disrupt cell division 
primarily by cross-linking DNA strands.  Cyclophosphamide is 
considered cell cycle phase non-specific. 
8.1.4 
Storage and Stability 
Tablets and injectable powder are stored at room temperature 25°C 
(77°F).  The temperature is not to exceed 30°C (90 F°).  
Reconstituted parenteral solutions are stable for 24 hours at room 
temperature for 6-14 days if refrigerated. 
8.1.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.1.5.1 
Dosage in Renal or Hepatic Failure 
Cyclophosphamide dosage adjustment for patients with 
renal or hepatic failure has not been adequately evaluated.  
8.1.6 
Preparation 
Preparation of standard regimens should follow site standards.  
For patients receiving regimens on CTSU protocols, protocol specific 
preparation must be followed. 
8.1.7 
Administration 
May be given orally, IV push, or by IV infusion. 
8.1.8 
Compatibilities 
Numerous compatibility studies have been published.  For specific 
details refer to handbook on injectable drugs by Lawrence A. Trissel.

ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
66 
8.1.9 
Availability 
Cyclophosphamide is commercially available as 25 mg and 50 mg 
tablets and for parenteral injection as 100 mg, 200 mg, 500 mg, 1 g, 
and 2 g vials. 
8.1.10 
Side Effects 
Side effects vary significantly based on the specific dose and duration 
of cyclophosphamide.  
8.1.10.1 
Incidence More Frequent (>5%) 
1. 
Anemia, leukopenia (usually asymptomatic; less 
frequently fever and/or chills)  
2. 
Thrombocytopenia (usually asymptomatic; less 
frequently unusual bleeding or bruising; black tarry 
stools; blood in urine or stools; pinpoint red spots on 
skin).  Nadir counts usually occur 7 to 12 days after 
administration and recovery usually compete by day 
17 to 21. 
3. 
Alopecia 
4. 
Anorexia, nausea and vomiting 
5. 
Gonadal suppression (azoospermia, missed 
menstrual periods) resulting in infertility.  Return of 
normal gonadal function and fertility occurs with time 
in many younger men and women. 
6. 
Hemorrhagic cystitis 
8.1.10.2 
Incidence Less Frequent (1-5%) 
1. 
Stomatitis 
8.1.10.3 
Incidence Rare (1%)  
1. 
Anaphylaxis (tachycardia, shortness of breath, 
wheezing, tightness in throat) 
2. 
Flushing or redness of face 
3. 
Diarrhea 
4. 
Skin rash 
5. 
Pneumonitis or interstitial pulmonary fibrosis 
6. 
Syndrome of inappropriate antidiuretic hormone 
(siadh) 
7. 
Chemical phlebitis (redness, swelling or pain at site 
of injection) 
8. 
Secondary malignancies 
9. 
Blurred vision, cardiac toxicity presenting as 
congestive heart failure 
10. 
Hemorrhagic mycodarditis 

ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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11. 
Cardiac necrosis 
12. 
Pericarditis (seen with high dose regimens used with 
bone marrow transplantation) 
8.1.11 
Drug Interactions 
8.1.11.1 
Digoxin 
Several studies conducted in lymphoma patients receiving 
combination chemotherapy including cyclophosphamide 
revealed a 20–50% reduction in digoxin absorption when 
digoxin tablets were administered.  When digoxin capsules 
were administered no significant decrease in digoxin 
absorption occurred.  To avoid decreased serum digoxin 
levels the use of digoxin in liquid form (liquid or capsules 
containing liquid digoxin) instead of tablets is 
recommended. 
8.1.11.2 
Pentostatin 
Two case reports describe fatal cardiac toxicity in patients 
receiving CTX  6.4 g/m² over 4 days and pentostatin 4 
mg/m² over 4 hours on day 3.  Until additional data from 
clinical trials demonstrate the safety of concurrent use of 
these drugs concurrent administration is not 
recommended. 
8.1.11.3 
Succinylcholine 
Cyclophosphamide may prolong the effects of 
succinylcholine by irreversibly inhibiting the enzyme 
pseudocholinesterase.  Limited clinical observations and in 
vitro  studies suggest that prolonged apnea might result 
when  succinlycholine is administered to some patients 
also receiving cyclophosphamide. Management options 
include avoiding concurrent therapy or if concurrent 
therapy can not be avoided, to monitor for prolonged 
succinlycholine effect in patients receiving both drugs. If 
cyclophosphamide has been administered within 10 days 
of succinylcholine, extreme caution should be used after 
succinylcholine administration. The anesthesiologist should 
be informed of the potential for succinylcholine-induced 
apnea and appropriate precautions and monitoring should 
be implemented. 
8.1.11.4 
Trastuzumab 
In early clinical trials the concurrent administration of 
cyclophosphamide and trastuzumab increased the 
incidence and severity of cardiac dysfunction.  Until 
additional data from clinical trials demonstrate the safety of 
concurrent use of these drugs concurrent administration is 
not recommended. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
68 
8.1.12 
Nursing Implications 
1. Monitor CBC, platelet count.  Advise patients of increased risk of 
infection with absolute neutrophil count less than 500 cells/mm³ 
and increased risk of bleeding with platelet counts less than 
20,000 cells/mm³.  Advise patients to call the clinic if they develop 
a fever above 101°F or notice any easy bruising,  petechiae 
(pinpoint red spots on skin), or prolonged bleeding. 
2. Advise patient of possible alopecia.  Instruct how to obtain wig, 
hairpiece, etc. 
3. Assess hydration and fluid balance.  Patients receiving larger doses 
should force fluids up to 2 liters above normal intake for 72 hours 
after administration.  Instruct patients to void more frequently to 
minimize occurrence of hemorrhagic cystitis.  For high-dose therapy 
MESNA may be used. 
4. Premedicate with antiemetics. 
5. Observe for possible phlebitis at injection site. 
6. Administer antiemetics as indicated. 
8.1.13 
References 
American Hospital Formulary Service 99 – Drug Information; 832-837. 
Cytoxan Package Insert, Princeton, NJ: Mead Johnson Oncology 
Products 1998; July Micromedex Inc. Vol. 101; 1999. 
USPDI Volume 1 1999; 1128-1134. 
Trissel L.A, Handbook on injectable drugs (8th Ed), Bethesda, MD: 
American Society of Hospital Pharmacists, 1994, Pp. 287-295. 
Cazin B, Gorin NC, Laporte JP. Cardiac complications after bone 
marrow transplantation: A report of a series of 63 consecutive 
transplants. Cancer 1986; 57:2061-2069. 
Gryn et. al. Pentostatin increases the acute toxicity of high dose 
cyclophosphamide. Bone Marrow Transplantation 1993; 12:217-220. 
Pedersen-Bjergaard J, Ersboll J, Sorenson HM. Risk of acute 
nonlymphocytic leukemia and preleukemia in patients treated with 
cyclophosphamide for Non-Hodgkin’s lymphoma. Ann Intern Med 
1985; 103:195-200. 
Stillwell TJ, Benson RJ. Cyclophosphamide-induced hemorrhagic 
cyctitis: A review of 100 patients. Cancer 1988; 61:451-457. 
Zucchero FJ, Ed. Evaluation of drug interactions. St. Louis: 
Professional Drug Systems, 1997; 2/35, 12/21. 
Hansten Pd, Ed. Drug interactions analysis and management. Applied 
Therapeutics, Inc., Vancouver, WA 1998; 185-186. 
Trastuzumab Package Insert, South 

ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
69 
8.2 
Methotrexate 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.2.1 
Other Names 
8.2.1.1 
Chemical Name 
N-[4-[[(2,4-Diamino-6-pteridinyl)methyl)] 
methylamino]benzoyl]-L-glutamic acid 
8.2.1.2 
Synonyms 
Methotrexate sodium, MTX, Mexate, Mexate-AQ, Folex, 
Folex PFS, Abitrexate, Rheumatrex, Amethopterin, NSC 
#740 
8.2.2 
Classification 
Antimetabolite 
8.2.3 
Mode of Action 
Methotrexate inhibits the enzyme dihydrofolate reductase, thereby 
blocking the conversion of folic acid to its active form, tetrahydrofolic 
acid.  Inhibition of this enzyme reduces purine synthesis and the 
conversion of deoxyuridylate to thymidylate which inhibits the 
synthesis of DNA, RNA and proteins.    
8.2.4 
Storage And Stability 
Store at room temperature protected from light.  Reconstituted 
solutions are stable at room temperature for at least 1 week.  
Solutions (50 mg/100 mL) in PVC bags of 5% dextrose may be frozen 
at –20oC for at least 30 days when thawed in 2 minutes by microwave 
radiation.  There is no loss of potency after 5 freeze-thaw cycles. 
8.2.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.2.6 
Preparation 
Preparation of standard regimens should follow site standards.  
For patients receiving regimens on CTSU protocols, protocol specific 
preparation must be followed. 
8.2.7 
Administration 
Usually administered by IV bolus (< 100 mg), or slow IV infusion over 
30 minutes or longer (> 100 mg). Has also been given intrathecally, 
intra- muscularly, orally, intra-arterially, intraperitoneally and 
intravesicularly. 

ECOG-ACRIN 
PACCT-1 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
70 
8.2.8 
Compatibilities 
Compatible with sodium bicarbonate, cytarabine, cephalothin, 
mercaptopurine, vincristine sulfate, hydrocortisone, leucovorin, 
furosemide, and amino acids.  At the "Y-site," compatible with 
fluorouracil, cisplatin and heparin. 
8.2.9 
Incompatibilities 
Incompatible in solution with bleomycin, fluorouracil, prednisolone 
sodium phosphate, droperidol, metoclopramide, and ranitidine.  
Aspirin, probenecid, and nonsteroidal anti-inflammatory drugs may 
prolong methotrexate clearance and increase toxicity.  They should 
not be given to patients receiving larger doses of methotrexate (for 48 
hours after a dose).  
8.2.10 
Availability 
Commercially available as a lyophilized powder for injection (20, 50, 
100, 250, and 1000 mg/vial), as a 25 mg/mL preservative free isotonic 
solution for injection (50, 100, 200 and 250 mg/vial), as a 2.5 mg/mL 
(5 mg vial) and 25 mg/mL (50 and 250 mg vials) preservative 
protected isotonic solution for injection and as a 2.5 mg tablet. 
8.2.11 
Side Effects 
1.  
Hematologic: Leukopenia, thrombocytopenia: dose-related, 
more likely with prolonged drug exposure; anemia.  
2.  
Dermatologic: Skin erythema and/or rash, sometimes pruritic; 
alopecia; photosensitivity; furunculosis; depigmentation or 
hyperpigmentation; acne; telangiectasia; skin desquamation 
(exfoliative dermatitis) and bullae formation; folliculitis. 
3.  
Gastrointestinal: Nausea and vomiting, uncommon with 
conventional doses, and usually mild; stomatitis, common, 
dose- and infusion duration- related and highly variable; 
diarrhea; anorexia; hematemesis; melena. 
4.  
Genitourinary: Renal dysfunction: dose-related, more likely to 
occur in patients with already compromised renal function, 
dehydration, or on other nephrotoxic drugs, manifested by 
increased creatinine, hematuria. 
5.  
Hepatic: Increased SGOT, mild and transient; hepatic fibrosis 
and cirrhosis, more likely to occur in patients receiving long-
term continuous or daily methotrexate treatment. 
6.  
Neurologic: Encephalopathy, more commonly with multiple 
intrathecal doses and in patients who have received cranial 
irradiation; tiredness, weakness, confusion, ataxia, tremors, 
irritability, seizures, coma.  Acute side effects of intrathecal 
methotrexate may include: dizziness, blurred vision, headache, 
back pain, nuchal rigidity, seizures, paralysis, hemiparesis. 
7.  
Allergic: Fever and chills; rash; urticaria; anaphylaxis. 
8.  
Ocular: Conjunctivitis; excessive lacrimation; cortical blindness 
has occurred with high doses. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
71 
9.  
Pulmonary: Pneumonitis, pulmonary fibrosis, cough, dyspnea. 
10. 
Other: Malaise; osteoporosis (aseptic necrosis of the femoral 
head); hyperuricemia; reversible oligospermia. 
8.2.12 
Nursing Implications 
1. 
Administer antiemetics as indicated. 
2. 
Monitor for hematologic toxicity. 
3. 
Observe for gastrointestinal toxicity (stomatitis, diarrhea); offer 
symptomatic care. 
4. 
For patients who are to begin methotrexate therapy at a dose 
of 1 g/m² or greater: Proper functioning of kidneys must be 
documented.  Proper hydration and alkalinization of urine must 
be maintained. 
5. 
Instruct patient to use sunscreen lotion or cream when 
exposed to the sun. 
6. 
Scheduling for methotrexate serum levels may be necessary in 
high dose situations. 
7. 
Time of administration of infusions may be critical - should be 
carefully monitored. An infusion pump may be necessary. 
8. 
High dose methotrexate (see route of administration) must be 
given with leucovorin rescue.  Educate patient and significant 
other about importance of compliance with medication 
schedule.  There may be financial implications due to the high 
cost of the drug. 
8.2.13 
References 
Alkins SA, Byrd JC, Morgan SK et al.  Anaphylactoid reactions to 
methotrexate. Cancer 1996; 77:2123-2126. 
Anon:  Drugs of choice for cancer chemotherapy.  Med Lett Drugs 
Ther 1997; 39:21-28. 
Anon: NCI Investigational Drugs Pharmaceutical Data. National 
Cancer Institute, Bethesda, MD, 1988. 
Athanikar N, Boyer B, Deamer R et al. Visual compatibility of 30 
additives with a parenteral nutrient solution.  Am J Hosp Pharm 1979; 
36:511-513. 
Benvenuto JA, Anderson RW, Kerkof K et al. Stability and 
compatibility of antitumor agents in glass and plastic containers.  Am J 
Hosp Pharm 1981; 38:1914-1918. 
Bleyer WA: The clinical pharmacology of methotrexate.  Cancer 1978; 
41:36. 
Evans WE, Crom WR, Abromowitch M et al. Clinical 
pharmacodynamics of high-dose methotrexate in acute lymphocytic 
leukemia.  N Engl J Med 1986; 314(8):471-477. 
Jolivet J, et al. The pharmacology and clinical use of methotrexate.  N 
Engl J Med 1983; 309: 1094-1104. 

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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
72 
McRae MP, King JC. Compatibility of antineoplastic, antibiotic and 
corticosteroid drugs in intravenous admixtures.  Am J Hosp Pharm 
1976; 33: 1010-13. 
Product Information: Methotrexate. Immunex Corporation, Seattle, 
WA, 1998. 
Shen DD, Azarnoff DL. Clinical pharmacokinetics of methotrexate. 
Clin Pharmacokinet 1978; 3: 1-13. 
8.3 
Fluorouracil (Infusional) 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.3.1 
Other Names 
5-Fluorouracil, 5-FU, Adrucil, Efudex. NSC #19893. 
8.3.2 
Classification 
Antimetabolite. 
8.3.3 
Mode of Action 
Fluorouracil is a pyrimidine antagonist that interferes with nucleic acid 
biosynthesis.  The deoxyribonucleotide of the drug inhibits thymidylate 
synthetase, thus inhibiting the formation of thymidylic acid from 
deoxyuridylic acid, thus interfering in the synthesis of DNA.  It also 
interferes with RNA synthesis. 
8.3.4 
Storage and Stability 
Stable for prolonged periods of time at room temperature if protected 
from light.  Inspect for precipitate; if apparent, agitate vial vigorously or 
gently heat to not greater than 140oF in a water bath.  Do not allow to 
freeze. 
8.3.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.3.6 
Preparation 
Preparation of standard regimens should follow site standards.  
For patients receiving regimens on CTSU protocols, protocol specific 
preparation must be followed. 
8.3.7 
Administration 
The drug will be given by protracted venous infusion. 
8.3.8 
Incompatibilities 
Incompatible with doxorubicin and other anthracyclines.  When giving 
doxorubicin IV push or through a running IV, flush line before giving 

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fluorouracil.  May form precipitate with fluorouracil in some 
concentrations. 
8.3.9 
Availability 
Commercially available in 500 mg/10 mL ampules and vials, and 1 
g/20 mL,  
2.5 g/50 mL, and 5 g/100 mL vials. 
8.3.10 
Side Effects 
1. 
Hematologic:  Leukopenia, thrombocytopenia, anemia, can be 
dose limiting; less common with continuous infusion. 
2. 
Dermatologic:  Dermatitis, nail changes, hyperpigmentation, 
Hand-Foot Syndrome with protracted infusions, alopecia. 
3. 
Gastrointestinal:  Nausea, vomiting, anorexia, diarrhea, can be 
dose limiting; mucositis, more common with 5-day infusion, 
occasionally dose limiting; severe, cholera-like diarrhea which 
can be fatal when given with leucovorin. 
4. 
Neurologic:  Cerebellar Syndrome (headache and cerebellar 
ataxia). 
5. 
Cardiac:  Angina, noted with continuous infusion. 
6. 
Ophthalmic:  Eye irritation, nasal discharge, watering of eyes, 
blurred vision. 
7. 
Hepatic:  Hepatitis with hepatic infusion. 
8.3.11 
Nursing Implications 
1. 
Monitor CBC, platelet counts. 
2. 
Administer antiemetics as indicated. 
3. 
Monitor for diarrhea.  Encourage fluids and treat 
symptomatically - may be dose limiting. 
4. 
Assess for stomatitis - oral care recommendations as 
indicated. 
5. 
Monitor for neurologic symptoms (headache, ataxia). 
6. 
Patients on continuous infusions may need instruction 
regarding central IV catheters and portable IV or IA infusion 
devices. 
7. 
Inform patient of potential alopecia. 
8.3.12 
References 
Hansen R, Quebbeman E, Ausman R, et al.  Continuous systemic 5-
fluorouracil in advanced colorectal cancer:  Results in 91 patients.  J 
Surg Oncol 40:177-181, 1989. 
Freeman NJ, Costanza ME.  5-Fluorouracil-associated cardiotoxicity.  
Cancer 61:36-45, 1988. 

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8.4 
Doxorubucin 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.4.1 
Other Names 
Adriamycin, Rubex, Adriamycin RDF, Adriamycin PFS, 
hydroxydaunorubicin, hydroxydaunomycin, ADR, NSC #123127. 
8.4.2 
Classification 
Anthracycline antibiotic. 
8.4.3 
Mode of Action 
Intercalation between adjoining nucleotide pairs in the DNA helix 
causes inhibition of DNA and DNA-dependent RNA synthesis.  Free 
radical generation is responsible for cardiac toxicity.  Doxorubicin also 
inhibits topoisomerase II. 
8.4.4 
Storage and Stability 
Rubex or Adriamycin RDF intact vials are stable protected from light 
at room temperature.  Adriamycin PFS vials must be refrigerated.  
Reconstituted solutions are stable for 24 hours at room temperature 
and 48 hours under refrigeration.  The Adriamycin RDF 150 mg 
multidose vial is stable after reconstitution for 7 days at room 
temperature or 15 days if refrigerated and protected from sunlight. 
8.4.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.4.6 
Preparation 
Preparation of standard regimens should follow site standards.  
For patients receiving regimens on CTSU protocols, protocol specific 
preparation must be followed. 
8.4.7 
Administration 
Intravenously, either as a bolus injection or as a continuous infusion 
through a central venous line. 
8.4.8 
Incompatibilities 
Physically incompatible with heparin, fluorouracil, aminophylline, 
cephalothin, dexamethasone, diazepam, hydrocortisone, and 
furosemide. 

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8.4.9 
Compatibilities 
Stable with vincristine in normal saline for 5 days at room temperature 
protected from light.  Also compatible in solution with 
cyclophosphamide. 
8.4.10 
Availability 
Commercially available as powder for injection in 10, 20, 50, 100, 150 
mg vials, and as 2 mg/mL solution for injection in 10, 20, 50, and 200 
mg vials. 
8.4.11 
Side Effects 
1. 
Hematologic:  Leukopenia (dose-limiting), also 
thrombocytopenia and anemia.  Nadir 10-14 days, recovery in 
21 days. 
2. 
Dermatologic:  Alopecia, usually complete; hyperpigmentation 
of nailbeds and dermal creases; radiation recall. 
3. 
Gastrointestinal:  Nausea and vomiting, sometimes severe; 
anorexia, diarrhea; mucositis, especially with daily x 3 
schedule. 
4. 
Cardiovascular:  Arrhythmias, ECG changes; rarely sudden 
death. Congestive heart failure due to cardiomyopathy related 
to total cumulative dose; risk is greater with total doses > 550 
mg/m², mediastinal irradiation pre-existing cardiac disease, 
advanced age; risk is reduced with weekly or continuous 
infusion regimens. 
5. 
Other:  Red discoloration of urine; fever; anaphylactoid 
reaction; may enhance cyclophosphamide cystitis or 
mercaptopurine hepatotoxicity. 
6.  
Local effects:  Vesicant if extravasated; flush along vein, facial 
flush. 
8.4.12 
Nursing Implications 
1. 
Monitor CBC, platelet counts. 
2. 
Vesicant - do not extravasate.  Refer to extravasation protocol 
if inadvertent infiltration occurs. 
3. 
Advise patient of alopecia.  Instruct on how to obtain wig, 
hairpiece, etc.  Hair loss generally occurs 2-4 weeks after 
injection and is usually complete. 
4. 
Advise patient of red discoloration of urine for 24 hours after 
administration of the drug. 
5. 
Administer antiemetics as indicated. 
6. 
Assess for stomatitis and treat symptomatically.  Generally 
occurs 7-10 days after injection. 
7. 
Be aware of "Adria" flare - most common reaction consists of an 
erythematous streak up the vein.  It is associated with urticaria 

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and pruritus.  Occasionally the use of corticosteroids and/or 
antihistamines has been useful. 
8. 
Monitor for signs and symptoms of cardiomyopathy.  Calculate 
total cumulative dose with each administration. 
8.4.13 
References 
Speth PA.  Clinical pharmacokinetics of doxorubicin.  Clin 
Pharmacokinetics 1988; 15:51-31. 
Von Hoff DD, et al.  Risk factors for doxorubicin-induced congestive 
heart failure.  Ann Intern Med 1979; 91:710-717. 
Lum BL, et al.  Doxorubicin:  Alteration of dose scheduling as a 
means of reducing cardiotoxicity.  Drug Intell Clin Pharm 1985; 
19:259-264. 
8.5 
Paclitaxel 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.5.1 
Other Names 
Taxol, Onxol, Nov-Onxol, Paclitaxel Novaplus, NSC# 125973 
8.5.2 
Classification 
Antimicrotubule agent. 
8.5.3 
Mode of Action 
Promotes microtubule assembly and stabilizes tubulin polymers by 
preventing their depolarization, resulting in the formation of extremely 
stable and nonfunctional microtubules, and consequently inhibition of 
many cell functions. 
8.5.4 
Storage and Stability 
The intact vials may be stored under refrigeration or at room 
temperature.  Freezing does not adversely affect the product.  
Solutions diluted to a concentration of 0.3 to 1.2 mg/mL in normal 
saline, 5% dextrose, 5% dextrose and normal saline, or 5% dextrose 
in Ringer’s solution are stable for up to 27 hours when stored at room 
temperature and normal room light. 
8.5.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.5.6 
Preparation 
Preparation of standard regimens should follow site standards.  

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For patients receiving regimens on CTSU protocols, protocol specific 
preparation must be followed. 
8.5.7 
Administration 
Usually administered as an intravenous infusion over 3 to 24 hours 
with an in-line 0.22 micron filter.  One-hour intravenous bolus 
infusions have been used in Phase I studies. 
8.5.8 
Incompatibilities 
Avoid the use of PVC bags and infusion sets due to leaching of DEHP 
(plasticizer).  Prior administration of cisplatin may increase 
myelosuppression because of reduced clearance of paclitaxel.  
Ketoconazole may inhibit paclitaxel metabolism, based on in vitro 
data. 
8.5.9 
Availability 
A concentrated solution of 6 mg/mL in polyoxyethylated castor oil 
(Cremophor EL) 50% and dehydrated alcohol 50% is commercially 
available in 5 mL vials. 100 mg/16.7 mL and 300 mg/50 mL vials are 
also available. 
8.5.10 
Side Effects 
1. 
Hematologic:  Myelosuppression (neutropenia, leukopenia, 
thrombocytopenia, anemia). 
2. 
Hypersensitivity:  Thought to be caused by the Cremophor 
vehicle.  Minor symptoms include hypotension, flushing, chest 
pain, abdominal or extremity pain, skin reactions, pruritus, 
dyspnea, and tachycardia.  More severe reactions include 
hypotension requiring treatment, dyspnea with bronchospasm, 
generalized urticaria, and angioedema.  The majority (53%) of 
the reported reactions occurred within 2-3 minutes of initiation 
of treatment and 78% occurred within the first 10 minutes.  
Reactions usually occurred with the first and second doses. 
3. 
Cardiovascular:  Atrial arrhythmia (sinus bradycardia [usually 
transient and asymptomatic], sinus tachycardia, and 
premature beats); significant events include syncope, 
hypotension, other rhythm abnormalities (including ventricular 
tachycardia, bigeminy, and complete heart block requiring 
pacemaker placement), and myocardial infarction.  
Hypertension (possibly related to concomitant medication -- 
Dexamethasone) may also occur. 
4. 
Neurologic:  Sensory (taste changes); peripheral neuropathy; 
arthralgia and myalgia (dose-related, more common when 
colony-stimulating factors are also administered); seizures; 
mood alterations; neuroencephalopathy; hepatic 
encephalopathy; motor neuropathy; and autonomic 
neuropathy (paralytic ileus and symptomatic hypotension). 
5. 
Dermatologic:  Alopecia (universal, complete and often 
sudden, between days 14-21); injection site reactions 

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(erythema, induration, tenderness, skin discoloration); 
infiltration (phlebitis, cellulitis, ulceration, and necrosis, rare); 
radiation recall; and rash. 
6. 
Gastrointestinal:  Nausea, vomiting, diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis (neutropenic enterocolitis), 
ischemic colitis, and pancreatitis. 
7. 
Hepatic:  Increased AST, ALT, bilirubin, alkaline phosphatase; 
hepatic failure, and hepatic necrosis. 
8. 
Other:  Fatigue, headache, light-headedness, myopathy, 
elevated serum creatinine, elevated serum triglycerides, and 
visual abnormalities (sensation of flashing lights, blurred 
vision). 
8.5.11 
Nursing Implications 
1. 
Monitor CBC and platelet count prior to drug administration. 
2. 
Symptom management of expected nausea, vomiting, and 
stomatitis. 
3. 
Monitor for and evaluate abdominal pain occurring after 
paclitaxel administration (especially in severely neutropenic 
patients and in those receiving G-CSF) due to the risk of 
ischemic and neutropenic enterocolitis. 
4. 
Advise patients of possible hair loss. 
5. 
Cardiac monitoring for assessment of arrhythmias in patients 
with serious conduction abnormalities. 
6. 
Monitor liver function tests. 
7. 
Advise patient of possible arthralgias and myalgias which may 
occur several days after treatment.  Monitor for symptoms of 
peripheral neuropathy. 
8. 
Monitor for signs and symptoms of hypersensitivity reactions.  
Insure that the recommended premedications have been 
given.  Premedications (diphenhydramine, steroids, and H2 
blocker) appear to reduce the incidence and severity of 
hypersensitivity reactions but do not provide complete 
protection.  Emergency agents (diphenhydramine and 
epinephrine) should be available. 
9. 
Evaluate IV site regularly for signs of infiltration.  It is not 
known if paclitaxel is a vesicant; however, the CremophorsEL 
vehicle for this drug can cause tissue damage.  
10. 
In-line filtration with a 0.22 micron filter should be used. 
8.5.12 
References 
Rowinsky EK, Casenave LA, Donehower RC.  Taxol:  A novel 
investigational microtubule agent.  J Natl Cancer Inst 1990; 82:1247-
1259. 

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Gregory RE, DeLisa AF.  Paclitaxel:  A new antineoplastic agent for 
refractory ovarian cancer.  Clin Pharm 1993; 12:401-415. 
Rowinsky EK, Eisenhauer EA, Chaudry V, et al.  Clinical toxicities 
encountered with paclitaxel.  Semin Oncology 1993; 20:1-15. 
Walker FE.  Paclitaxel:  Side effects and patient education issues.  
Semin Oncology Nurs 1993; 9 (suppl 2):6-10. 
8.6 
Epirubicin 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.6.1 
Other Names 
Ellence,  4'epidoxorubicin hydrochloride, IMI-28, ADR 143, NSC 
#256942 
8.6.2 
Classification 
Anthracycline antibiotic. 
8.6.3 
Mode of Action 
Intercalation between adjoining nucleotide pairs in the DNA helix 
causes inhibition of DNA and DNA-dependent RNA synthesis.  Free 
radical generation is responsible for cardiac toxicity.  Epirubicin also 
inhibits topoisomerase II.  
8.6.4 
Storage and Stability 
This product is available as a solution and should be stored under 
refrigeration. 
8.6.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.6.6 
Preparation 
Preparation of standard regimens should follow site standards.  
For patients receiving regimens on CTSU protocols, protocol specific 
preparation must be followed. 
8.6.7 
Administration 
Intravenously into the side arm of a freely flowing solution of normal 
saline or D5W over 3-5 minutes.  If the patient has a venous access 
device, epirubicin may be diluted further for infusion. 
8.6.8 
Incompatibilities 
Heparin and dexamethasone are incompatible.  Alkaline solutions (pH 
> 8) cause decomposition of epirubicin and result in a color change of 
the drug from red to blue-purple. 

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8.6.9 
Availability 
Commercially available in 50 mg /25 mL and 200 mg/100 mL vials for 
injection from Pfizer Oncology. 
8.6.10 
Side Effects 
1. 
Hematologic:  Severe myelosuppression, dose limiting, with 
nadir of WBC about 12-15 days after treatment; modest 
thrombocytopenia with nadir 8-11 days after treatment. 
2. 
Gastrointestinal:  Significant nausea and vomiting, diarrhea, 
mucositis, anorexia. 
3. 
Dermatological:  Alopecia, regional phlebitis, nail pigmentation 
(rare), vesicant. 
4. 
Cardiovascular:  Previous radiation of marrow-producing bones 
and/or preventive chemotherapy with anthracene or 
anthracycline drugs lowers the cumulative dose that may cause 
the development of CHF.  Cardiotoxicity, manifested as 
tachycardia, premature ventricular beats, or flattening T-waves, 
may occur with cumulative doses > 700 mg/m².  With 
cumulative doses > 1000 mg/m², left ventricular failure may 
occur (clinical CHF). 
5. 
Neurological:  Asthenia (rare). 
6. 
Other:  Fever, development of secondary AML or MDS. 
8.6.11 
Nursing Implications 
1. 
Check CBC, differential, and platelets, and bilirubin before 
treatment. 
2. 
Give supportive care for nausea and vomiting; administer 
antiemetic therapy. 
3. 
Monitor for development of congestive heart failure (basilar 
rales, S3, gallop dyspnea). 
4. 
Advise patient regarding risk of infection and bleeding. 
5. 
If extravasation occurs, treat with ice for 30 minutes 3-4 times 
daily. 
8.6.12 
References 
Cersosimo RJ, Hong WK.  Epirubicin:  A review of the pharmacology, 
clinical activity and adverse effects of an Adriamycin analogue.  J Clin 
Oncol 1986; 4:425. 
Ganzina F.  4'-epi-doxorubicin, a new analogue of doxorubicin:  A 
preliminary overview of preclinical and clinical data.  Cancer Treat 
Rev 1983; 10:1-22. 
Robustelli D, Cuna G, et al.  Clinical evaluation of 4'-epi-doxorubicin in 
advanced solid tumors.  Invest New Drugs 1983; 1:349-353. 

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Walde D, et al.  High dose epirubicin in previously untreated patients 
with advanced metastatic cancer:  A phase I study.  Proc Am Soc Clin 
Oncol 1988; 7:73. 
8.7 
Docetaxel 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.7.1 
Other Names 
Taxotere, RP 56976, NSC #628503. 
8.7.2 
Classification 
Antimicrotubule agent. 
8.7.3 
Mode of Action 
Docetaxel, a semisynthetic analog of taxol, promotes the assembly of 
tubulin and inhibits microtubule depolymerization.  Bundles of 
microtubules accumulate and interfere with cell division. 
8.7.4 
Storage and Stability 
Docetaxel is stored at 4oC protected from light.  The solvent vials may 
be stored at room temperature or at 4oC.  The premix solution is 
stable for 8 hours at room temperature (15o- 25oC) or refrigerated (at 
2o- 8oC).  The final dilution is also stable for 8 hours. (Please note that 
the company is no longer recommending that the final product be 
placed in PVC bags). 
8.7.5 
Dose Specifics 
Please refer to Appendix II for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   
If treating physician elects to use regimen other than those specified 
in Appendix II, please contact study chair. 
8.7.6 
Preparation 
Just prior to use, allow the docetaxel vial to reach room temperature 
for 5 minutes.  Add the entire contents of the ethanol diluent vial and 
mix by gently rotating the vial for 15 seconds.  Allow to stand for 5 
minutes at room temperature, and check that the solution is 
homogeneous and clear (persistent foam is normal).  The resulting 
solution contains 10 mg/mL of docetaxel.  Please note that the 
solution contains 15% overfill.  Dosing amounts should be based in 
the concentration per extractable volume, not the total volume of the 
vial.  The desired dose is diluted in D5W or NS.  The volume of the 
infusion should be adjusted in order to have a final docetaxel 
concentration of between 0.3 mg/mL and 0.9 mg/mL. Non-PVC-
containing intravenous infusion bags and administration sets should 
be used to avoid patient exposure to the plasticizer DEHP. 
8.7.7 
Administration 
Rev. 9/06 

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Docetaxel has been administered as a 1 to 24 hour infusion.  A 
peristaltic infusion pump is recommended. 
8.7.8 
Incompatibilities 
Intravenous bags and administration sets containing DEHP (di-[2-
ethylexyl] phthalate).  No further information available. 
8.7.9 
Availability 
Docetaxel is commercially available in single-dose vials containing 20 
mg (0.5 ml) or 80 mg (2.0 ml) docetaxel (anhydrous). 
8.7.10 
Side Effects 
1. 
Cardiac:  arrhythmias, pericardial effusions, palpitations. 
2. 
Hematologic: dose-related neutropenia, leukopenia, 
thrombocytopenia, anemia, hypoglycemia, hypernatemia. 
3. 
Gastrointestinal: nausea and vomiting, diarrhea, oral 
mucositis, pancreatitis, esophagitis. 
4. 
Neurologic:  reversible dysthesias or paresthesias, peripheral 
neuropathy, mild or moderate lethargy or somnolence, 
headache, seizures. 
5. 
Hypersensitivity: hypersensitivity (local or general skin rash, 
flushing, pruritus, drug-fever, chills and rigors, low back pain), 
severe anaphylactoid reactions (flushing with hypo- or 
hypertension, with or without dyspnea). 
6. 
Dermatologic: alopecia, desquamation following localized 
pruriginous maculopapular eruption, skin erythema with 
edema, extravasation reaction (erythema, swelling, 
tenderness, pustules), reversible peripheral phlebitis, nail 
changes. 
7. 
Hepatic: increased transaminase, alkaline phosphatase, 
bilirubin; hepatic failure; hepatic drug reaction. 
8. 
Pulmonary: dyspnea with restrictive pulmonary syndrome, 
pleural effusions. 
9. 
Other: asthenia, dysgeusia, anorexia, conjunctivitis, arthralgia, 
muscle aches, myopathy, peripheral edema, fluid retention 
syndrome, ascites, flu-like symptoms, fever. 
8.7.11 
Nursing Implications 
1. 
Monitor CBC and platelet count prior to drug administration. 
2. 
Symptom management of expected nausea, vomiting, and 
mucositis. 
3. 
Advise patients of possible hair loss. 
4. 
Monitor for signs and symptoms of hypersensitivity reactions.  
Insure that recommended premedications are given. 
5. 
Monitor liver function tests. 
Rev. 9/06 

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6. 
Evaluate site regularly for signs of infiltration. 
7. 
Monitor for symptoms of peripheral neuropathy. 
8. 
Monitor for signs of fluid retention and cutaneous reactions. 
1.1.1 
References 
Investigator’s Brochure: Docetaxel. Rhone-Poulenc Rorer, June 14, 1995. 
Pazdur R, et al.  Phase I trial of Taxotere; Five-day schedule.  J Natl Cancer Inst 
84:1781-8, 1992. 
Pazdur R, et al.  Phase I trial of Taxotere (RP56976).  Proc Am Soc Clin Oncol  
11:111, 1992. 
Burris H, et al.  A phase I clinical trial of Taxotere as a 6-hour infusion repeated 
every 21 days in patients with refractory solid tumors.  Proc Am Soc Clin Oncol  
11:137, 1992. 
Bissett D, et al.  Phase I study of Taxotere (RP56976) given as a 24-hour 
infusion.  Proc Am Assoc Cancer Res  33:526, 1992. 
Bruno R, et al.  Clinical pharmacology of Taxotere (RP56976) given as a 1-2 
hour infusion every 2-3 weeks.  Proc Am Assoc Cancer Res  33:261, 1992. 
DeValeriola D, et al.  Phase I pharmacokinetic study of Taxotere (RP56976) 
administered as a weekly infusion.  Proc Am Assoc Cancer Res  33:1563, 1992. 
8.8 
Tamoxifen 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.8.1 
Other Names 
Nolvadex, tamoxifen citrate, NSC# 180973 
8.8.2 
Classification   
Hormone antagonist (antiestrogen). 
8.8.3 
Mode of Action 
Tamoxifen and its metabolites possess antiestrogenic activity due to 
their ability to compete with estradiol for binding to receptors in the 
cells of tumors that contain high amounts of estrogen receptors (such 
as breast cancer).  The tamoxifen-estrogen receptor complex is 
translocated from the cytoplasm of cancer cells to the nucleus where 
it reduces DNA synthesis and cellular responses to estrogen.  
Tamoxifen also displays mild estrogenic activity and induces secretion 
of transforming growth factor beta (TGF-beta), which has inhibitory 
effects on many types of epithelial cells. 
8.8.4 
Storage and Stability 
Tamoxifen is stored at room temperature protected from light. 
8.8.5 
Dose Specifics 
Please refer to Appendix III for standard regimen dose and schedule.   
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule.   

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If treating physician elects to use regimen other than those specified 
in Appendix III, please contact study chair. 
8.8.6 
Preparation 
Not applicable, tablet is ready for administration. 
8.8.7 
Administration 
Oral. 
8.8.8 
Incompatibilities 
Tamoxifen is a potent inhibitor of hepatic cytochrome P450 mixed 
function oxidases (MFO). The effect of tamoxifen on the metabolism 
and excretion of other drugs requiring MFO for activation is unknown.  
Phenobarbital decreased tamoxifen serum level significantly in one 
patient. Concomitant bromocriptine therapy has been shown to 
elevate serum tamoxifen levels Tamoxifen may potentate the 
anticoagulant effects of warfarin. 
8.8.9 
Availability 
Tamoxifen is commercially available in 10 mg and 20 mg tablets. 
8.8.10 
Side Effects 
1.  
Hematologic: Thrombocytopenia, usually mild and transient, 
leukopenia, anemia. 
2.  
Dermatologic: Rash, erythema. 
3.  
Gastrointestinal: Nausea, vomiting, anorexia (may lead to 
weight loss), diarrhea or constipation, distaste for food. 
4.  
Genitourinary: Vaginal bleeding or discharge, menstrual 
changes (amenorrhea, menstrual irregularities), pruritus 
vulvae.  
5.  
Hepatic: Increased liver enzymes, cholestasis, increased 
bilirubin, and fatty changes in the liver. 
6.  
Neurologic: Depression, dizziness, lightheadedness, 
headache, confusion, lassitude, and syncope. 
7.  
Cardiovascular: Hot flashes, thrombophlebitis, 
thromboembolism, pulmonary embolism, fluid retention and 
edema. Thrombotic events, DVT, clotting factor abnormalities. 
8.  
Ocular: Retinopathy, corneal opacity, slight increased risk of 
cataracts; corneal scarring and retinal changes have been 
reported. 
9. 
Metabolic: Hypercalcemia. 
10. 
Other: Tumor "flare" may occur in the first month of therapy, 
manifested as an increase in tumor-related symptoms, such as 
bone pain, increase in tumor size, erythema.  Weight gain, 
fluid retention, and edema. 

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11. 
Effects in pregnancy: classified as Category D; women should 
not become pregnant while taking tamoxifen. 
12. 
Secondary cancers: Tamoxifen increases the risk for uterine 
cancer and the possibility of death from this disease.  Patients 
receiving tamoxifen should have routine gynecologic exams 
and report any menstrual irregularities, abnormal vaginal 
bleeding, changes in vaginal discharge and/or pelvic pain or 
pressure.  Tamoxifen may possibly increase the risk for 
gastrointestinal cancers. 
8.8.11 
Nursing Implications 
1. 
Monitor carefully for tumor flare reactions. 
2. 
Teach patients and families to recognize signs and symptoms 
of hypercalcemia. 
3. 
Advise patient of potential vaginal bleeding and menstrual 
changes, hot flashes. 
8.8.12 
References 
Legha SS.  Tamoxifen in the treatment of breast cancer.  Ann Intern 
Med  1988; 109:219-228. 
Love RR.  Tamoxifen therapy in primary breast cancer:  Biology, 
efficacy and side effects.  J Clin Oncol  1989; 7:803-815. 
Kaiser-Kupfer MI, Lippman ME.  Tamoxifen retinopathy.  Cancer Treat 
Rep  1978; 62:315-320. 
Lipton A, Harvey HA, Hamilton RW.  Venous thrombosis as a side 
effect of tamoxifen treatment.  Cancer Treat Rep  1984; 68:887-889. 
8.9 
Exemestane 
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.9.1 
Other names 
Aromasin®, NSC# 713563 
8.9.2 
Classification 
Steroidal aromatase inhibitor.  
8.9.3 
Mode of Action 
Exemestane irreversibly inhibits aromatase activity (approximately 
98%) and reduces plasma estrone, estradiol and estrone sulphate 
levels by 85-95%. Exemestane is 150-times more potent than 
aminoglutethimide in inhibiting aromatase. Maximal aromatase 
suppression occurs at exemestane doses of 10-25 mg.  
8.9.4 
Storage and Stability 
Exemestane is stored at room temperature protected from light.  

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8.9.5 
Dose Specifics 
Please refer to Appendix III for standard regimen dose and schedule. 
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule if this drug is used.   
8.9.6 
Preparation  
Not applicable 
8.9.7 
Administration 
Exemestane is administered orally with food. 
8.9.8 
Incompatibilities 
No clinically relevant changes in the results of clinical laboratory tests 
have been observed. There are no known drug-drug interactions 
reported.  
8.9.9 
Availability 
Exemestane is commercially available as a 25 mg tablet..  
8.9.10 
Side Effects 
1. 
Gastrointestinal: nausea, vomiting, abdominal pain, anorexia, 
diarrhea.  
2. 
Hematologic: lymphocytopenia 
3. 
Dermatologic: Hot flushes, rashes. 
4. 
Hepatic: Increased GGT, SGOT (AST), SGPT (ALT). 
5. 
Neurologic: Headache, dizziness, insomnia, depression, 
anxiety, fatigue. 
6. 
Pulmonary: Cough 
7. 
Cardiovascular: thrombophlebitis. 
8. 
Musculoskeletal: bone pain, back pain, arthralgia, limb pain  
9. 
Other: Hair thinning, sweating. 
8.9.11 
Nursing/Patient Implications 
Inform patients of potential side effects (joint/bone pain, diarrhea, 
asthenia, headache, hot flushes, nausea). 
8.9.12 
References 
http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=e
xemestane 
8.10 
Anastrozole  
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.10.1 
Other names 
Arimidex, NSC# 719344 

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8.10.2 
Classification and Chemical Information 
Non-steroidal aromatase inhibitor. 
8.10.3 
Mode of Action 
Anastrozole selectively inhibits aromatase and lowers serum estradiol 
concentrations without affecting adrenal corticosteroids or 
aldosterone. Many breast cancers have estrogen receptors, and 
growth of these tumors can be stimulated by estrogens. In 
postmenopausal women, the principal source of circulating estrogen 
is conversion of adrenally-generated androstenedione to strone by 
aromatase in peripheral tissue, with further conversion of esterone to 
estradiol. 
8.10.4 
Storage and Stability 
Stored at room temperature and protected from light.  
8.10.5 
Dose Specifics 
Please refer to Appendix III for standard regimen dose and schedule. 
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule if this drug is used. 
8.10.6 
Preparation 
Not applicable.  
8.10.7 
Route of Administration 
Oral. 
8.10.8 
Availability 
Commercially available, Anastrozole is supplied as 1mg film-coated 
tablets.  
8.10.9 
Side Effects 
1. 
Gastrointestinal: diarrhea, nausea, vomiting, abdominal pain, 
anorexia. 
2. 
Hematologic: Anemia, leukopenia (2-5%). 
3. 
Dermatologic: Hot flushes, rashes. 
4. 
Hepatic: Increased GGT, SGOT (AST), SGPT (ALT). 
5. 
Neurologic: Headache, pain, back pain, dizziness, insomnia, 
anxiety. 
6. 
Pulmonary: Increased cough, dyspnea, sinusitis, bronchitis, 
rhinitis. 
7. 
Cardiovascular: Hypertension, thrombophlebitis. 
8. 
Musculoskeletal: bone pain, back pain, arthralgia, limb pain  
9. 
Other: hair thinning, sweating. 

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NCI Update Date: December 16, 2014 
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8.10.10 
Drug Interactions 
Anastrozole does not appear to cause significant inhibition of 
cytochrome p450 mediated metabolism. Anastrozole did not alter the 
pharmacokinetics or activity of warfarin in a study of 16 male 
volunteers (Center For Drug Evaluation 2001). 
8.10.11 
Nursing/Patient Implications 
Inform patients of potential side effects (joint/bone pain, diarrhea, 
asthenia, headache, hot flushes, nausea). 
8.10.12 
References 
http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=a
nastrozole 
8.11 
Letrozole  
NOTE: 
Please refer to package insert for complete prescribing and toxicity 
information. 
8.11.1 
Other names 
Femara, NSC# 719345 
8.11.2 
Classification and Chemical Information 
Non-steroidal aromatase inhibitor. 
8.11.3 
Mode of Action 
Letrozole is an orally active highly selective, non-steroidal competitive 
inhibitor of the aromatase enzyme system. it binds to the P-450 
portion of the aromatase enzyme to lower serum estradiol 
concentrations with no clinically relevant effect on progesterone or 
corticosteroidal synthesis. Aromatase inhibitors block the aromatase 
enzyme, consequently lowering estrogen levels and thereby deprive 
the tumor of its growth stimulus. 
8.11.4 
Storage and Stability 
Stored at room temperature and protected from light. 
8.11.5 
Dose Specifics 
Please refer to Appendix III for standard regimen dose and schedule. 
If patient is participating in another CTSU trial, please refer to protocol 
specified regimen and schedule if this drug is used.   
8.11.6 
Preparation 
Not applicable.  
8.11.7 
Route of Administration 
Oral. 
8.11.8 
Availability 
Commercially available, Letrozole is supplied as 2.5 film-coated 
tablets.  

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8.11.9 
Side Effects 
1. 
Gastrointestinal: nausea, constipation, diarrhea, vomiting, 
anorexia, dyspepsia, and abdominal pain. 
2. 
Hematologic: Anemia, leukopenia. 
3. 
Dermatologic: Hot flushes, rashes. 
4. 
Hepatic: Increased GGT, SGOT (AST), SGPT (ALT). 
5. 
Neurologic: Headache, dizziness, insomnia, anxiety. 
6. 
Pulmonary: Dyspnea, cough, chest wall pain. 
7. 
Cardiovascular: Hypertension, thrombophlebitis. 
8. 
Musculoskeletal: bone pain, back pain, arthralgia, limb pain 
9. 
Other: Hair thinning, sweating. 
8.11.10 
Drug Interactions 
Co-administration of tamoxifen and letrozole decreases serum 
letrozole concentration by 38%.  
8.11.11 
Nursing/Patient Implications 
Inform patients of potential side effects (joint/bone pain, diarrhea, 
asthenia, headache, hot flushes, nausea). 
8.11.12 
References 
http://www.accessdata.fda.gov/scripts/cder/onctools/labels.cfm?GN=l
etrozole

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NCI Update Date: December 16, 2014 
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9. 
Statistical Considerations 
This section incorporates major changes made to the statistical design in November 
2008.  The revised design parallels the original design, but the design was updated to 
reflect a substantially higher rate of non-adherence with the treatment assignment than 
allowed in the original design, leading to an increase in the accrual goal for the 
randomized cohort from 4,390 to 6,860 patients.  The null and the alternative 
hypotheses and the type I error and the power are the same as in the original design.  
The assumptions on the distribution of OncoType DX Recurrence Scores (RS) and on 
the accrual rates were also updated to reflect the experience with the study so far.  The 
difference that could be detected in the low RS stratum (arm A) was also modified to 
reflect lower accrual to this group than originally expected. 
The primary endpoint is invasive disease-free survival (DFS), defined to be time from 
randomization to first event, where the first event is any of ipsilateral breast tumor 
recurrence, local recurrence, regional recurrence, distant recurrence, contralateral 
second primary invasive cancer, second primary non-breast invasive cancer (excluding 
non-melanoma skin cancers), or death without evidence of recurrence (as defined in 
reference 4). DFS is used for the primary endpoint rather than distant relapse-free 
interval (DRFI, as defined in Section 6), which was used as the primary endpoint in the 
development of the assay, because DFS is the standard endpoint for evaluating 
adjuvant treatments for breast cancer, and the important question here, as in other 
treatment studies, is whether chemotherapy results in an overall DFS benefit of sufficient 
magnitude to justify its use. Patients will be followed for distant failure following local 
recurrence. (Note: In various presentations, the primary endpoint of the analyses of the 
assay in the B-20 and B-14 studies was called DRFS, and it was called ‘distant 
recurrence’ in the NEJM paper, but the definition used is the same as DRFI here.)  DRFI 
is a key secondary endpoint, and RFI and OS as defined in Section 6 will also be 
analyzed.   
Patients being considered for this study will have their RS evaluated, either after pre-
registration (most cases) or prior to initial registration.  Patients with an RS of 11 – 25 will 
be randomized. The randomization will be stratified on tumor size (≤ 2 cm vs. > 2 cm), 
menopausal status (pre vs. post), planned chemotherapy (taxane containing or not), 
planned radiation therapy [whole breast, no boost planned vs. whole breast, boost 
planned vs. partial breast irradiation planned vs. no planned radiation therapy (for 
patients who have had a mastectomy)], and RS group (11-15 vs. 16-20 vs. 21-25, added 
mid-study), as described in Section 4. 
The overall DFS hazard rate on the tamoxifen + CMF arm of B-20 was .025 / year, which 
under an exponential distribution, gives 5-year and 10-year DFS rates of approximately 
88% and 78%.  In the preliminary results, the 5-year and 10-year DRFIs in the RS 11 – 
25 group on tamoxifen+chemo are 97% and 94%, and the 5-year and 10-year DFS rates 
are 91% and 76%.  For purposes of the calculations here, we assume exponential failure 
distributions with 5-year and 10-year DFS rates of 90% and 81% and 5-year and 10 year 
DRFI rates of 97% and 94% with chemo+hormonal therapy for the RS 11 – 25 group. 
This study uses a non-inferiority design to determine whether patients with Recurrence 
Score (RS) between 11 and 25 derive benefit from adjuvant chemotherapy. Studies 
have indicated that patients with a low RS receive little if any benefit from chemotherapy 
and patients with a high RS receive a substantial benefit.  This is biologically plausible, 
since the RS is driven primarily by genes reflecting cell proliferation.  The test of non-
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inferiority here uses a null hypothesis of no difference, as when testing for superiority, 
but with a larger type I error (one-sided 10%) and smaller type II error (5%) than usual.  
A decrease in the 5-year DFS rate from 90% with chemotherapy to 87.0% or lower on 
hormonal therapy alone would be considered unacceptable.  This difference 
corresponds to a 32.2% increase in the DFS failure hazard rate from not giving 
chemotherapy (the hazard ratio for hormones alone / chemo + hormones is 1.322).  DFS 
will be compared using a stratified log rank test, with the test stratified on the same 
factors used in the randomization (including on RS group 11-15 vs. 16-20 vs. 21-25, 
which was not added to the stratification until midway through the study).  The primary 
analysis will compare treatment groups defined by the randomized treatment 
assignment.  Patients not meeting the protocol eligibility criteria will be excluded from the 
primary comparison. The local lab’s assessment of hormone receptor status and Her2 
status will be used to determine eligibility.  A secondary analysis comparing groups 
defined by treatment received will also be performed.  Both the primary assigned 
treatment and secondary as treated comparisons need to be non-significant for a clear 
conclusion of non-inferiority of hormonal therapy alone.  
It is possible that not all patients will receive their assigned therapy.  Since the primary 
analysis will compare the randomized treatment groups, treatment non-adherence will 
dilute the treatment effect and reduce the power of this study.  Based on data available 
as of October 30, 2008, it is estimated that 17% of the patients assigned to hormonal 
therapy plus chemotherapy are not receiving chemotherapy, and 7% of the patients 
randomized to hormonal therapy alone are receiving chemotherapy.  To adjust the 
sample size to maintain adequate power for the primary comparison with these rates of 
non-adherence, an increase of 73% in the number of patients randomized relative to a 
design with 100% adherence is needed (based on the Lachin-Foulkes correction).   
The design assumes randomization of 6,860 patients with RS of 11 – 25 over 3.81 years 
(1800/year), of which it is assumed up to 5% may be ineligible for this study (so at least 
6,517 eligible patients will be enrolled).  Full information corresponds to 835 DFS events 
in the subset of eligible patients.  This is expected to occur in summer 2014 (at a median 
follow-up of about 5.8 years) if the 5-year DFS rates are 90% with chemotherapy and 
87% without, and in spring/summer 2015 (at a median follow-up of about 6.7 years) if 
the 5-year DFS rates are 90% in both arms.  These projections take into account a 2.5% 
early lost to follow-up rate (based on the number of patients withdrawing consent).  
Allowing time for data submission and review, actual analysis times could be as much as 
a year later.  Based on information available on this study through October 7008, 61% of 
the pre-registered patients have RS 11-25 and are randomized, 13% have RS < 11 and 
are registered to arm A, 16% have RS > 25 and are registered to arm D, and 10% are 
not enrolled on any of the arms.  Thus up to 11,246 patients may need to be screened to 
give the required number of randomizations.   
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee (DMC). 
The DMC meets twice each year. The first interim analysis will be performed at the first 
DMC meeting when at least 25% of the total planned number of DFS events (209 events 
in the primary analysis subset) has been reported. Interim analyses will be performed for 
each subsequent DMC meeting until either the criteria for early stopping are met or the 
total planned number of DFS events has been reported, except that a scheduled interim 
analysis will not be performed if the increment in the information since the previous 
interim analysis is less than 10% of the total planned information. At each interim 
analysis (and at the final analysis), the stratified log rank test statistic will be computed. 
The stopping boundary for rejecting non-inferiority will be based on a truncated version 
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of the Lan- Demets error spending rate function corresponding to an O’Brien-Fleming 
shaped boundary with an overall one-sided type I error of 10%. At early analyses, the 
boundary will be truncated at a level corresponding to a one-sided nominal significance 
of 0.002. The boundary function will be computed to maintain the type I error rate 
adjusting for the effects of the truncation and the effects of the early stopping in favor of 
non-inferiority, discussed below. If the boundary is crossed at an interim analysis or at 
the final analysis, then the hypothesis of non-inferiority will be rejected. If the criteria for 
rejecting the hypothesis of non-inferiority are not met, then it will be concluded that 
hormonal therapy alone is not inferior to combined chemo+hormonal therapy. 
To allow for early stopping in favor of non-inferiority, this study will also be monitored 
using conditional power for the primary assigned treatment comparison above and using 
repeated confidence interval (RCI) methodology. At each interim analysis, the 
conditional power of the logrank test for the primary comparison at a type I error rate of 
10% (one-sided) will be computed using simulations (incorporating the estimated 
distribution of treatment non-adherence). The two-sided 95% RCI on the log hazard ratio 
(for received hormones alone vs. received chemo + hormones), will also be computed. 
Since ITT and as treated analyses have well-known potential biases in the presence of 
treatment non-adherence, the hazard ratio in the subpopulation that would receive the 
assigned treatment if assigned to either arm will be estimated using a full mixture 
likelihood approach (Cuzick et al, JRSSB, 69:565-588, 2007) and the RCI obtained by 
inverting the corresponding likelihood ratio test.  The RCI will use the critical value from 
the O’Brien-Fleming error spending rate function with an overall one-sided 2.5% error 
rate. If the conditional power of the assigned treatment analysis is < 10% and the upper 
limit of the RCI lies below the minimum unacceptable log ratio of log(1.322), then the 
study will be stopped in favor of non-inferiority. This monitoring rule has deliberately 
been chosen to be conservative, since the results must be convincing that the 
conclusion of non-inferiority is based on an adequate amount of information rather than 
on an underpowered comparison. 
Accrual rates, the distribution of Recurrence Scores and treatment adherence rates will 
continue to be closely monitored throughout the study.  If there are significant deviations 
from the assumptions stated above, then design modifications to ensure that adequate 
power will be available will be considered by the Steering Committee.  If the 
modifications needed are not feasible, then early termination of this study will be 
discussed with the Steering Committee, the Breast Intergroup and CTEP.  These rates 
will also be reported to the DMC at every DMC meeting while this study is ongoing, and 
the DMC may also recommend changes to the design or early termination of this study.   
At the time of the final analysis, DRFI will also be compared using a stratified log rank 
test with one-sided type I error of 10%.  Under the accrual, follow-up and adherence 
assumptions given above, the DRFI test will have 95% power to detect a difference in 
DRFI corresponding to 5-year DRFI rates of 97% on chemo+hormonal therapy vs. 
95.2% on hormonal therapy alone.  This analysis requires 284 DRFI failures in the 
subset of eligible patients.  Note that in this analysis, patients who die without developing 
distant (breast cancer) metastases are censored at the time of death, and other 
intervening DFS events (eg local-regional recurrence) are ignored.  While ideally this 
study would include an early stopping rule based on differences in DRFI, the expected 
number of events during the accrual period is too low to provide a meaningful stopping 
rule, and once accrual is completed, the release of results will be based on the primary 
endpoint. 
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Survival will also be compared.  Using a stratified log rank test with one-sided type I 
error of 10%, at a time when 443 deaths have been observed, there would be 95% 
power to detect a difference in survival corresponding to 5-year survival rates of 95% on 
chemo+hormonal therapy vs. 92.8% on hormonal therapy alone.   
Because of the high non-adherence with treatment assignment, estimated effects from 
the assigned treatment analyses will be biased towards no difference.  Multiple analyses 
will be performed to estimate the actual effects of chemotherapy.  These analyses will 
include comparing groups by treatment received (the as treated analysis), comparing 
treatments excluding the patients not receiving their assigned treatments (per protocol 
analysis), and newer statistical methods for estimating causal effects of treatment.  Cox 
proportional hazards models stratified on the randomization stratification factors 
(including on RS group 11-15 vs. 16-20 vs. 21-25, which was not added to the 
stratification until midway through the study) will be used to estimate the treatment 
hazard ratios for the as treated and per protocol analyses.  Details of the causal 
inference methods will be given in the statistical analysis plan for the study.   
The interaction of the treatment effect with RS will also be examined for each of the 
endpoints within the various estimation methods.  Smoothing spline methods (34) will be 
used to estimate the treatment hazard ratio as a function of RS and to test for treatment 
by RS interaction.  One analysis will just analyze the patients in the randomized group 
(RS 11 – 25).  A second analysis will be done estimating the failure rates as a function of 
RS separately in the chemo and no chemo groups.  This analysis will use patients from 
Arms A and B to estimate the relationship without chemotherapy and patients from arms 
C and D to estimate the relationship with chemotherapy.  This analysis should lead to 
more precise estimates of the relationships at the extremes of the intermediate group 
than the analysis limited to the RS 11 – 25 group.  However, the question of whether 
there could be different patient selection in the three groups, potentially leading to biases 
in the second analysis, will also need to be considered. 
Another secondary objective is to validate whether patients with Recurrence Scores <11 
(Arm A) have failure rates that are low enough that adjuvant chemotherapy is unlikely to 
be of much absolute benefit.  Based on experience through October 7008, 13% of the 
pre-registered entries are RS < 11 and are being enrolled for follow-up on arm A. 
Assuming 11,284 patients are pre-registered and 95% of the registered patients are 
eligible, then 1,394 eligible patients would be expected to be enrolled and followed on 
arm A.  Based on data from NSABP B-20 and B-14, it is expected that the 10-year DRFI 
rate will be about 95% and the 10-year DFS rate will be between 80% and 85%.  The 
null hypothesis of a 10-year DRFI rate of 95% will be tested by fitting an exponential 
model and using the Wald test statistic for the log hazard rate.  With 1,394 eligible 
patients entered over 3.81 years and 3.5 years of additional follow-up, a one-sided test 
with type I error 2.5% will have power of at least 85% for the alternative that the 10-year 
DRFI rate is 93%.  Full information for this test is 75 distant recurrence failures. 
All patients with an elevated Recurrence Score > 25 (Arm D) who are assigned to 
receive chemotherapy will also be followed for relapse and survival. This will provide an 
extremely valuable resource for further correlative studies, and will be required for 
achieving the second primary objective (2.1.2) of evaluating emerging "Cancer Clinical 
Tests" as they develop. Identifying patients with a high Recurrence Score (>25) who 
relapse despite adjuvant chemotherapy will be just as informative as identifying patients 
with a low RS (<11) who relapse without chemotherapy. The ability to evaluate emerging 
future "Cancer Clinical Tests" will only be possible if outcome data is collected for all 
patients enrolled in all arms (A-D) of the trial. 

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For objective 2.2.4, the prognostic significance of the genomic variables (overall RS and 
the individual gene group scores for proliferation, HER2, ER, invasion, and other genes) 
will be evaluated by fitting proportional hazards regression models containing standard 
factors such as tumor size, hormone receptor status and tumor grade in addition to the 
genomic variables.  The endpoint for the primary analyses will be DRFI, and models 
where the log hazard ratio is linear in the genomic variables will be used for the primary 
test of significance.  For each genomic variable, the model will be fit using the standard 
factors and the genomic variable and the significance of the genomic variable will be 
determined.  Additional analyses will be done to explore the functional form of the 
relationships using penalized spline methods and other exploratory modeling 
techniques.  Joint models combining the gene group variables will also be fit to evaluate 
whether the different gene groups are of independent prognostic significance. 
ER, PgR and Her2 will be centrally evaluated.  Study eligibility (and hence whether 
cases are included in the primary analysis) will be determined by the results from the 
local labs.  Secondary analyses excluding cases that are ER and PR negative on central 
review and excluding cases that are Her2 positive on central review will be performed to 
examine the sensitivity of the results to possible misclassification of these factors by the 
local labs. 
Another objective of this study is to compare the prognostic and predictive power of 
Adjuvant! with the GHI RS and to determine if the classical information reflected in 
Adjuvant! adds significantly to RS.  The Adjuvant! continues to undergo refinement and 
enhancement, but roughly it begins by estimated 10-year breast cancer specific mortality 
(BCSM) from SEER data based on tumor size, grade, nodal status and ER status.  The 
benefit of treatment is estimated from the Oxford overview, and the effects of competing 
risks are factored in based on age and co-morbidities.  Following the methodology in 
John Bryant’s presentation at St. Gallen (2005), the Adjuvant! 10-year BCSM will be 
used to rank the risk level of the patients enrolled in this study.  The Adjuvant! risk 
rankings (ARR) will then be analyzed in a similar way to the GHI RS.  In the group of 
patients who do not receive chemotherapy (both the randomized group and the RS ≤ 10 
cohort), models for DFS and DRFI will be fit containing RS and ARR separately and 
together to compare the prognostic power of these variables separately and in 
combination with other factors.  Models with both RS and ARR will be used to determine 
whether either adds significant prognostic information to the other.  A similar analysis will 
be done in the cohort of chemotherapy treated patients.  Within the randomized group, 
analyses examining interaction of the ARR and the effect of chemotherapy, similar to 
those for RS, will also be performed.   
Return of Research Results:  The results of correlative science studies, including 
genomic studies, will require mature clinical results with at least five years of clinical 
followup, or longer. Since the research results are not anticipated to have clinical 
relevance to either the patient or their family members, these results will not be 
disclosed to the patient. If, unexpectedly, results are obtained that may have clinical 
relevance, IRB review and approval will be sought regarding the most appropriate 
manner of disclosure and whether or not validation in a CLIA certified setting is required. 
Research data will not be shared with individual patients when the data are generated. 
Sharing of research data with individual patients may occur when data have been 
validated by multiple studies, and testing done in CLIA-approved laboratories. The 
results of the research relative to objective 2.11 (the primary clinical objective) and 2.21 
(a secondary clinical objective) will be released by the ECOG-ACRIN Data Monitoring 
Committee (DMC) in accordance with the ECOG-ACRIN DSMC Policies and Procedures 

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95 
and with the criteria stipulated in the statistical section of the protocol. Use of tissue and 
clinical information for objective 2.12 (specimen bank) will require review by the PACCT 
Correlative Science Committee (as described in Appendix- VIII). Release of data 
regarding secondary objectives (2.21, 2.22, and 2.23) will require that a sufficient 
amount of time elapsed to achieve the primary objective, that the data analysis and 
review has been completed, and that the ECOG-ACRIN statistician has written a 
technical report describing the results. Standard procedures described in the ECOG-
ACRIN DSMC Policies and Procedures will be followed in order to safeguard against the 
inadvertent release of data. 
Based on previous data from E2197, the anticipated accrual in subgroups defined by 
gender and race is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
256 
0 
256 
Not Hispanic or Latino 
10992 
0 
10992 
Ethnic Category: Total of all subjects 
11248 
0 
11248 
Racial Category 
American Indian or Alaskan Native 
27 
0 
27 
Asian 
151 
0 
151 
Black or African American 
857 
0 
857 
Native Hawaiian or other Pacific Islander 
4 
0 
4 
White 
10209 
0 
10209 
Racial Category: Total of all subjects 
11248 
0 
11248 
The accrual targets in individual cells are not large enough for definitive treatment 
comparisons to be made within these subgroups.  Therefore, overall accrual to the study 
will not be extended to meet individual subgroup accrual targets. 
Quality of Life Analysis Plan 
Perceived cognitive function as assessed by the FACT-Cog Version 3 will be used as 
the primary quality of life endpoint. The primary question for the Quality of Life 
component is to assess differences in perceived cognitive impairment among women 
randomized to receive hormonal treatment alone (Arm B) versus chemotherapy + 
hormonal treatment (Arm C). Participants receiving treatment on Arms A and D will also 
complete the Quality of Life assessment. Secondary analyses will examine whether 
participants assigned to the Secondary Study Group are similar to participants receiving 
comparable treatment through the Primary Study Group with regard to patient-reported 
outcomes measures. We will allow total accrual of 1,000 participants to the Quality of 
Life component of this trial. To ensure that we have adequate power to examine 
differences between Arms B and C, we will monitor accrual to the Primary Study Group 
to ensure an adequate sample size. If needed, we will close the Quality of Life 
component to accrual from participants on Arms A and D if we do not achieve 
anticipated accrual to the Primary Study Group.
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Primary endpoint: 
• 
Comparison of FACT-Cog Perceived cognitive impairment scores between 
participants on Arm B and Arm C at 3 month assessment  
Secondary endpoints: 
• 
Comparison of FACT-Cog scores between Arms B and C at 3, 12, 18, 24 and 36 
months 
• 
Differences in FACT-Cog change scores from randomization to 3, 6, 12, 18, 24 
and 36 months 
• 
Differences between Arms B and C on other patient-reported outcomes 
measures 
• 
Differences between participants receiving hormonal treatment alone (Arm B 
versus Arm A) on patient-reported outcomes measures 
• 
Differences between participants receiving chemotherapy followed by hormonal 
treatment (Arm C versus Arm D) on patient-reported outcomes measures 
FACT-Cog summary scores, Version 3 scoring 
 
 
 
 
  
  
N 
Mean 
SD 
Median 
Pre-tx 
(n = 80) 
FACT-Cog Perceived Cognitive Impairments (0-80) 
78 
64.57 
12.16 
67.2 
FACT-Cog Impact on QOL (0-16) 
78 
13.95 
3.58 
16 
FACT-Cog Comments from Others (0-16) 
78 
14.85 
1.85 
16 
FACT-Cog Perceived Cognitive Abilities (0-36) 
74 
26.25 
6.22 
26.4 
Cycle 4 Day 1 
(n = 79) 
FACT-Cog Perceived Cognitive Impairments (0-80) 
77 
57.56 
16.18 
62.2 
FACT-Cog Impact on QOL (0-16) 
76 
12.89 
4.25 
15 
FACT-Cog Comments from Others (0-16) 
77 
14.46 
2.10 
16 
FACT-Cog Perceived Cognitive Abilities (0-36) 
75 
26.04 
7.07 
27 
6 month post- 
T1 
(n = 64) 
FACT-Cog Perceived Cognitive Impairments (0-80) 
64 
58.26 
14.63 
60.6 
FACT-Cog Impact on QOL (0-16) 
64 
13.48 
3.83 
15 
FACT-Cog Comments from Others (0-16) 
63 
14.24 
2.76 
16 
FACT-Cog Perceived Cognitive Abilities (0-36) 
64 
28.18 
5.67 
28.3 
NOTE: 
 Data not available for 5 newly created items (2 perceived cognitive function, 1 
comments from others, 2 perceived cognitive 
As of November 3, 2009, 5408 of the planned 6860 patients have been randomized, 
leaving 1452 remaining to be randomized to arms B (hormonal therapy alone) and C 
(chemo + hormonal therapy) in the TAILORx primary study group.  At the current rate, 
the accrual goal should be reached in early August, 2010.  During that period, it is 
projected that an additional 800 patients should be enrolled in the secondary study 
groups.  The potential number of participants in the QOL evaluation will depend on how 
quickly the amendment is activated and approved by IRBs.  
The primary analysis will compare arms in the ‘per-protocol’ population, with cases not 
adhering to the chemo assignments excluded.  Secondary analyses comparing all 
patients as treated and all patients as assigned (ITT) will also be examined.  Current 
data suggest 17% of the patients assigned to chemo are not receiving it and 7% of the 
patients assigned to hormones alone are receiving chemo. Since enrollment and 
baseline assessment for the cognitive and QoL evaluations will occur before chemo 
 

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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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adherence status is definitively known, the enrollment requirements will be increased by 
a factor of 1/0.85=1.176.  So far, 62% of the randomized participants are post-
menopausal and 38% are pre-menopausal. 
The primary analysis to determine the effects of chemotherapy will use linear mixed 
models (as implemented for example in SAS PROC MIXED) to perform repeated 
measures regression analysis of the follow-up evaluations, with the baseline evaluation 
included as a covariate.  Initially, a model allowing separate means for each treatment at 
each assessment will be used, but more parsimonious models for the changes over 
assessments will be considered.  One particular model that will be examined is a 
piecewise linear model allowing a change in slope at the end of chemo.  The primary 
analysis will treat missing data as missing at random, but sensitivity analyses using 
selection models to allow for various assumptions about the relationship between 
probability of missing data and cognitive function will also be analyzed.  Power 
calculations will be based on ordinary t-tests without considering the adjustment for the 
baseline evaluation.  This should give a conservative approximation to the analysis 
adjusting for baseline levels, if there is a reasonable degree of correlation between the 
baseline and follow-up levels and if missing follow-up information is missing at random.   
The primary endpoint of cognitive function at 3 months will be evaluated using the 
FACT-COG.  The primary FACT-COG evaluation will be the difference in the 3-month 
‘Perceived Cognitive Impairments’ scale.  In the pilot data in the table above, there was 
an average drop of 6-7 points from baseline to cycle 4 of chemotherapy and to 6 
months, with an average population standard deviation of about 15.  The correlation 
between the baseline and follow-up evaluations was also 0.5 to 0.6.  With 235 patients 
per arm, a t-test comparing the 3-month evaluations will have 90% power for a mean 
difference of 4.5 points (0.3 standard deviations), allowing a two-sided type I error of 5%.  
Within the postmenopausal and premenopausal subsets, there will be 90% power to 
detect a mean difference of 5.7 and 7.35 points (0.38 and 0.49 standard deviations), 
respectively.  Because of the correlation of the baseline and 3-month evaluations, the 
regression adjustment for the baseline evaluation should increase the power of these 
comparisons.  We assume up to 10% of the cases may have incomplete information 
through the 3 month evaluation, so 522 patients are needed to give 235/arm analyzable.  
ECOG-ACRIN has demonstrated experience in E1Z03 in collecting a longitudinal data 
set with over 94% adherence with submitting data.  This study took an active approach 
with sites being reminded in advance of scheduled assessment times.   
Assuming there is significantly larger cognitive impairment or perceived cognitive 
impairment at 3 months for patients treated with chemo, a major secondary objective is 
investigating whether this difference persists, and if not, how long it takes to recover 
from the effects of chemo.  Assuming an additional 5% drop out (giving 223/arm in the 
per-protocol analysis), a 5%-level two-sample t-test comparing the 12-months post 
randomization evaluations will have 90% power to detect mean differences in the FACT-
COG Perceived Cognitive Impairment scale of 4.65, 5.85 and 7.50 points (0.31, 0.39, 
and 0.50 population standard deviations) in the overall, postmenopausal and 
premenopausal groups.  The question of the duration of chemo-related impairment (or 
perceived impairment) will be investigated through modeling the assessments as a 
function of time in the repeated measures model.  Simultaneous confidence intervals for 
differences over time will be determined from a model where the effects are allowed to 
vary smoothly over time which gives a reasonable fit to the data. 
The impact of other variables, such as baseline characteristics and demographic factors 
will be evaluated by including them as covariates in the repeated measures regression 

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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
98 
analysis.  The relationship of cognitive function to outcomes in other domains, such as 
symptoms of depression and anxiety (assessed by the Hospital Anxiety and Depression 
Scale) and fatigue (assessed by the FACT fatigue scale) will be evaluated by including 
the values as (time-dependent) covariates in the longitudinal models. 
Allowing up to 15% of those participating in the cognitive and QOL components to be 
non-adherent with the chemotherapy assignment, and hence excluded from the primary 
per-protocol analysis, a total of 614 patients need to be enrolled from the primary study 
group.  At current rates, it is expected that 64% of the patients entering the primary and 
secondary study groups will be randomized in the primary study group.  Thus 
participation by a total of 1000 patients should be sufficient to meet the objectives of this 
project. 
Study Monitoring 
This study will be monitored by the ECOG-ACRIN Data Monitoring Committee (DMC). 
The DMC meets twice each year. For each meeting, all monitored studies are reviewed 
for safety and progress toward completion. When appropriate, the DMC will also review 
interim analyses of outcome data. Copies of the toxicity reports prepared for the DMC 
meetings are included in the study reports prepared for the ECOG-ACRIN group 
meeting (except that for double blind studies, the DMC may review unblinded toxicity 
data, while only pooled or blinded data will be made public). These group meeting 
reports are made available to the local investigators, who may provide them to their 
IRBs. Only the study statistician and the DMC members will have access to interim 
analyses of outcome data. Prior to completion of this study, any use of outcome data will 
require approval of the DMC. Any DMC recommendations for changes to this study will 
be circulated to the local investigators in the form of addenda to this protocol document. 
A complete copy of the ECOG-ACRIN DMC Policy can be obtained from the ECOG-
ACRIN Operations Office – Boston. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
99 
10. 
Tissue and Blood Specimens 
NOTE: 
REQUIREMENTS FOR PATIENTS PARTICIPATING IN EL112LAB 
(REGISTERED TO STEP 3). SEE Appendix XII. 
This section provides guidelines for the submission of biological materials as follows: 
• 
Section 10.1: For patients who have not had the Recurrence Score 
previously determined, outlines sample and form submissions associated with 
request for the Oncotype DX assay.  Submissions are during pre-registration. 
• 
Section 10.2: Applicable to all patients.  Reporting of Recurrence Score 
results; required for all patients prior to registration/randomization. 
• 
Section 10.3: Applicable to all patients. Submissions to the ECOG-ACRIN 
Central Biorepository and Pathology Facility, for purposes of central review and, 
with patient consent, banking for future research.  Review and banking objectives 
for the CBPF are summarized Appendix VIII. 
As of June 2007, ECOG-ACRIN requires all samples submitted from patients 
participating in PACCT-1/TAILORx be logged into the ECOG-ACRIN Sample Tracking 
System (STS) [see section 10.4].  
NOTE to CRAs and Pathologists: Additional guidelines for the requested pathology 
submissions (tissue and related reports) are found 
in Appendix V.  
10.1 
Pre-Registration Submissions 
This section outlines the submission of original diagnostic tumor tissue to 
establish the Oncotype DX Recurrence Score (RS status).  This is MANDATORY 
for patients with unknown Recurrence Scores (most patients).  For submissions 
required after registration/randomization from all patients, proceed to Section 
10.3. 
All residual material from tissue submitted to GHI during pre-registration will be 
forwarded to the ECOG-ACRIN Central Biorepository and Pathology Facility 
(CBPF).  Requests for return of tissue blocks for purposes of patient 
management must be directed to the CBPF. 
10.1.1 
Ordering the Oncotype Specimen Kit 
Prior to pre-registration, contact Genomic Health Customer Service 
(866-662-6897) and request the “Oncotype Specimen Kit”.     
If the kit is not available at time of pre-registration, it must be ordered 
within 24 hours following pre-registration. The kit will be shipped 
overnight and will contain instructions, a shipping kit (includes 
cryotubes and slide cassette), a mailer, and a requisition form 
containing barcode labels to place on the submitted materials. One 
Oncotype Specimen Kit and Requisition form should be completed 
per patient.  
DO NOT MIX BARCODE LABELS BETWEEN PATIENTS. 
Rev. 2/13 
Rev. 12/14 
Rev. 9/07 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
100 
Summary submission guidelines, including a draft requisition form, are 
provided in Appendix V. Oncotype DX information provided in the 
packet is located in Appendix X. 
10.1.2 
Sample and Form Submissions   
Sample submissions to GHI must be logged into the ECOG-ACRIN 
Sample Tracking System (STS) to allow tracking of sample 
submissions on the PACCT-1 /TAILORx trial.  Participating sites will 
correspond directly with GHI, not via STS.  The CBPF will log receipt 
of materials from GHI into the STS. Due to the size of the trial, receipt 
logging will not occur in real time.  For more information on the STS, 
see Section 10.4. 
 
Material 
Report/Forms 
Required 
Ship to: 
Rev. 12/14 
Primary Tumor 
Tissue1 
• Oncotype DX 
Requisition Form 
• ECOG-ACRIN 
Generic Specimen 
Submission Form 
(#2981) 
Identify all submitted 
materials with ECOG-
ACRIN case# AND 
study# (PACCT-1 / 
TAILORx), as well as a 
bar code from the kit 
Customer Service  
Genomic Health, Inc. 
301 Penobscot Drive 
Redwood City, CA 94063 
Telephone: 866-662-6897 
Rev. 12/14 
Concurrent forms 
submission to 
CBPF 
• Pathology Report 
with immunologic 
studies, if available 
• Surgical Report  
• Copy of Oncotype 
DX Requisition Form 
•  ECOG-ACRIN 
Generic Specimen 
Submission Form 
(#2981) 
Send forms to CBPF at 
the time tissue is sent 
to GHI. 
Identify all forms with 
ECOG-ACRIN case# 
AND Oncotype DX 
Requisition# 
Fax (preferred) to:  
713-563-6506 
Attn: Rebecca Haas 
Or Send to:  
ECOG-ACRIN Central Biorepository 
and Pathology Facility  
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for 
ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
 
 
 
Rev. 8/08 
 
 
 
 
Rev. 8/08 
Concurrent forms 
submission to 
CTSU Houston 
Office 
• 
Pathology/Surgical 
Reports  
Pathology and/or 
Surgical Reports to the 
CTSU Houston Office 
should be 
accompanied by the 
TAILORx Source 
Document Tracking 
Form and TAILORx 
CTSU Data 
Transmittal Form. 
Fax to 301-545-0406 
 
1.   Residuals will be forwarded from GHI to ECOG-ACRIN CBPF for correlative studies and banking.  If CBPF 
determines insufficient materials are available for correlative studies, an additional block will be required.  In 
this case, your site will be notified by CBPF. 
10.1.3 
Notification of Results 
Genomic Health will notify the institution of the recurrence score (RS) 
via the mechanism selected on the Oncotype Requisition Form within 
14 days of receipt of the tissue by Genomic Health.  If you do not 
receive an RS within 14 days, contact GHI Customer Service at 866-
662-6897.  Genomic Health will not distribute reports directly to the 
ECOG-ACRIN Operations Office – Boston. 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
101 
10.2 
Submitting the RS to the ECOG-ACRIN Operations Office – Boston   
The site must report the RS to the ECOG-ACRIN Operations Office – Boston 
prior to registration/randomization.  The following instructions apply to all patients 
(patients with no RS before pre-registering, as well as patients with a known RS 
prior to pre-registration). 
• 
Make a copy of the first page of the form with the patient’s name blacked 
out (redacted) and replaced by initials (last initial, first initial).  Make sure 
the patient’s ECOG-ACRIN sequence number appears on the form.  For 
a sample form, please see Appendix X of the protocol. 
• 
Fax the first page of the form to the ECOG-ACRIN Operations Office – 
Boston, ATTN: TAILORx Pre-Study, 617-582-8578.  Include the patient’s 
sequence number and initials on the cover sheet. 
• 
ECOG-ACRIN Operations Office – Boston staff will enter the score in a 
database table.  Please allow 24 hours on weekdays, 72 hours on 
weekends (please also make allowances for holidays) before registering 
your patient to step 2. 
10.3 
Registration/Randomization Submissions (All Patients) 
Samples are submitted to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF). 
Primary tumor tissue is required for central review including validation of 
diagnosis, histopathology evaluation and testing of ER, PR, and Her2/neu status 
as outlined in Appendix VIII.  If slides were submitted to GHI during pre-
registration for RS score determination OR if the RS score was determined 
PRIOR to pre-registration, tissue submission for the central evaluation is 
MANDATORY. For all patients, if any submitted materials are deemed 
inadequate for the required diagnostic studies, submission of additional 
pathology materials will be required. 
Submissions for future research:  Additional tissue (including frozen tissue, if 
available) is requested to be submitted from patients who answer “yes” to “My 
tissue may be kept for use in future research to learn about, prevent, or treat 
cancer”.  Blood samples are to be submitted from patients who answer “yes” to “I 
give permission for samples of my blood to be drawn and sent to ECOG-ACRIN 
to be kept for use in future research to learn about, prevent, or treat cancer.”   
All shipments are to be logged into the ECOG-ACRIN STS to allow tracking of 
sample submissions on the PACCT-1/TAILORx trial. 
10.3.1 
Kits 
The kits contain blood collection tubes and shipping supplies to allow 
combined or split frozen/ambient submissions.   
To order the kit, complete the PACCT-1 Peripheral Blood Collection 
and Shipping Kit Order Form (Appendix VI) (include the ECOG-
ACRIN patient case number) and fax to Zemotak-International at 800-
815-4675.   
It is recommended that the kits be requested within one day after pre-
registration, and prior to registration/randomization.  Do not request 
kits prior to pre-registration.
Rev. 7/10 
Rev. 12/14 

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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
102 
10.3.2 
Sample Submission Summary 
 
Biological 
Materials 
Shipping note: 
(Section 10.3.4) 
Report/Forms 
Expectancy of submissions 
 
 
 
Primary Tumor 
Tissue1 
ECOG-ACRIN 
CBPF 
(Section 10.3.3) 
Ambient temp, 
batch shipping 
acceptable 
• 
Pathology Report1 
• 
Surgical Report  
• 
Immunologic studies, if available 
• 
STS-generated shipping manifest 
or ECOG-ACRIN Generic 
Specimen Submission Form 
(#2981) 
 
Copies of these reports and the 
completed form must be sent with each 
tumor tissue submission. 
An additional block or 
acceptable alternative 
material is requested (not 
required) if  
1) 
Patient consented to 
banking 
AND 
2) 
Tissue block 
submitted to GHI 
after pre-registration 
(most patients will 
be in this category). 
A tissue block or acceptable 
alternative material is 
required if  
1) 
Patient had obtained 
an RS of 11-25 prior 
to pre-registration 
OR  
2) 
Residual material 
from GHI submission 
was insufficient for 
correlative studies.  
ECOG-ACRIN CBPF 
will contact the site 
in this circumstance. 
Rev. 12/14 
Rev. 12/14 
 
Frozen Tumor 
Tissue 
(if available)1,2,3 
Ship to CBPF 
using collection 
and shipping kit2 
• 
Pathology Report 
• 
Surgical Report  
• 
Immunologic studies, if available 
• 
STS-generated shipping manifest 
or ECOG-ACRIN Generic 
Specimen Submission Form 
(#2981) 
OR   
• 
TAILORx Virtual Frozen Tissue 
Bank Form (#2675). 
If available AND patient has 
consented to banking of 
samples for possible future 
use: 
1) 
Submit frozen 
material to ECOG-
ACRIN CBPF with 
indicated forms  
OR 
2) 
Retain frozen tissue 
on site and submit 
TAILORx Virtual 
Frozen Tumor Form 
(#2675) to CBPF. 
 
Plasma, EDTA 
purple top2 
Ship to CBPF on 
dry ice 
(preferred) or 
frozen packs.  
May be batch 
shipped. 
If logged in Sample Tracking System 
(STS), include STS shipping manifest. 
If STS unavailable, include TAILORx 
Material Submission Form (#2539) or 
ECOG-ACRIN 
Generic 
Specimen 
Submission Form (#2981)4 
Submit if patient has 
consented to banking.  
Samples are drawn after 
registration/randomization 
and prior to start of therapy. 
Rev. 12/14 
Serum, SST2 
 
Peripheral blood, 
citrate CPT2 
Ship to CBPF at 
ambient temp, 
day of collection 
Rev. 12/14 
Peripheral blood 
PAXgene DNA2 
Rev. 8/08 
1.  Fax: Pathology report with TAILORx Source Document Tracking Form and TAILORx CTSU Data 
Transmittal Form. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
103 
 
2.  Collection and shipping kits ordered by faxing PACCT-1 Collection and Shipping Kit Order Form (Appendix- 
VI) to Zemotak-International at 800-815-4675. 
Rev. 12/14 
3.  If frozen tissue will be retained at the local site, submit a completed TAILORx Virtual Frozen Tissue Bank Form 
(#2675) to the ECOG-ACRIN CBPF (fax to 713-563-6506, Attn: Rebecca Haas) 
Rev. 8/08 
4.   In this event, a copy of the Material Submission Form must be faxed to the CTSU with a TAILORx CTSU Data 
Transmittal Form.  Refer to Appendix XI 
10.3.3 
Tumor Tissue 
Tissue is to be submitted within two weeks following 
registration/randomization.  Do not submit tissue from patients who 
have not pre-registered to the PACCT-1 /TAILORx trial.  
10.3.3.1 
Fixed Tissue 
One (1) paraffin block of the primary cancer.  Submit with 
forms as noted in the table 10.3.2.  This will be required for 
some patients, and is requested for others, as follows: 
• 
Pre-registration of patient with known RS score (no 
samples submitted to GHI on protocol):  
MANDATORY 
• 
Pre-registration of patient with unknown RS score 
(materials submitted per protocol section 10.1, 
above.  Most patients will be in this category): 
o If slides, rather than a block, were submitted to 
Genomic Health: Submission of tissue to CBPF 
is MANDATORY 
o Blocks submitted to Genomic Health: additional 
materials are requested to be submitted to the 
ECOG-ACRIN CBPF.  Be aware that if the 
material forwarded to the CBPF by Genomic 
Health is inadequate for the required diagnostic 
studies, submission of additional pathology 
materials will be required 
If an institution will not allow block release, the institution 
MUST contact the ECOG-ACRIN CBPF (Tel: 844-744-
2420, Email: eacbpf@mdanderson.org) to request 
alternative submission requirements. 
Samples are to be shipped at ambient temperature within 
two weeks following registration/randomization.  If 
possible, ship with peripheral blood samples. 
10.3.3.2 
Frozen Tissue 
If available, submit from patients consenting to banking.  
Submit with forms as noted in the table 10.3.2.   
Tissue must remain frozen during the shipment.  Ship 
overnight on dry ice, Sunday through Thursday only. Do 
not ship the day before a holiday.  
Rev. 7/10 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
104 
Frozen tissue may be batched and shipped with the frozen 
plasma and serum samples. 
If the STS if unavailable on the day of the shipment, 
complete an ECOG-ACRIN Generic Specimen Submission 
Form (#2981) and fax to the ECOG-ACRIN CBPF at 713-
563-6506. 
NOTE: 
Available frozen tissue may remain at local 
sites until requested by the ECOG-ACRIN 
CBPF.  If materials will be retained until 
requested, submit a completed TAILORx Virtual 
Frozen Tissue Bank Form (#2675) to the 
ECOG-ACRIN CBPF. 
10.3.4 
Blood samples  
Submit from patients consenting to banking. 
Samples are drawn after registration/randomization and prior to start 
of therapy.  Collect Sunday through Thursdays preferred. Samples 
collected on a Friday must be submitted as a split shipment (see 
10.3.5, Part B).  Do not collect on the day before a holiday. 
All blood samples are shipped via OVERNIGHT delivery using the 
airbill provided in the kit. If STS is unavailable on the day of the 
shipment, complete an ECOG-ACRIN Generic Speciment Submission 
Form (#2981) and fax to the ECOG-ACRIN CBPF at 713-563-6506. 
• 
Samples shipped at ambient temperature must be sent on the 
day of collection. In hot weather, please include a kool pack 
but wrap/insulate samples so the samples cannot freeze.  
• 
Frozen samples are to be shipped on dry ice (preferred) or 
frozen kool packs.  Multiple patient samples may be batched 
and shipped monthly. Ship on Sunday through Thursday only.  
Do not ship the day before a holiday.  
All blood samples are to be submitted with an STS shipping manifest 
or a completed ECOG-ACRIN Generic Specimen Submission Form 
(#2981) if STS is unavailable. 
NOTE: 
These guidelines are for the U.S., Hawaii, Puerto Rico and 
proximal Canadian sites only.  International sites must 
contact the ECOG-ACRIN CBPF to make special 
arrangements. 
Ship Frozen 
1. 
Serum:  SST red/grey marble top vacutainer 
a. 
Draw peripheral blood into vacutainer. 
b. 
Allow blood to coagulate 20 minutes, then centrifuge 
at 25oC, 1500xg (2700-3000 rpm) for 15 minutes.  
c. 
Pipette the serum into 4 cryotubes provided in the kit. 
d. 
Store frozen, below –20oC (-70 oC preferred), until 
shipped 
Ship Ambient 
2. 
Peripheral Blood: citrate CPT (blue/black top) 
Rev. 12/14 
Rev. 12/14 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
105 
a. 
Draw 8mL peripheral blood into vacutainer and gently 
invert 8-10 times. 
b. 
Within 20 minutes of collection, centrifuge at 1500xg 
(2700-3000 rpm) for 20 minutes. 
c. 
Resuspend cells within the tube by gently inverting 1 
time.  
d. 
Ship at ambient temperature the day of collection. 
Ship Frozen 
3. 
Plasma: EDTA purple top tube  
a. 
Draw peripheral blood into vacutainer and gently 
invert 8-10 times. 
b. 
Within 20 minutes of collection, centrifuge at 1500xg 
(2700-3000 rpm) for 15 minutes.  
c. 
Pipette the plasma into 4 cryotubes provided in the 
kit and store frozen, below –20oC (-70 oC preferred), 
until shipped 
d. 
Remaining Cells: EDTA purple top tube 
Ship Ambient 
e. 
Replace the stopper on the EDTA tube containing the 
cells and ship ambient the day of collection  
Ship Ambient 
4. 
Peripheral blood: one PAXgene DNA tube 
a. 
Draw peripheral blood into vacutainer, then gently 
invert tube 8-10 times. 
b.  Ship at ambient temperature the day of collection. 
10.3.5 
Shipping Guidelines 
These guidelines are for the U.S., Hawaii, Puerto Rico and proximal 
Canadian sites only.  International sites must contact the ECOG-
ACRIN CBPF to set up special arrangements. 
All blood and frozen tissue samples are shipped via OVERNIGHT 
delivery using the airbill (FedEx account number 212898813-PACCT) 
provided in the kit. If frozen tissue is submitted, the frozen samples 
MUST be shipped on DRY ICE. 
Log the shipment into the ECOG-ACRIN STS the day of shipment. If 
STS is unavailable at time of shipment, complete an ECOG-ACRIN 
Generic Specimen Submission Form (#2981) and fax to the ECOG-
ACRIN CBPF at 713-563-6506. Once STS is available, retrospectively 
log the submissions using the actual collection and shipping dates. 
Fixed, paraffin embedded tissue samples are to be packaged to 
prevent breakage and shipped no later than two weeks following 
registration/randomization. Samples may be submitted with the 
ambient blood shipment.  
A. 
Combination Shipment: Shipping Both Frozen and Ambient 
Samples Together.  
For shipments with blood draws performed Monday through 
Thursday ONLY.   
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
106 
• 
Line the styrofoam containers with enough absorbent 
material to absorb any contents that may leak.   
• 
Each frozen sample must be in its own cryovial or sealed 
container. The frozen samples are then placed into a 
biohazard bag, sealed and placed into the large 
styrofoam container.  
• 
Add DRY-ICE or Frozen Brick into large styrofoam. Use 
enough of DRY ICE to last 4 days. Cover the 
Styrofoam.  
• 
Place room temp samples (PaxgeneDNA, CPT and EDTA 
cell tube) into small styrofoam/cardboards provided. 
Fixed tissue blocks may be submitted with these 
samples. 
• 
Place the styrofoam containers into large cardboard box. 
• 
Affix IATA labels (UN3373, Biohazard, and DRY-ICE label 
if dry-ice is used) on the cardboard box. Sites outside 
of US borders must include CDCP permit label on 
shipment. 
• 
Place documents (STS Shipping manifest or Material 
Submission Form) on top, then seal box.  
B. 
SPLIT SHIPMENT FOR FRIDAY COLLECTION            
For blood specimens drawn on Friday and/or before holidays, 
ambient shipments MUST be mailed the day of collection.  
Keep frozen plasma and serum at –20oC or colder until next 
business day to ship. Package in the individual styrofoam 
containers as outlined above and ship in separate cardboard 
boxes.  
Affix IATA labels (UN3373, Biohazard, DRY ICE if applicable) 
on the cardboard boxes. Sites outside of US borders must 
include CDCP permit label on shipment.   
Ship to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room 
G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
10.4 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). As of June 2007, the 
software will allow the use of either 1) an ECOG-ACRIN user-name and 
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password previously assigned (for those already using STS), or 2) a CTSU 
username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking  
https://webapps.ecog.org/Tst.  
Important:  Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software.  A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
A shipping manifest must be generated and shipped with all sample submissions. 
For the EL112LAB Ancillary Study, if STS is unavailable at time of sample 
submission, a completed Generic Specimen Submission Form (#2981) is to be 
faxed to the receiving laboratory and included with the sample shipment. When 
STS becomes available, the submissions must be retroactively logged into the 
system, using actual submission dates and tracking numbers. Indicate on the 
submission for the appropriate Lab: 
• 
ECOG-ACRIN CBPF   
• 
FCCC Clinical Protocol Support Lab 
Please direct your questions or comments pertaining to the STS to  
ecog-acrin.tst@jimmy.harvard.edu. 
10.5 
[“Processing of Specimen in ECOG-ACRIN Central Biorepository and Pathology 
Facility” Deleted in Addendum #2] 
Processing information is available in Appendix VII. 
10.6 
Banking 
Samples submitted and derivatives of the submitted materials will be retained at 
the ECOG-ACRIN Central Repository for possible use in future ECOG-ACRIN 
approved studies. Residual materials from any laboratory studies, including the 
Oncotype DX Assay by Genomic Health, will also be returned to the ECOG-
ACRIN Central Repository for possible use in future ECOG-ACRIN approved 
studies.  If future use is denied or withdrawn by the patient, the samples will be 
removed from consideration for use in any future study. 
Blocks from patients who have consented to banking will be available for 
purposes of individual patient management on specific written request. Submit 
requests to the ECOG-ACRIN CBPF. 
10.7 
Lab Data Transfer Guidelines  
Data from any other laboratory study utilizing these materials will be submitted 
electronically to the ECOG-ACRIN Operations Office – Boston by the central 
laboratory(ies) on a pre-arranged schedule. 
10.8 
Sample Inventory Submission Guidelines  
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Inventories of all samples collected, aliquoted, and used will be submitted to the 
ECOG-ACRIN Operations Office – Boston upon request. Inventories will be 
submitted electronically by any laboratory holding and/or using any specimens 
associated with this study. All other correspondence should be addressed to the 
attention of the ECOG-ACRIN Translational Science Team. 
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11. 
Records to Be Kept 
Please refer to the PACCT-1 Forms Packet for the forms submission schedule and 
copies of all forms. The PACCT-1 Forms Packet may be downloaded by accessing the 
ECOG World Wide Web Home Page (http://www.ecog.org) or CTSU website 
(www.CTSU.org).  
Data management activities for the PACCT-1 (TAILORx) study will be performed by the 
Cancer Trials Support Unit (CTSU).  For this reason, investigators and study support 
staff involved in the collection and reporting of study data must be registered members 
of the CTSU.  Please see the CTSU website (www.ctsu.org) for details on registering as 
a CTSU member.   
Data management activities for the QOL portion of the study will be done by the ECOG-
ACRIN Operations Office – Boston. 
Data Completion and Submission Guidelines 
All ECOG-ACRIN and non-ECOG-ACRIN sites are required to submit patient data via 
the CTSU (with the exception of Expedited Adverse Event Reporting and the 
AML/MDS/ALL Report Form; please follow instructions in section 5.3 for submission of 
AE data).  
NOTE: 
All ECOG-ACRIN and non-ECOG-ACRIN sites are required to submit the 
QOL data directly to the ECOG-ACRIN Operations Office – Boston. 
Sites that are pre-selected by ECOG-ACRIN to participate in the CTSU RDC system 
should take special note of the RDC instructions in the CTSU appendix of this protocol 
(Appendix XI).  The CTSU help desk is available to answer questions about data 
submission at 1-888-823-5923 or ctsucontact@westat.com. 
This study will be monitored by the CTEP Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study will be used in support of a US marketing application (New Drug 
Application), all records pertaining to the trial (including source documents) must 
be maintained for: 
• 
two years after the FDA approves the marketing application, or 
• 
two years after the FDA disapproves the application for the indication 
being studied, or 
• 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
Rev. 9/06 
Rev. 9/07 
  Rev. 11/07 
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12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
References 
1. 
Jemal A, Tiwari RC, Murray T, et al. Cancer Statistics, 2004. CA: A Cancer 
Journal for Clinicians. 54: 8-29, 2004. 
2. 
Chu KC, Tarone RE, Kessler LG, Ries LA, Hankey BF, Miller BA, Edwards BK. 
Recent trends in U.S. breast cancer incidence, survival, and mortality rates. J 
Natl Cancer Inst 88: 1571-1579, 1996. 
3. 
Jatoi I, Miller AB. Why is breast-cancer mortality declining? Lancet Oncol 4: 251-
254, 2003.  
4. 
Fisher B, Dignam J, Wolmark N, et al. Tamoxifen and chemotherapy for lymph 
node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89: 
22: 1673-1682, 1997.  
5. 
Fisher B, Jeong JH, Dignam J, Anderson S, Mamounas E, Wickerham L, 
Wolmark N. Findings from recent National Surgical Adjuvant Breast and Bowel 
Project adjuvant studies in stage I breast cancer. J Natl Cancer Inst Monogr 30: 
62-66, 2001.  
6. 
Fisher B, Jeong JH, Bryant J, et al: Findings from two decades of National 
Surgical Adjuvant Breast and Bowel Project clinical trials involving breast cancer 
patients with negative axillary nodes. Proceedings of the San Antonio Breast 
Cancer Symposium, December 11-14, 2002, San Antonio, TX (abstr 16) 
7. 
Early Brest Cancer Trialists’ Collaborative Group. Polychemotherapy for early 
breast cancer: an overview of the randomized trials. Lancet 352: 930-942-1998.  
8. 
Morrow M, Krontira H. Who should not receive chemotherapy? Date from 
American databases and trials. J Natl Cancer Inst 30: 109-113, 2001.  
9. 
Loprinzi CL, Thome SD. Understanding the utility of adjuvant systemic therapy 
for primary breast cancer. J Clin Oncol 19: 972-979, 2001. 
10. 
Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, Parker HL. 
Computer program to assist in making decision about adjuvant therapy for 
women with early breast cancer. J Clin Oncol 19: 980-991, 2001. 
11. 
Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, S. Hans-Jörg.  
Meeting Highlights: Updated International Expert Consensus on the Primary 
Therapy of Early Breast Cancer. J Clin Oncol 21: 3357-3365,  2003. 
12. 
Clark GM.  Prognostic and Predictive Factors. In: Harris JR, Lippman ME, 
Morrow M, Osborne CK. Diseases of the Breast Lippincott Williams & Wilkins. 
Philadelphia, PA, 2000, pp489-514 
13. 
National Institutes of Health Consensus Development Panel. National Institutes 
of Health Consensus Conference Statement: Adjuvant therapy for Breast 
Cancer, November 1-3, 2000. J Natl Cancer Inst Monographs 30: 5-15, 2001. 
14. 
SEER Cancer Statistics Review, 1975-2000, National Cancer Institute, Bethesda, 
MD, http://seer.cancer.gov/cst/1975_2000. (Accessed 2003).

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
111 
15. 
Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of the 
prognostic model ADJUVANT! for early breast cancer. J Clin Oncol 2005; 
23:2716-25.  
16. 
Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast 
tumours. Nature 406: 747-752, 2000.   
17. 
Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast 
carcinomas distinguish tumor subclasses with clinical implications. PNAS 98: 
10669-10874, 2001.  
18. 
Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor 
subtypes in independent gene expression data sets. PNAS 109: 8418-8423, 
2003. 
19. 
van ’t Veer L ,Dai H, van de Vijver MJ, et al. Gene expression profiling predicts 
clinical outcome of breast cancer. Nature 415:530-6, 2002. 
20. 
van de Vijver J, He YD, Van’t Veer LJ, et al. A gene-expression signature as a 
predictor of survival in breast cancer. N Engl J Med 347:1999-2009, 2002.  
21. 
Piccart, MJ, Loi S, Van’t Veer L, et al. Multi-center external validation study of the 
Amsterdam 70-gene prognostic signature in node negative untreated breast 
cancer: are the results still outperforming the clinical-pathological criteria. San 
Antonio Breast Cancer Symposium 2004 (new abstract #38) (www. sabcs.org). 
22. 
Wang V, Klijn, JG, Zhang Y, et al. Gene-expression profiles to predict distant 
metastasis of lymph-node-negative primary breast cancer. Lancet 365: 671-679, 
2005. 
23. 
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of 
tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351:2817-
26. 
24. 
Cobleigh MA, Tabesh B, Bitterman P, et al. Tumor gene expression and 
prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin 
Cancer Res 2005; 11:8623-31. 
25. 
Esteban J, Baker J, Cronin M, et al. Tumor gene expression and prognosis in 
breast cancer: multi-gene RT-PCR assay of paraffin-embedded tissue. Proc Am 
Soc Clin Oncol 22: 850, 2003 (abstr 3416). 
26. 
Paik S, Shak S, Tan G, et al. A multigene assay to predict recurrence of 
tamoxifen-treated, node-negative breast cancer. N Eng J Med 351; 2817-2826, 
2004.  
27. 
Esteva FJ, Sahin AA, Cristofanilli M, et al. Prognostic role of a multigene reverse 
transcriptase-PCR assay in patients with node-negative breast cancer not 
receiving adjuvant systemic therapy. Clin Cancer Res 2005; 11:3315-9. 
28. 
Habel LA, Quesenberry CP, Jacobs, K, et al. A large case-control study of gene 
expression and breast cancer death in Northern California Kaiser Permanente 
population. Breast Cancer Research and Treatment 88 (Suppl 1), S118, 2004 
(abstr 3019). 
29. 
Paik S, Tang G, Shak S, et al. Gene Expression and Benefit of Chemotherapy in 
Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer. J Clin 
Oncol 2006. 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 
Rev. 9/06 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
112 
30. 
Hayes DF. Markers of increased risk for failure of adjuvant therapies. Breast 12: 
543-549, 2003. 
31. 
Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in 
postmenopausal women after five years of tamoxifen therapy for early-stage 
breast cancer. N Eng J Med 349; 1793-1802, 2003. 
32. 
Baum M, Buzdar AU, Cuzick J, et al. Anastrozole alone or in combination with 
tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal 
women with early breast cancer: first results of the ATAC randomized trial. 
Lancet 359; 2131-2139, 2002 (Erratum, Lancet 360; 1520, 2002). 
33. 
Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after 
two to three years of tamoxifen in postmenopausal women with primary breast 
cancer. N Eng J Med 350: 1081-1092, 2004. 
34. 
Gray, Journal of the American Statistical Association, 87:942-951, 1992. 
35. 
Adjuvant Breast Cancer Trials Collaborative Group.  Polychemotherapy for early 
breast cancer:  results from the International Adjuvant Breast Cancer 
Chemotherapy Randomized Trial. J Natl Cancer Inst 2007; 99(7):506-515. PMID: 
17405995 
36. 
Ahles, T. Do systemic cancer treatments affect cognitive function? Lancet 
Oncology 2004; 5: 270-271. 
37. 
Ahles, T. A., Saykin, A. J., Furstenberg, C. T., Cole, B., Mott, L. A., Skalla, K. et 
al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-
term survivors of breast cancer and lymphoma. Journal of Clinical Oncology, 
2002; 20:485-493. PMID: 11786578  
38. 
Anderson-Hanley, C., Sherman, M. L., Riggs, R., Agocha, V. B., & Compas, B. E. 
Neuropsychological effects of treatments for adults with cancer: a meta-analysis 
and review of the literature. J Int.Neuropsychol.Soc 2003; 9:967-982. PMID: 
14738279  
39. 
Benton, A.L. & Hamsher, K.D. Multilingual aphasia examination. 1989; Iowa City, 
Iowa. AJA Associates. 
40. 
Bernhard J, Zahrieh D, Coates AS et al.  Quantifying trade-offs: quality of life and 
quality-adjusted survival in a randomized trial of chemotherapy in 
postmenopausal patients with lymph node-negative breast cancer.  Br J Cancer 
2004; 91(11):1893-1901. PMID: 15545973 
41. 
Bower JE, Ganz PA, Desmond kA, et al.  Fatigue in breast cancer survivors:  
Occurrence, correlates, and impact on quality of life.  J Clin Oncol 2000; 
18(4):743-753. PMID: 10673515 
42. 
Brezden, C.B., Phillips, K. A., Abdolell, M., Bunston, T., & Tannock, I. F. 
Cognitive function in breast cancer patients receiving adjuvant chemotherapy. 
Journal of Clinical Oncology 2000;18: 2695-2701. PMID: 10894868 
43. 
Bruning PF, Pit MJ, de Jong-Bakker M, van den Ende A, Hart A, van Enk A.  
Bone mineral density after adjuvant chemotherapy for premenopausal breast 
cancer.  Br J Cancer 1990; 61(2):308-310. PMID: 2310683 
44. 
Cella, D.F., Tulsky, D.S., Gray, G. et al. The Functional Assessment of Cancer 
Therapy (FACT) scale: Development and validation of the general measure. J 
Clin Oncol 1993; 11:570-579. PMID: 8445433
Rev. 1/10 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
113 
45. 
Chaytor, N. & Schmitter-Edgecombe, M. The ecological validity of 
neuropsychological tests: A review of the literature on everyday cognitive skills. 
Neuropsychology Review 2003; 13(4):181-197. PMID: 15000225 
46. 
Cimprich, B. & Ronis, D.L. An environmental intervention to restore attention in 
women with newly diagnosed breast cancer. Cancer Nursing 2003 ; 26 : 284-
294. PMID: 12886119 
47. 
Crivellari D, Price K, Gelber RD et al.  Adjuvant endocrine therapy compared with 
no systemic therapy for elderly women with early breast cancer:  21-year results 
of International Breast Cancer Study Group Trial IV.  J Clin Oncol 2003; 21(24): 
4517-423. PMID: 14673038 
48. 
Curran, D., Van Dongen, JP, Aaronson NK, et al. Quality of life of early-stage 
breast cancer patients treated with radical mastectomy or breast-conserving 
procedures: Results of EORTC trial 10801. European Journal of Cancer 1998; 
34:307-314. PMID: 9640214 
49. 
de Groot, J. C., de Leeuw, F. E., Oudkerk, M., Hofman, A., Jolles, J., & Breteler, 
M. M. Cerebral white matter lesions and subjective cognitive dysfunction: The 
Rotterdam Scan Study. Neurology 2001; 56(11):1539-1545. PMID: 11402112 
50. 
Denmark-Wahnefried W, Rimer BK, Winer EP.  Weight gain in women diagnosed 
with breast cancer.  J Am Diet Assoc 1997; 97(5):519-516; quiz 527-528. PMID: 
9145091 
51. 
Desai J., Wagner, L. I., Beaumont, J., Sweet, J., Butt, Z., and Cella, D. Cognitive 
functioning among breast cancer patients prior to chemotherapy. Psycho-
Oncology 2005; 14 Suppl 1: S32-33. 
52. 
Falletti MG, Sanfilippo A, Maruff P, et al. The nature and severity of cognitive 
impairment associated with adjuvant chemotherapy in women with breast cancer: 
A meta-analysis of the current literature. Brain Cogn 2005; 59:60-70. PMID: 
15975700 
53. 
Fallowfield, L., Cella, D., Cuzick, J., Francis, S., Locker, G., & Howell, A. Quality 
of life in postmenopausal women in the Arimidex, Tamoxifen alone, or in 
combination (ATAC) adjuvant breast cancer trial. Journal of Clinical Oncology 
2004, 22: 4261-4271. PMID: 15514369 
54. 
Ferguson, R. J., McDonald, B. C., Saykin, A. J., & Ahles, T. A. (2007). Brain 
structure and function differences in monozygotic twins: Possible effects of 
breast cancer chemotherapy. Journal of Clinical Oncology 2007; 25: 3866 – 
3870. PMID: 17761972 
55. 
Ganz PA, Desmond KA, Leedham B, Rowland JH, Meyerowitz BE, Belin TR.  
Quality of life in long-term disease-free survivors of breast cancer:  a follow-up 
study.  J Natl Cancer Inst 2002; 94(1):39-49. PMID: 11773281 
56. 
Ganz PA, Kwan L, Stanton AL, Krupnick JL, Rowland JH, Meyerowitz BE, et al.  
Quality of life at the end of primary treatment of breast cancer:  first results from 
the moving beyond cancer randomized trial.  J Natl Cancer Inst 2004; 96(5):376-
387. PMID: 14996859 
57. 
Goodwin PJ, Ennis M, Pritchard KI, Trueau M, Hood N.  Risk of menopause 
during the first year after breast cancer diagnosis.  J Clin Oncol 1999; 17:2365-
2370. PMID: 10561298 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
114 
58. 
Gotay, C.C. & Pagano, I.S. (2007). Assessment of Survivor Concerns (ASC): A 
newly proposed brief questionnaire. Health and Quality of Life Outcomes 2007; 
5:15. PMID: 17352831 
59. 
Howell SJ, Berger G, Adams JE, Shalet SM.  Bone mineral density in women 
with cytotoxic-induced ovarian failure. Clin Endocrinol (Oxf) 1998; 49(3):397-402. 
PMID: 9861333 
60. 
Jacobs SR, Jacobsen PB, Booth-Jones M, Wagner LI, & Anasetti C. Evaluation 
of the Functional Assessment of Cancer Therapy Cognitive Scale with 
hematopoetic stem cell transplant patients. Journal of Pain and Symptom 
Management 2007; 33: 13-23. PMID: 17196903 
61. 
Jenkins, V., Shilling, V., Fallowfield, L., Howell, A., & Hutton, S. (2004). Does 
hormone therapy for the treatment of breast cancer have a detrimental effect on 
memory and cognition? A pilot study. Psycho-Oncology 2004;13: 61-66. PMID: 
14745746 
62. 
Kemeny MM, Wellisch, DK, Schain WS. Psychosocial outcome in a randomized 
surgical trial for treatment of primary breast cancer. Cancer 1988; 62:1231-1237. 
PMID: 3044575 
63. 
Kohli, S., Griggs, J.J., Roscoe, J.A., Jean-Pierre, P., Bole, C., Mustian, K.M., Hill, 
R., Smith, K., Gross, H., & Morrow, G.R. Self-reported cognitive impairment in 
patients with cancer. Journal of Oncology Practice 2007; 3: 54-59. 
http://jop.ascopubs.org/cgi/content/abstract/3/2/54 
64. 
Lai JS, Butt Z, Wagner L, Sweet JJ, Beaumont JL, Vardy J, Jacobsen PB, 
Jacobs SR, Shapiro PJ, & Cella, D. (manuscript under review). Evaluating the 
Dimensionality of Perceived Cognitive Function: An illustration using the 
Functional Assessment of Cancer Therapy – Cognition (FACT-Cog). 
65. 
Land SR, Kopec JA, Yothers G et al.  Health-related quality of life in axillary 
node-negative, estrogen receptor-negative breast cancer patients undergoing AC 
versus CMF chemotherapy:  findings from the National Surgical Adjuvant Breast 
and Bowel Project B-23.  Breast Cancer Res Treat 2004; 86(2):153-164. PMID: 
15319567 
66. 
Levine MN, Bramwell VH, Pritchard KI et al.  Randomized trial of intensive 
cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with 
cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with 
node-positive breast cancer.  National Cancer Institute of Canada Clinical Trials 
Group.  J Clin Oncol 1998;16(8):2651-2658. PMID: 9704715 
67. 
Lezak, M., Howieson, D., Loring, D., & Hannay, H.F.J. Neuropsychological 
assessment (4th ed.) 2004; New York: Oxford University Press. 
68. 
Mar Fan HG, Houede-Tchen N, Yi QL, Chemerynsky I, Downie FP, Sabate K, 
Tannock IF.  Fatigue, menopausal symptoms, and cognitive function in women 
after adjuvant chemotherapy for breast cancer:  1- and 2-year follow-up of a 
prospective controlled study.  J Clin Oncol 2005; 23(31):8025-8032. PMID: 
16258100 
69. 
Martin M, Pienkowski T, Mackey J et al.  Adjuvant docetaxel for node-positive 
breast cancer.  N Engl J Med 2005; 352(22):2302-2313. PMID: 15930421

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
115 
70. 
Martin M, Liuch A, Segui MA et al.  Toxicity and health-related quality of life in 
breast cancer patients receiving adjuvant docetaxel, doxorubicin, 
cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide 
(FAC):  impact of adding primary prophylactic granulocytecolony stimulating 
factor to the TAC regimen.  Ann Oncol 2006; 17(8):1205-1212. PMID: 16766587 
71. 
Mast ME. (1998). Survivors of breast cancer: Illness uncertainty, positive 
reappraisal, and emotional distress. Oncology Nursing Forum 1998; 25: 555-562. 
PMID: 9568610 
72. 
McCaffrey, R.J., Ortega, A., Orsillo, S.M., Nelles, W.B., & Haase, R.F. Practice 
effects in repeated neuropsychological assessments. Clinical Neuropsychol 
1992; 6: 32-42. 
73. 
McNair DM, Kahn RJ. (1984). Self-assessment of cognitive deficits. In: Crook T, 
Ferris SH, Bartus RT, Eds. Assessment in geriatric psychopharmacology. New 
Canaan, CT: Mark Powley Associates, pp. 137-143. 
74. 
Minett, T. S., Dean, J. L., Firbank, M., English, P., & O'Brien, J. T. (2005). 
Subjective memory complaints, white-matter lesions, depressive symptoms, and 
cognition in elderly patients. The American Journal of Geriatric Psychiatry 
2005;13(8): 665-671. PMID: 16085782 
75. 
National Cancer Policy Board. Meeting psychosocial needs of women with breast 
cancer. Hewitt M, Herdman R, Holland J (Eds). Washington, DC: The National 
Academies Press. 2004 
76. 
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in 
Oncology (2007). Cancer-Related Fatigue. www.nccn.org  
77. 
Partridge AH, Burstein HJ, Winer EP.  Side effects of chemotherapy and 
combined chemohormonal therapy in women with early-stage breast cancer.  J 
Natl Cancer Inst Monogr 2001; 30:135-142. PMID: 11773307 
78. 
Pistrang, N., Barker, C. Disclosure of concerns in breast cancer. Psycho-
Oncology 1992; 1:183-192. 
http://search.ebscohost.com/login.aspx?direct=true&db=aph&AN=12399642&site
=ehost-live 
79. 
Radloff, L. The CES-D scale : A self-report depression scale for research in the 
general population. Applied Psychological Measures 1977 ; 1 : 385-401. 
80. 
Rey, A. L’examen psychologique dans les cas d’encephalopathic traumatique. 
Archives de Psychologie 1941 ; 28 : 286-340. 
81. 
Saykin, A. J., Ahles, T. A., & McDonald, B. C. Mechanisms of chemotherapy-
induced cognitive disorders: neuropsychological, pathophysiological, and 
neuroimaging perspectives. Semin Clin.Neuropsychiatry 2003; 8: 201-216. 
PMID: 14613048 
82. 
Saykin, A. J., Wishart, H. A., Rabin, L. A., Santulli, R. B., Flashman, L. A., West, 
J. D. et al. Older adults with cognitive complaints show brain atrophy similar to 
that of amnestic MCI. Neurology 2006; 67(5): 834-842. PMID: 16966547 
83. 
Sbordone, R.J. (1996). Sbordone, Ecological validity: Some critical issues for the 
neuropsychologist. In: R.J. Sbordone and C.J. Long, Editors, Ecological validity 
of neuropsychological testing, St Lucie Press, Boca Raton, FL (1996), pp. 15–41.

ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
116 
84. 
Schagen, S. B., van Dam, F. S., Muller, M. J., Boogerd, W., Lindeboom, J., & 
Bruning, P. F. Cognitive deficits after postoperative adjuvant chemotherapy for 
breast carcinoma. Cancer 1999; 85: 640-650. PMID: 10091737 
85. 
Schagen, S. B., Muller, M. J., Boogerd, W., & van Dam, F. S. Cognitive 
dysfunction and chemotherapy: neuropsychological findings in perspective. 
Clinical Breast Cancer 2002; 3 Suppl 3: S100-S108. PMID: 12533270 
86. 
Schover, L.R., Yetman, RJ, Tuason LJ, et al. Partial mastectomy and breast 
reconstructions: A comparison of their effect on psychosocial adjustment, body 
image, and sexuality. Cancer 1995; 75: 54-64. PMID: 7804978 
87. 
Servaes, P., Verhagen, C., & Bleijenberg, G. Fatigue in cancer patients during 
and after treatment: Prevalence, correlates and interventions. European Journal 
of Cancer 2002; 38: 27-43. PMID: 11750837 
88. 
Shilling, V., Jenkins V., Fallowfield L.J., Howell, A. The effects of oestrogens and 
anti-oestrogens on cognition. The Breast 2001; 10: 484-491. PMID: 14965628 
89. 
Silverman, D.H., Dy, C.J., Castellon, S.A., Lai, J., Pio, B., Abraham L., Waddell 
K., Peterson L, Phelps M, Ganz P. Altered frontocortical, cerebellar, and basal 
ganglia activity in adjuvant-treated breast cancer survivors 510 years after 
chemotherapy.  Breast Cancer Research and Treatment 2006; 103:303-311. 
PMID: 17009108 
90. 
Sloan J.A., McLeod, H., Sargent, D., Zhao, X., Fuchs, C., Ramanathan, R. et al. 
Preliminary evidence of relationship between genetic markers and oncology 
patient quality of life (QOL). Journal of Clinical Oncology, 22, 14S, 5. 
91. 
Smith, A. Symbol digit modalities test manual. 1982. Los Angeles, CA: Western 
Psychological Services. 
92. 
Spencer S, Lehman J, Wynings C et al. Concerns about breast cancer and 
relations to psychosocial well-being in a multiethnic sample of early-stage 
patients. Health Psychology 1999;18:159-168. PMID: 10194051 
93. 
Spooner, DM and Pachana, NA. Ecological validity in neuropsychological 
assessment: A case for greater consideration in research with neurologically 
intact populations. Archives of Clinical Neuropsychology 2006; 21: 327-337. 
PMID: 16769198 
94. 
Stasi, R., Abriani, L., Beccaglia, P., Terzoli, E., & Amadori, S. Cancer-related 
fatigue: Evolving concepts in evaluation and treatment. Cancer 2003; 98, 1786-
1801. 
95. 
Tannock, I.F., Ahles, T.A., Ganz, P.A., & van Dam, F.S. Cognitive impairment 
associated with chemotherapy for cancer: Report of a workshop. Journal of 
Clinical Oncology 2004; 22: 2233-2239. PMID: 15169812 
96. 
Unverzagt, F.W., Monahan, P.O., Moser, L.R., Zhao, Q., Carpenter, J.S., Sledge, 
G.W. & Champion, V. The Indiana University Telephone-Based Assessment of 
Neuropsychological Status: A new method for large scale neuropsychological 
assessment. Journal of the International Neuropsychological society 2007; 13: 
799-806. 

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PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
117 
97. 
Van Dam, F.S.A.M., Schagen, S.B., Muller, M.J. et al. Impairment of cognitive 
function in women receiving adjuvant treatment for high-risk breast cancer: High-
dose versus standard-dose chemotherapy. Journal of the National Cancer 
Institute 1998; 90: 210-218. 
98. 
Vardy, J., Rourke, S., & Tannock, I.F. Evaluation of cognitive function associated 
with chemotherapy: A review of published studies and recommendations for 
future research. Journal of Clinical Oncology 2007; 25: 2455-2463. 
99. 
Vardy, J., Wong, K., Yi, Q.L., Park, A., Maruff, P., Wagner, L. & Tannock I.F. 
Assessing cognitive function in cancer patients. Supportive Care in Cancer 2006; 
14: 1111-1118. PMID: 16538498 
100. 
Vickberg SMJ. Fears about breast cancer recurrence: Interviews with a diverse 
sample. Cancer Practice 2001; 9: 237-243. PMID: 11879320 
101. 
Vogelzang, N.J., Breitbart, W., Cella, D., Curt, G.A., Groopman, J.E., Horning, 
S.J. et al. Patient, caregiver and oncologist perceptions of cancer-related fatigue: 
Results of a tripart assessment survey. Seminars in Hematology 1997; 34: 4-12. 
PMID: 9253778 
102. 
Von Ah, D., Harvison, K.W., Monahan, P.O., Moser, L.R., Zhao, Q., Carpenter, 
J.S., Sledge, G.W., Champion, V.L. & Unverzagt, F.W. Cognitive function in 
breast cancer survivors compared to healthy age- and education-matched 
women. In press; The Clinical Neuropsychologist. 
103. 
Wagner, L.I. & Cella, D. (2006). Quality of life and psychosocial issues. In G. 
Bonadonna, G. Hortobagyi, & P. Valagussa (Eds.), Textbook of Breast Cancer: A 
Clinical Guide to Therapy (3rd ed.), pp. 343 – 362. London, England: Taylor & 
Francis Group. 
104. 
Wagner, L.I., Cella, D. & Peterman, A. (2003). Methodological considerations in 
the treatment of fatigue. In R. Portenoy & E. Bruera (Eds.), Issues in Palliative 
Care Research in Palliative Care: Methodologies and Outcomes, pp. 173-185.  
Oxford, England: Oxford University Press. 
105. 
Wagner, L., Sweet, J., Cella, D., and Doninger, N. Chemotherapy-related 
cognitive deficits: A qualitative examination of providers and patients. Annals of 
Behavioral Medicine 2003; 25 Suppl: S056-S056.  
106. 
Wagner, L., Lai, J-S., Cella, D., Sweet, J., and Forrestal, S. Chemotherapy-
related cognitive deficits: Development of the FACT-Cog instrument. Annals of 
Behavioral Medicine 2004; 27 Suppl: S010. 
107. 
Wagner, L.I., Sweet, J.J., Butt, Z., Beaumont, J., Havlin, K., Sabatino, T., & Cella, 
D. (2006). Trajectory of cognitive impairment during breast cancer treatment: A 
prospective analysis. Journal of Clinical Oncology, 2006 ASCO Annual Meeting 
Proceedings Part I. 2006; 24 Suppl:18S. 
http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview
=abst_detail_view&confID=40&abstractID=34472 
108. 
Wagner, L.I., Sweet, J.J., Butt, Z., Lai, J.S. & Cella, D. (manuscript in 
preparation). Measuring Perceived Cognitive Function: Development of the 
Functional Assessment of Cancer Therapy – Perceived Cognitive Function 
(FACT-Cog) Instrument. 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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109. 
Wechsler, D. WAIS-III administration and scoring manual. 1997; San Antonio: 
The Psychological Corporation. 
110. 
Wefel, J.S., Lenzi, R., Theriault, R.L., Davis, R.N., & Meyers, C.A. The cognitive 
sequelae of standard-dose adjuvant chemotherapy in women with breast 
carcinoma: Results of a prospective, randomized, longitudinal trial. Cancer 2004; 
100: 2292-2299. PMID: 15160331 
111. 
Yellen, S. B., Cella, D. F., Webster, K., Blendowski, C., & Kaplan, E. Measuring 
fatigue and other anemia-related symptoms with the Functional Assessment of 
Cancer Therapy (FACT) measurement system. Journal of Pain and 
SymptomManagement 1997; 13(2): 63-74. PMID: 9095563 
112. 
Ziner, K. & Champion, V. Fear of breast cancer recurrence and health care 
provider interaction. Poster presented at the Midwest Nursing Research Society 
Annual Meeting 2007. 

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Version Date: April 25, 2014 
 
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
Appendix I 
 
Informed Consent Template [Deleted in Update #7] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Update #7 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines 
 

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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
Appendix I-A 
 
EL112LAB: North American Breast Cancer Groups Biospecimen  
Bank for Determinants of Late Relapse in Operable Breast Cancer 
Suggested Patient Consent Form [Deleted in Update #7] 
 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I-A was removed from the protocol document in Update #7 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply 
with NCI formatting guidelines 
 
Rev. 2/13, 3/13 

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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix II 
 
Chemotherapy Regimens 
 
Regimen 
Code 
Regimen  
Name 
Regimen Dose/Schedule 
Regimen 
Schedule 
No. of 
Cycles 
 
1 
Oral CMF 
C 100 mg/m2/day PO x 14 days 
M 40 mg/m2 IV days 1, 8 
F 600 mg/m2 IV days 1, 8 
Every 4 
weeks 
6 
 
2 
IV CMF 
C 600 mg/m2 IV 
M 40 mg/m2 IV 
F 600 mg/m2 IV 
Every 3 
weeks 
6-8 
 
3 
Standard AC 
A 60 mg/m2 IV 
C 600 mg/m2 IV 
Every 3 
weeks 
4 
 
4 
Dose dense AC 
A 60 mg/m2 IV 
C 600 mg/m2 IV 
Plus G-CSF 
Every 2 
weeks 
4 
 
5 
Standard  AC - T 
A 60 mg/m2 and C 600 mg/m2 IV 
every 3 weeks x 4 cycles ⇒ T 175 mg/m2 every 3 weeks x 4 cycles 
Every 3 
weeks 
8 
 
6 
Dose dense  AC - T 
A 60 mg/m2 and C 600 mg/m2 IV plus G-CSF every 2 weeks x 4 cycles ⇒ T 175 mg/m2 plus G-
CSF every 2 weeks x 4 cycles 
Every 2 
weeks 
8 
Rev. 9/07 
7 
FEC 
F – 500 mg/m2 IV 
E – 50-100 mg/m2 IV 
C – 500 mg/m2 IV 
Every 3 
weeks 
6 
Rev. 9/07 
8 
TAC 
T - 75 mg/m2 
A - 50 mg/m2 
C - 500 mg/m2 
NOTE:   TAC should be used only in women  </= 70 years of age 
Every 3 
weeks 
4-6 
Rev. 9/06 
9 
TC 
T - 75 mg/m2 
C - 600 mg/m2 
Every 3 
weeks 
4 
Rev. 9/06 
10 
Other protocol-
specified regimens 
Participating in other CTSU trials including chemotherapy 
As specified 
in protocol 
As specified 
in protocol 

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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Rev. 9/06 
11 
Other regimens not 
protocol-specified 
Contact study chair: 
Not participating in other CTSU trials; treating physician elects to use regimen other than 
regimens 1-9; contact study chair, Joseph Sparano, M.D. 
 
 
Rev. 9/06 
Abbreviations:  
 
C – cyclophosphamide; 
A – doxorubicin (Adriamycin);  
M – methotrexate;  
F – 5-fluorouracil; 
T - paclitaxel (Taxol) in AC-T regimens (regimen codes 5 or 6), or docetaxel (Taxotere) in TC and TAC regimens 
(regimen codes 8 and 9)  
E - epirubicin; G-CSF – granulocyte colony stimulating factor (or pegfilgrastim);  
IV  - intravenous 

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Version Date: April 25, 2014 
 
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
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The TAILORx Trial 
 
Appendix III 
 
Hormonal Therapy Regimens 
Years 1- 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rev. 9/07 
Regimen 
Code 
Menopausal Status Regimen 
A 
Pre, Peri, or Post 
Tamoxifen 20 mg PO daily 
B 
Post 
Anastrazole (Arimidex) 1 mg PO daily 
C 
Post 
Letrozole (Femara) 2.5 mg PO daily 
D 
Post 
Exemestane (Aromasin) 25 mg PO daily 
E 
Pre or Peri 
Participating in another CTSU study; as specified in 
treatment protocol  
F 
Post 
Participating in another CTSU study; as specified in 
treatment protocol 
G 
Pre or Peri 
Ovarian suppression (surgery, irradiation, or Gn RH 
analogue) may be used in conjunction with tamoxifen or an 
aromatase inhibitor, and may continue beyond 5 years. 
NOTE: 
Patients who are intolerant of one hormonal regimen may switch to another regimen. 
Years 6-10 
 
Regimen 
Code 
Menopausal 
Status at year 6 
Treatment during years 1-5 
Treatment years 6-10 
1 
Pre or Peri 
Tamoxifen 20 mg PO daily 
No further treatment 
2 
Post 
Tamoxifen 20 mg/ PO daily 
Any aromatase inhibitor  
3 
Post 
Any aromatase inhibitor 
No further treatment 
4 
Post 
Any aromatase inhibitor 
May continue aromatase 
inhibitor 
5 
Pre or Peri 
Any treatment 
Participating in CTSU 
study; as specified in 
protocol 
6 
Post 
Any treatment 
Participating in CTSU 
study; as specified in 
protocol 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
124 
Definition of Menopausal Status: 
Menopausal will be defined according to the following criteria: 
Post-menopausal:    
• 
Woman 60 years of age or older 
• 
Woman aged 45-59 years with spontaneous cessation of menses for at least 12 
months prior to registration 
• 
Woman aged 45-59 years with cessation of menses for less than 12 months prior to 
registration AND an FSH level in the postmenopausal range (or >34.4 IU/L if 
institutional range is not available) 
• 
Woman aged 45-59 years on hormone replacement therapy who have discontinued 
hormone replacement therapy at diagnosis of breast carcinoma and have an FSH 
level in the postmenopausal range according to institutional/laboratory standards (or 
34.4 IU/L if the institutional range is not available) 
• 
Prior bilateral oophorectomy 
• 
Woman younger than 60 years of age who have had a prior hysterectomy (without 
bilateral oophorectomy) AND who have an FSH level in the postmenopausal range 
(or >34.4 IU/L if institutional range is not available) 
Pre- or peri-menopausal: 
Not meeting definition for postmenopausal outlined above

ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix IV 
 
Submission of Biological Materials and Related Documents 
[Removed in Addendum #2] 
See Section 10 
Rev. 9/07 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
126 
Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix V 
 
Pathology Submission Guidelines 
The following items are included in Appendix V: 
1. 
Checklist for PACCT-1 Material Submissions 
2. 
Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
3. 
Instructional memo to submitting pathologists 
4. 
Copy of Genomic Health Oncotype DX Requisition Form with study-specific 
instructions 
NOTE: 
Pathology Submission Form (#638 v04.2) is no longer required for this protocol. 
If the ECOG-ACRIN Sample Tracking System (STS) is unavailable at the time of 
specimen submission, a completed ECOG-ACRIN Generic Specimen 
Submission Form (#2981) is to serve as the shipping manifest. Retroactively 
enter all submissions into STS using actual submission dates.
Rev. 9/07 
Rev. 12/14 
Rev. 9/07 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
127 
Checklist for PACCT-1 Material Submissions: 
ECOG-ACRIN requires that all samples submitted from patients participating in this study be 
logged and tracked via the ECOG-ACRIN Sample Tracking System (STS).  See section 10.4. 
A. Pre-registraton: MANDATORY if Oncotype DX Recurrence Score NOT previously 
performed 
Contact Genomic Health Customer Service (866-662-6897) and request the “Oncotype 
Specimen Kit”.  If the kit is not available at time of pre-registration, it must be ordered within 
24 hours following pre-registration.  
One Oncotype Specimen Kit and Requisition form should be completed per patient.  
DO NOT MIX BARCODE LABELS BETWEEN PATIENTS. 
Submit to GENOMIC HEALTH: (see Appendix X) 
____ Primary Tissue Block (place barcode label on back of cassette) 
 
 
OR 
Fifteen (15) 5 um serial unstained slides, oriented similarly and air dried. Label each 
slide with barcode and number in the order they were cut.  
NOTE: Proper sterile sectioning technique MUST be followed. Failure to follow sterile 
technique can affect testing and delay results. If sterile technique cannot 
be followed, submission of a tumor block is strongly recommended. 
____ Shipping Manifest from Sample Tracking System (STS) 
____ Completed ECOG-ACRIN Generic Specimen Submission Form (#2981) 
____ Completed Oncotype DX Requisition Form 
The form is to be completed as instructed in the kit except for the following fields 
(see sample requisition form in this appendix): 
• 
For the “PROCESSING CODE” enter the protocol number and the ECOG-
ACRIN patient case number assigned at pre-registration (e.g. PACCT-1-
10001). 
• 
Method of payment (section III): Complete with patient’s insurance information. 
• 
ADDITIONAL PHYSICIAN (section V): Enter the contact information of the 
Institutional CRA coordinating the PACCT-1 study. 
• 
COMMENT, section VII (REQUIRED): Enter the protocol number “PACCT-1” and 
the patient’s ECOG-ACRIN case number. 
• 
“BLOCK RETURN” information (section VI). After testing, all residual block 
material will be forwarded by Genomic Health to the ECOG-ACRIN Central 
Tissue Repository at ECOG-ACRIN CBPF. 
o BLOCK RETURN CONTACT = ECOG-ACRIN Central Biorepository and 
Pathology Facility 
o BLOCK RETURN ADDRESS = MD Anderson Cancer Center, Department of 
Pathology, Unit 085, Tissue Qualification Laboratory for ECOG-ACRIN, 
Room G1.3586, 1515 Holcombe Blvd 
o CITY = Houston, STATE = TX, ZIP = 77030 
Rev. 9/07 
Rev. 7/10 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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o BLOCK RETURN PHONE NUMBER = 844-744-2420 
Submit to the ECOG-ACRIN CBPF and the CTSU: 
____ Pathology and surgical reports, including immunological studies if performed.  
____ Copy of completed ECOG-ACRIN Generic Specimen Submission Form (#2981) with 
GHI barcode 
____ 
Shipping Manifest from Sample Tracking System (STS) to ECOG-ACRIN 
CBPF only 
B. Registration/Randomization (STEP 2)  
The required materials are to be submitted to the ECOG-ACRIN Central Biorepository and 
Pathology Facility after pre-registration, but no later than two weeks following patient 
registration/randomization to the PACCT-1/TAILORx trial. 
NOTE: 
Frozen tumor tissue is requested on all registered/randomized patients 
consenting to banking. See Section 10.3 for kit requests, sample preparation, 
and shipping guidelines. 
There are two registration scenarios for submission: 
1. Oncotype DX Recurrence Score (score 11-25) performed PRIOR to pre-registration. 
 
____ Primary Tumor Tissue Block - Submission is MANDATORY 
 
____ Additional Primary Tissue Block, if available and patient consented to banking 
 
Include the following with ALL pathology submissions: 
____ Pathology and surgical reports, including immunological studies if performed.  
____ Copy of completed ECOG-ACRIN Generic Specimen Submission Form (#2981) 
____ Shipping Manifest from Sample Tracking System (STS) 
 
2. Oncotype DX Recurrence Score performed after pre-registration, prior to 
registration/randomization 
A. 
If SLIDES were sent to GHI   
____ Primary Tumor Tissue Block - Submission is MANDATORY 
____ Additional Primary Tissue Block, from patients who consented to banking 
____ Frozen tissue, if available and patient consented to banking 
Include the following with ALL pathology submissions: 
____ Pathology and surgical reports, including immunological studies if 
performed.  
____ Copy of completed ECOG-ACRIN Generic Specimen Submission Form 
(#2981) 
____ Shipping Manifest from Sample Tracking System (STS)
Rev. 2/13 
Rev. 2/13 
Rev. 12/14 
Rev. 12/14 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
129 
B. 
If Tissue Block was sent to GHI, submit the following from patients who 
consented to banking their tissue 
NOTE: 
If the residual material from GHI submission was insufficient for 
correlative studies, submission of additional tumor tissue is 
mandatory.  ECOG-ACRIN CBPF will contact the site in this 
circumstance 
____ Additional Primary Tissue Block 
____ Frozen tissue, if available  
Include the following with ALL pathology submissions: 
____ Pathology and surgical reports, including immunological studies if 
performed.  
____ Copy of completed ECOG-ACRIN Generic Specimen Submission Form 
(#2981) 
____ Shipping Manifest from Sample Tracking System (STS). 
C. Registration (STEP 3) To Ancillary Study EL112LAB 
Tumor tissue samples, blocks preferred, from recurrence biopsy are to be submitted. See 
Appendix XII.
Rev. 2/13 
Rev. 2/13 
Rev, 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
130 
Guidelines for Submission of Pathology Materials 
 
 
 
 
Rev. 9/07 
The following items should always be included when submitting pathology materials to the 
ECOG-ACRIN Central Biorepository and Pathology Facility: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981) 
• 
Shipping Manifest from Sample Tracking System (STS) 
These are also requested for samples submitted to Genomic Health on PACCT-1 
Instructions: 
1. Provide the following information to the pathologist. 
• 
Patient's name (last, first) 
• 
Protocol number 
• 
Protocol case number (the patient's ECOG-ACRIN sequence number)  
• 
Patient's hospital number 
• 
Institution 
• 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist's instructional memo, and forward it, along with the 
List of Required Material, to the appropriate pathologist. 
3. The pathologist should return to you the required pathologic samples and surgical pathology 
reports, along with the completed ECOG-ACRIN Generic Specimen Submission Form 
(#2981). If any other reports are required, they should be obtained from the appropriate 
department at this time. 
4. Keep a copy of the ECOG-ACRIN Generic Specimen Submission Form (#2981) for your 
records. 
5. Double check that ALL required forms, reports, and pathology samples are included in the 
package to send to the Central Biorepository and Pathology Facility or Genomic Health.  
Pathology specimens submitted for a patient WILL NOT be processed by the Central 
Biorepository and Pathology Facility until all necessary items are received. 
6. Tissue to be submitted for the determination of Oncotype Recurrence Score is to be 
shipped as outlined in section 10.1.   
Customer Service 
 
 
 
Genomic Health, Inc.  
 
 
 
301 Penobscot Drive 
 
 
 
Redwood City, CA 94063 
To order specimen kits and requisition forms, contact Genomic Health Customer Service 
(866-662-6897).
Rev. 9/06 
Rev. 12/14 
Rev. 9/07 
Rev. 12/14 
Rev. 9/07 
Rev. 12/14 
Rev. 9/07 
Rev. 12/14 
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ECOG-ACRIN 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
131 
7. Mail all pathology reports, surgical reports, and pathology materials for additional laboratory 
studies and banking to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
If you have any questions concerning the above instructions, or if you anticipate any 
problems in meeting the pathology material submission deadline of 72 hours for the 
Recurrence Score assessment, or within two weeks following registration/randomization for 
banking samples, contact the Pathology Coordinator at the ECOG-ACRIN Central 
Biorepository and Pathology Facility at Tel: 844-744-2420 or email 
eacbpf@mdanderson.org. 
8. 
Copies of submitted pathology reports must be submitted to CTSU as indicated in 
Appendix XI. 
 
Rev. 9/07 
Rev. 9/07 
Rev. 12/14 
Rev. 9/07 

 
132 
MEMORANDUM 
TO:  
 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Pathology Committee 
DATE:  
 
SUBJECT: 
Submission of Pathology Materials for Program for the Assessment of 
Clinical Cancer Tests (PACCT-1): Trial Assigning IndividuaLized 
Options for Treatment. The TAILORx Trial. 
The patient named on the attached ECOG-ACRIN Generic Specimen Submission Form 
(#2981) has been entered onto an ECOG-ACRIN protocol by ________________________ 
(ECOG-ACRIN Investigator). This protocol requires the submission of pathology materials 
for determination of Oncotype DX Recurrence Score (RS), pathology review, laboratory 
studies, and banking. 
For submission of tissue to Genomic Health for RS assessment, complete the Oncotype DX 
Requisition Form provided in the Oncotype DX Specimen Kit.   On the requisition form, the 
PROCESSING CODE must be completed with the protocol number PACCT-1, and the 
patient’s ECOG-ACRIN case number.  Complete the BLOCK RETURN section with the 
ECOG-ACRIN CBPF information as indicated on page 2 of Appendix V.  All residual 
material will be forwarded to the ECOG-ACRIN Central Biorepository and Pathology Facility 
–Research Laboratory (CBPF) after testing. 
Copies of the completed forms and pathology report are to be forwarded to the ECOG-
ACRIN CBPF. 
Keep copies for your own records, and return the completed Forms, the surgical pathology 
report(s), the slides and/or blocks, and any other required material (see attached List of 
Required Material) to the Clinical Research Associate (CRA).  The CRA will forward all 
required pathology material to the appropriate laboratories. 
Blocks, slides and frozen tissue submitted for this study will be retained at the ECOG-ACRIN 
Central Repository for future studies.  Paraffin blocks will be returned by the ECOG-ACRIN 
CBPF upon written request for purposes of patient management. 
 Questions may be directed to Genomic Health Customer Service (650-556-9300) or the 
ECOG-ACRIN CBPF (Tel: 844-744-2420 or  email: Eacbpf@mdanderson.org). 
Name:______________________________________  
Address: ____________________________________  
Phone: _____________________________________  
Thank you.
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ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
THIS IS AN EXAMPLE REQUISITION FORM 
PLEASE DO NOT USE 
 
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ECOG-ACRIN 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
THIS IS AN EXAMPLE REQUISITION FORM 
PLEASE DO NOT USE 
 
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ECOG-ACRIN Generic Specimen Submission Form     Form No. 2981v3 
Page 1 of 1 
135 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per patient, per time- 
point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all specimens into STS once the system 
is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 
Courier 
Tracking Number    
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
 
Sample Type  
(fluid or fresh tissue, 
 include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or 
Sample ID 
Anatomic 
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
 
 
 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % Lymphocytes % 
 
 
 
 
Study Drug Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 
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PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix VI  
 
PACCT-1 and EL112LAB Peripheral Blood Collection and Shipping Kit Order Form 
FAX Completed form to Zemotak-International at (800) 815-4675. 
NOTE: 
Kits for EL112LAB patients may be ordered within one month prior to visit, including 
that for patients who are potentially eligible to step 3 but not yet consented.  
EL112LAB1 kits are not protocol or patient specific and can be interchanged 
between patients and trial. Protocol # requested for tracking purposes.  
Date: 
# of EL112LAB1  CBPF Sample Submission Kits:  PACT1 _____ E5103______ 
For collection of Plasma (CTAD, PST, PPT), Cells (CTAD) and Serum (RST) 
# CellSave (CTC) Kit [E5103 ONLY] 
______ 
For collection of CellSave (CTC) Whole Blood at time of first EL112LAB blood draw, Submission 
to Fox Chase Cancer Center 
Kits to be shipped to: 
Institution Contact:  ___________________________________________ 
Phone number for contact:  ____________________________________ 
E-mail for contact:  ___________________________________________ 
Institution Address:  __________________________________________ 
__________________________________________ 
__________________________________________ 
Sample Submission Schedule Summary Information 
Protocol 
Receiving Lab 
At time of Step 3 
registration** 
Years 1,2,3,4 and 5 
from step 3 registration 
Relapse** 
PACT1 
CBPF 
EL112LAB1 Kit 
 
EL112LAB1 Kit 
E5103 
CBPF 
EL112LAB1 Kit 
EL112LAB1 Kit 
EL112LAB1 Kit 
Fox Chase 
CellSave (CTC) 
 
 
** Tissue to be submitted per protocol. 
NOTE: 
Questions are to be directed to the ECOG-ACRIN CBPF, Attn: Adekunle Raji 
Tel: (844) 744-2420, E-Mail: eacbpf@mdanderson.org 
 
Comments (please note Protocol # and relevant ECOG-ACRIN patient IDs):  
 
Rev. 10/13 
Rev. 12/14 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
137 
Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix VII  
 
PACCT-1 Shipment Notification Form - REMOVED 
All samples submitted from patients participating in PACCT-1 must be logged into the 
online ECOG-ACRIN Sample Tracking System (see Section 10.4). In the event that STS is 
not available at time of sample shipment, use the Generic Specimen Submission Form 
(#2981) found in the forms packet. When STS is available, shipments must be logged 
retroactively into the system, indicating the actual dates of collection and shipment.
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PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
138 
Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix- VIII  
 
Correlative Science for the PACCT-1 Trial 
Background: The clinical trial design of the PACCT-1 trial is based the Genomic Health 
analysis of NSABP B20 described in the preliminary data section. To summarize, the low 
risk group receiving tamoxifen alone experienced an event rate of five relapses out of 
135 cases (4%).  In the intermediate group there were eight relapses out of 45 cases 
(18%).  In the high risk group there were 18 relapses out of 47 cases (38%).  These 
estimates were validated with samples from the tamoxifen arm of the B14 trial.  On the 
chemotherapy plus tamoxifen arm of NSABP B20, the event rates were, 5%, 10% and 
11% respectively.  The advantage for chemotherapy was only statistically significant in 
the high risk group RR 0.258 (0.126-0.528). The design of the PACCT-1 trial is 
essentially a prospective trial to confirm these findings in the context of contemporary 
practice. 
Even if the risk estimates provided by the B14 and B20 analysis are replicated, there 
remain areas for assay improvement, for example: 
1. The registry design will allow study of patients in the low risk group who relapse 
(5%) since they were misclassified as low risk.  Identifying the molecular 
signatures of the tumors that do unexpectedly poorly would allow additional 
biomarkers to be added to the model to ensure that as few patients as possible 
are under-treated. 
2. The registry design will also allow the study of patients in the intermediate and 
high risk groups who relapse despite tamoxifen and chemotherapy.  If patients 
with treatment resistant tumors can be prospectively identified they could be 
singled out for more effective treatment. 
3. There are too few cases in the intermediate group to be certain what the 
chemotherapy benefit is seen within this group.  The randomization of patients 
with intermediate risk scores to chemotherapy versus observation in the PACCT-
1 study is designed to answer this question.  If chemotherapy is shown to provide 
benefit, the over treatment problem will remain substantial for the intermediate 
group because overall the risk status is still favorable.  Alternative risk models or 
a modification of the assay will be a critical focus for further investigation. 
Procedures for accessing samples:  A large number of samples will be accrued 
during the conduct of the PACCT-1 trial.  These samples will be used for independent 
analyses using alternative approaches and statistical models proposed by academic or 
industry investigators.  An important consideration is that the PACCT-1 research must 
be conducted in an “open source” environment as the best models may, in the end, 
involve a synthesis of a number of different biomarker approaches.  The following 
research outlines are not intended to be specific or inclusive, but are designed to inform 
institutional review boards, patients and investigators of the scope of the research that is 
likely to be undertaken.  The samples will be banked at ECOG-ACRIN (FFPE, plasma, 
serum, cells, DNA, RNA and frozen tumor from the virtual tumor bank) and access will 
depend on further approval.  The only correlative science aims that are considered 
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“embedded” are tests for ER, PgR by IHC and HER2 FISH using whole sections, the 
construction of a TMA and a centralized histopathology grading exercise.  Activating an 
new analysis requires the development of a concept sheet (using the standard TBCI 
form) with the active collaboration of the PACCT-1 correlative science committee (CSC) 
to ensure all the relevant components of an application have been provided and the 
proposal has high scientific merit (this is mandatory).  The concept will then be submitted 
to the TBCI correlative science committee for approval (see 
http://ctep.cancer.gov/resources/tbci/).  An approved concept will lead to a PACCT-1 
sub-protocol that will be approved by the CIRB and CTEP.  Institutional IRB approval of 
sub-protocols involving sample analysis will only have to be sought from institutions that 
will receive samples for analysis. All samples will be stripped of identifiers and the 
marriage of clinical and research data will use an honest broker approach to prevent the 
identity of a patient being divulged to laboratory investigators or individual laboratory 
results inappropriately communicated to physicians or patients. 
Summary of approved banking procedures for PACCT-1.  The following banking 
procedures are intrinsic to this protocol and are embedded aspects of the study. 
1. The procurement of five 4 micron sections for H+E, ER IHC, PgR IHC, HER2 
FISH and one spare for assay failures. 
2. TMA construction with three cores. 
3. Baseline plasma and serum banking 
4. Genomic DNA banking from peripheral blood 
5. RNA “left over” from the Genomic Health Assay. 
6. Consent for the acquisition of samples from the “virtual frozen tumor bank”. 
The following considerations provide the rationale for these banking procedures: 
Processing of blocks:  The FFPE blocks will be accessed on an ongoing basis at the 
ECOG-ACRIN CBPF. A cutting schema will be in place for 5 sections for ER IHC, PgR 
IHC, HER2 FISH, Standard H+E and one spare for assay failure problems.  The H+E will 
be reviewed for “block mapping” and central grade assignment and 3 or more cores will 
be removed for TMA construction.  The remaining specimen will then be banked until 
they are ready to be accessed for further analysis through approved sub-protocols. 
If the institution demands the return of the block, after sampling for the tissue microarray 
cores, ten 10 micron sections will be cut and stored in microfuge tubes at -70°C 
(macrodissection will have to be performed at this time if required) and additional 20 five 
micron sections will be cut and mounted on charged slides for storage before returning 
the blocks.  Whole sections will be stored at 4°C in oxidation free storage boxes 
Tissue Microarray (TMA) Construction: The goal of the TMA construction will be a 
resource that can be used to study additional biomarkers in a format that preserves 
resources to the greatest possible extent.   
Tumor RNA banking:  We anticipate that there will be RNA remaining from a significant 
proportion of the specimens after the Oncotype assay has been performed.  This RNA 
will be sent in a timely manner in batches to ECOG-ACRIN for storage.  Sub-protocols 
will be encouraged that test alternative risk models based on mRNA profiling have been 
developed and present alternative solutions to the problem of outcome prediction in 
early stage breast cancer.  These assays, like Oncotype DX, will typically also be based 
on q RT PCR, although other RNA analysis techniques such as microarray analysis 
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PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
140 
could also be entertained. For those cases that RNA is not available, three 10 micron 
sections (six 10 micron sections if macro dissected) of the tissue submitted to the CBPF 
will be processed to extract total RNA for correlative science studies. 
Tumor and adjacent normal tissue DNA.  RNA expression profiling reflects the effect 
of somatic mutation, most obviously through gene over-expression as a result of gene 
amplification.  However other somatic mutations such as deletions and single nucleotide 
mutations probably play an important role in determining the eventual clinical outcome.  
The ability to identify these abnormalities is amenable to high-though put techniques 
such as DNA sequencing and array-based comparative genomic hybridization.   
Baseline plasma and serum banking: Considerable advances in proteomic techniques 
have taken place in the last several years.  These techniques may ultimately prove valuable 
in defining patients with low volume residual disease though the presence of circulating 
tumor products or though certain immune responses to the presence of malignant cells.  
These techniques could prove very valuable in the area of prognosis, which is essentially an 
exercise in the identification of patients with metastatic spread of tumor.  These samples 
could also be used to study steroid hormone level and other risk factors for the development 
of breast cancer. 
Baseline Genomic DNA banking: When clinical data become available from the 
PACCT-1 study, studies of genetic variation can be focused on the impact of genetic 
variation in the efficacy and safety of adjuvant endocrine and chemotherapy treatment.  
For example an Aromatase SNP has already been linked to the outcome of AI therapy 
for advanced disease.  Colomer et al recently reported that advanced disease patients 
with the aromatase polymorphism rs4646 had markedly better time to progression upon 
treatment with letrozole in comparison with those with a “normal” gene.    
Virtual frozen tumor bank. Frozen samples from tumors are reasonably often banked 
under institutional banking protocols.  The consent form of the PACCT-1 trial includes 
language that requests permission to access these samples to address specific 
questions that have been approved though the process outlined above. If patients 
provide consent to future research, frozen tumor tissue that has been collected at the 
local institution will be submitted after registration/randomization or, if retained at the 
local site until requested, will be considered part of the “Virtual Tumor Bank”. In the 
MA27 clinical trial a virtual tumor bank was piloted.  In the initial cohort of over 1000 
patients, approximately 10% of cases were recorded to have frozen tumor banked at the 
institution and that the patient had given permission for the tissue to be sent to another 
institution for analysis.  Thus in a large trial, such as PACCT-1, a relatively large number 
of frozen tumors will be accrued.  ACOSOG will conduct a targeted effort to increase the 
number of tumors banked and available for analysis though this mechanism. 
Central testing of ER, PR, Her2/neu: 
In order to validate the performance of the Oncotype Dx assay, ER, PR, and HER2 centrally 
assayed by ECOG-ACRIN CBPF using tissue microarray sections. ER and PR will be 
assayed with FDA approved Dako PharmDx kits and scored using Allred Scoring system. 
HER2 amplification will be evaluated using Vysis PathVysion FISH assay.  
Web based pathology review:  
H&E slides will be scanned with ScanScope (or other web enabled pathology image 
archiving system) to post the images on the web to the pathology community to 
develop consensus review of histologic grade and mitotic activity index that will 
eventually incorporated for Adjuvant! Evaluation. 
Rev. 9/07 
Rev. 9/06 
 
Rev. 9/06 
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ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
141 
Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix IX 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can be 
downloaded from the ECOG web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN and 
the NCI to increase awareness of the importance of clinical trials and improve accrual and 
follow-through. We appreciate your help in this effort. 
 ___________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important clinical trial.  Many questions remain 
unanswered in cancer.  With the help of people like you who participate in this research, we 
will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care.  Your physician and research staff 
will maintain very close contact with you.  This will allow your physician to provide you with 
the best care while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank you 
again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
142 
Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix X 
 
Oncotype DX Assay Information 
 
This appendix contains examples of the “Oncotype DX Patient Report” and information 
sheets (provided in the Oncotype DX Specimen Kit) distributed by Genomic Health.   
For patients without determined Recurrence Scores:  
To order the “Oncotype Specimen Kit” contact Genomic Health Customer Service 
(866-662-6897).  Kit should be ordered prior to pre-registration. The kit will be 
shipped overnight and will contain instructions, shipping supplies (including 
cyrotubes and slide cassette), and a requisition form containing barcode labels to 
place on the submitted materials.   
As outlined in Appendix V, materials are submitted AFTER pre-registration to 
Genomic Health.  An example of the “Oncotype DX Requisition Form” and 
instructions on how the requisition form MUST be completed are in Appendix V. 
Only one Oncotype Specimen Kit and Requisition form should be completed per 
patient. 
Recurrence Scores determined prior to or during pre-registration: 
After pre-registration, fax a redacted copy of the first page of the “Oncotype DX 
Patient Report” (labeled with protocol number (PACCT1), patient initials and case 
number) to the ECOG-ACRIN Operations Office (FAX: 617-582-8578, Attn: Pre-
registration/PACCT-1). 
Registration/randomization may proceed 24 to 72 hours after submission of the 
report the ECOG-ACRIN Operations Office.   
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
143 
 
 
 
 
 
 
 
 
 
 
 
  
            
D,J                
 
 
                                          PACCT1/#####    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. REDACT 
3. ADD PROTOCOL# AND CASE: 
PACCT1/##### 
2. Add Pt Initials 
DO NOT 
REDACT 
4. FAX REDACTED COPY OF REPORT (labeled as above)  
TO 617-582-8578, ATTN: PACCT1/Pre-registration 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Rev. 7/10 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
145 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
146 
Rev. 7/10 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
147 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
148 
Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix XI 
 
Cancer Trials Support Unit (CTSU) Participation Procedures 
REGISTRATION/RANDOMIZATION 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of the CTSU.  Each investigator must have an NCI investigator number and must maintain 
an “active” investigator registration status through the annual submission of a complete 
investigator registration packet (FDA Form 1572 with original signature, current CV, 
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with 
original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI.  These 
forms are available on the CTSU registered member Web site or by calling the PMB at 240-
276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval 
for this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. All forms and documents associated with 
this study can be downloaded from the PACCT-1 Web page on the CTSU registered 
member Web site (http://members.ctsu.org).  Patients can be registered only after pre-
treatment evaluation is complete, all eligibility criteria have been met, and all pertinent forms 
and documents are approved and on file with the CTSU.  
Requirements for PACCT-1 site registration: 
• 
CTSU IRB Certification 
• 
IRB/Regulatory Approval Transmittal Sheet 
Pre-study requirements for patient enrollment on PACCT-1: 
• 
Patient must meet all inclusion criteria, and no exclusion criteria should apply. 
• 
Patient has signed and dated all applicable consents and authorization forms. 
• 
All baseline laboratory tests and prestudy evaluations performed (including tumor, blood, 
and plasma samples). 
• 
Contact Genomic Health Customer Service (866-662-6897) and request the “Oncotype 
Specimen Kit” for mandatory submission of one tumor block for the determination of the 
Oncotype DX Recurrence Score.  If the kit is not available at time of pre-registration, it 
must be ordered within 24 hours following pre-registration. Materials must be submitted 
no later than 3 days after pre-registration as outlined in section 10.1. 
[If patient previously had an Oncotype DX Recurrence Score performed by Genomic 
Health, and the RS is 11-25, blocks should be submitted for central review following 
registration as outlined in section 10.3.] 
CTSU Procedures for Patient Enrollment 
Please see Section 4 of the protocol for instructions on using the OPEN registration system. 
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Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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Reminder: If the “Oncotype Specimen Kit” is not available at time of pre-registration, it must 
be ordered within 24 hours following pre-registration. 
Oncotype DX Assay and Recurrence Scoring  
• 
If patient previously had an Oncotype DX Recurrence Score performed by Genomic 
Health, and the RS is 11-25, a redacted copy of the first page of the Oncotype DX 
Patient Report should be FAXed to the ECOG-ACRIN Operations Office – Boston 
(617-582-8578, ATTN: Pre-registration/PACCT-1) within 24 to 72 hours (if weekend or 
holiday) of pre-registration. Indicate on the report the protocol number (PACCT-1), and 
patient’s ECOG-ACRIN pre-registration sequence number. 
• 
If patient is having an Oncotype DX Assay performed by Genomic Health, Genomic 
Health will notify the submitting site of the assay results within 14 working days of 
receipt of the sample. Once received, FAX a redacted copy of the first page of the 
“Oncotype DX Patient Report” to the ECOG-ACRIN Operations Office – Boston prior to 
registration/randomization (617-582-8578, ATTN: Pre-registration /PACCT-1). Indicate 
on the report the protocol number (PACCT-1), and patient’s ECOG-ACRIN pre-
registration sequence number. 
Important notes: 
• 
In all cases, the first page of the “Oncotype DX Patient Report” must be faxed to the 
ECOG-ACRIN Operations Office – Boston prior to proceeding to 
registration/randomization. 
• 
It will take 24 hours and up to 72 hours (if weekend or holiday) for ECOG-ACRIN to 
enter the Oncotype DX Patient Report results in their system, therefore CTSU 
CANNOT register/randomize a patient until this time has lapsed. 
Registration/Randomization  
Important: It will take 24 hours and up to 72 hours (if weekend or holiday) for ECOG-ACRIN 
to enter the Oncotype DX Patient Report results in their system, therefore CTSU CANNOT 
register/randomize a patient until this time has lapsed. 
Patients must not start protocol treatment prior to registration/randomization. 
Treatments should begin within 14 working days after registration/randomization. 
DATA SUBMISSION  
All documentation associated with this study may be downloaded from the PACCT-1 Web 
page located on the CTSU registered member Web site (http://members.ctsu.org).  CTSU 
investigators must use the current version of all documents and forms and adhere to the 
PACCT-1 schedule for data submission. 
Submission via Hard Copy  
Original and amended post-enrollment CRFs (including Specimen Submission forms), 
clinical reports and responses to query and delinquency letters must be faxed directly to the 
CTSU Data Operations Center accompanied by a properly completed TAILORx CTSU Data 
Transmittal Form. Copies of clinical reports must also be accompanied by a completed 
TAILORx Source Document Tracking Coversheet (Form #2533). Please remember to 
include the Patient ID and protocol number on all pages of the report and redact the 
patient's name. 
Rev. 9/06 
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       9/07 
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Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
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A TAILORx CTSU Data Transmittal Form must accompany all data submissions. Data 
submitted with an improperly completed TAILORx CTSU Data Transmittal Form or without a 
TAILORx CTSU Data Transmittal Form will be returned to the site for corrective action 
without being processed. Fax documents to 301-545-0406. 
Submission via Remote Data Capture  
(These instructions are ONLY for pre-selected RDC sites.  These sites were selected 
by ECOG-ACRIN and will submit patient data via CTSU’s  RDC system.) 
All participating sites are required to submit patient data via the CTSU’s Remote Data 
Capture (RDC) system. The CTSU Remote Data Capture system allows sites to enter 
patient data into an Oracle Clinical ® (OC) database over a secure Internet connection.  The 
RDC system also allows for data correction at the point of entry, and is used to 
communicate and resolve issues relating to discrepant data. Sites can connect to the OC-
RDC application via the Remote Data Capture link on the CTSU member website.  
Institutional pathology reports and other clinical reports cannot be entered in the OC-RDC 
application; therefore, a copy accompanied by a completed TAILORx Source Document 
Tracking Coversheet (Form #2533) should be faxed to the CTSU Data Operations for 
tracking purposes. Please include the Patient ID and protocol number on all pages of the 
report and redact the patient’s name. Submit along with a completed TAILORx CTSU Data 
Transmittal Form. 
Sites experiencing technical problems (e.g., firewall issues) with RDC must contact the 
CTSU help desk  
(1-888-823-5923) to obtain permission for a waiver to submit hard-copy CRFs in lieu of 
using RDC.   
SPECIAL MATERIALS OR SUBSTUDIES 
Submission of Mandatory Tumor Block: 
Mandatory submission of one tumor block for the determination of the Oncotype DX 
Recurrence Score is to be submitted to Genomic Health (see section 10 and Appendix V).  
Kits for tissue submission and Oncotype DX Recurrence Score assessments must be 
ordered within 24 hours following pre-registration. Samples are to be submitted within 3 
days of pre-registration. Pathology report and the ECOG-ACRIN Generic Specimen 
Submission Form (#2981) must be completed and copies distributed to both Genomic 
Health (with the samples and requisition form) and the ECOG-ACRIN CBPF.  If the 
Recurrence Score was previously determined by Genomic Health, tissue block MUST be 
submitted to the ECOG-ACRIN CBPF within 2 weeks following randomization. 
All materials and reports must be labeled with the Patient ID and protocol number; patient 
names should be redacted from the pathology report.  Specimens should not be submitted 
to the CTSU, although CTSU should be copied on all transmittal forms (Oncotype DX 
Requisition Form) and pathology reports. Starting June 2007, all specimens submitted for 
this study must be entered and tracked using the ECOG-ACRIN Sample Tracking System. 
Upon registering new patients to these studies, you can expect to receive an automatic 
email with instructions for logging into the system and shipping samples. You can also 
access the Tracking System from the CTSU Member Web Site. Go to the PACCT-1 protocol 
page and click on the link provided under the Case Report Forms header. See protocol 
Section 10 and Appendix V for further details on shipping details, sample collection and 
preparation.   
Special Notes for pre-selected Remote Data Capture (RDC) sites: 
Rev. 9/06 
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       8/08 
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PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
151 
 
Institutional pathology reports and other clinical reports cannot be entered in the OC-RDC 
application; therefore hard copy should be submitted as described in the section above 
under the header “Submission of Mandatory Tumor Block” and accompanied by a 
completed TAILORx Source Document Tracking Coversheet (Form #2533). 
Sites experiencing technical problems (e.g., firewall issues) with RDC must contact the 
CTSU help desk (1-888-823-5923) to obtain permission for a waiver to submit hard-copy 
CRFs in lieu of using RDC. 
Additional Studies/Banking: 
Provided patient consent is obtained, primary tumor tissue is to be submitted within two 
weeks following registration/randomization for laboratory studies (defined in section 10) and 
banking for future research.  Peripheral blood and plasma samples, requested for banking 
for possible use in future studies, are to be collected after registration/randomization, prior to 
start of treatment. 
Shipping and collection kits for the frozen tissue and blood samples are ordered by 
completing the PACCT-1 Peripheral Blood Collection and Shipping Kit Order Form 
(Appendix VI) and Faxing to Zemotak-International at 800-815-4675.  For submissions 
pertaining to the EL112LAB Ancillary, guidelines for collection and submissions are outlined 
in Appendix XII.  For all other submissions, see Section 10, Appendix V and Appendix VI for 
details on sample collection, preparation, and shipping.  All materials and reports must be 
labeled with the Patient ID and protocol number; patient names should be redacted from the 
pathology report.  Specimens should not be submitted to the CTSU, although CTSU should 
be copied on all transmittal forms (Generic Material Submission Form (#2981) if STS is 
unavailable) and the pathology reports.  
Special Notes for pre-selected Remote Data Capture (RDC) sites: 
All Specimen bank submission CRFs must also be entered in the CTSU RDC system. 
Institutional pathology reports and other clinical reports cannot be entered in the OC-RDC 
application; therefore, hard copy should be submitted as described in the section above 
under the header “Additional Studies/Banking” and accompanied by a completed TAILORx 
Source Document Tracking Coversheet (Form #2533). 
Sites experiencing technical problems (e.g., firewall issues) with RDC must contact the 
CTSU help desk (1-888-823-5923) to obtain permission for a waiver to submit hard-copy 
CRFs in lieu of using RDC. 
ADVERSE EVENT (AE) REPORTING  
Assessing and submitting expedited reports 
All toxicities should be graded according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
The CTCAE version 4.0 is identified and located on the CTEP website at 
http://ctep.cancer.gov. All appropriate treatment areas should have access to a copy 
of the CTCAE version 4.0. CTSU investigators should assess adverse events according to 
the instructions and tables in Section 5.3 of the protocol. All reporting should be conducted 
within the time frames specified in Section 5.3 of the protocol.   
CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) 
regarding submission of documentation of adverse events.  Local IRBs must be informed of 
all reportable serious adverse events.  
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Expedited reports should be transmitted electronically using the CTEP CTEP-AERS 
application. A link to the CTEP-AERS application can be found on the CTSU member 
homepage. 
Some adverse events require CTEP-AERS 24-hour notification to NCI and ECOG-ACRIN 
(refer to table 5.3.3).  Select the 24 Hour Notification reporting track in the CTEP-AERS 
system.  A full CTEP-AERS report is due within 5 calendar days. 
NOTE: Although most study data, from ECOG-ACRIN and non-ECOG-ACRIN institutions 
alike, is submitted to CTSU Data Operations, this does not include Expedited 
Adverse Event Reporting; data regarding expedited AEs must be submitted to 
ECOG-ACRIN and the NCI (not CTSU).  Please follow instructions in protocol 
section 5.3 for submission of AE data. 
Secondary AML/MDS/ALL reporting: 
Upon diagnosis of AML/MDS/ALL, please submit copies of the following to ECOG-ACRIN: 
• 
NCI Secondary AML/MDS/ALL Report Form,  
 
• 
Pathology report confirming the AML/MDS/ALL 
• 
Cytogenetics report (if available) 
[Deleted in Addendum #2] 
Reporting other secondary malignancies: 
Upon diagnosis of a secondary cancer, please submit copies of the following to the CTSU 
within 30 days of diagnosis: 
* Second Primary Form (#1677)  
* A copy of the pathology report (if available)  
* Any additional supporting documentation 
[Deleted in Addendum #2] 
DRUG PROCUREMENT: 
CTSU investigators should refer to Section 8 for detailed instructions on drug procurement, 
formulation, storage, administration, and potential toxicities.   
Commercial agents: 
Cyclophosphamide, Methotrexate, Fluorouracil (Infusional), 
Doxorubucin, Paclitaxel, Epirubicin, Docetaxel, Tamoxifen, 
Exemestane, Anastrozole, Letrozole 
REGULATORY AND MONITORING 
Study Audit 
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 
314 and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation 
Program (CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the conduct of 
clinical trials and study data validity, all protocols approved by NCI/CTEP that have patient 
enrollment through the CTSU are subject to audit. 
Responsibility for assignment of the audit will be determined by the site’s primary affiliation 
with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered 
through CTSU will become the responsibility of the Group receiving credit for the enrollment. 
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9/07
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For CTSU Independent Clinical Research Sites (CICRS), the CTSU will coordinate the 
entire audit process.  
For patients enrolled through the CTSU, you may request the accrual be credited to any 
Group for which you have an affiliation provided that Group has an active clinical trials 
program for the primary disease type being addressed by the protocol. Per capita 
reimbursement will be issued by the credited Group provided they have endorsed the trial, 
or by the CTSU if the Group has not endorsed the trial. 
Details on audit evaluation components, site selection, patient case selection, materials to 
be reviewed, site preparation, on-site procedures for review and assessment, and results 
reporting and follow-up are available for download from the CTSU Operations Manual 
located on the CTSU Member Web site. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
The HIPAA Privacy Rule establishes the conditions under which protected health 
information may be used or disclosed by covered entities for research purposes. Research 
is defined in the Privacy Rule referenced in HHS 45 CFR 164.501. Templated language 
addressing NCI-U.S. HIPAA guidelines are provided in the informed consent section of this 
protocol document; however, authorization for the release of Protected Health Information is 
considered separate and distinct from the Informed Consent process for participation in this 
clinical trial.  Templated language addressing NCI-U.S. HIPAA guidelines are provided in 
the HIPAA Authorization Form located on the CTSU website 
The HIPAA Privacy Rule does not affect participants from outside the United States. 
Authorization to release Protected Health Information is NOT required from patients enrolled 
in clinical trials at non-US sites. 
Clinical Data System–Web (CDS-Web) Monitoring 
This study will be monitored by the Clinical Data System (CDS-Web).  The sponsoring 
Group fulfills this reporting obligation by transmitting the CDS data collected from the study-
specific case report forms, via the Web to the NCI Center for Biometrics (NCICB). 
Cumulative CDS data are submitted quarterly. 

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Program for the Assessment of Clinical Cancer Tests (PACCT-1): 
Trial Assigning IndividuaLized Options for Treatment:  
The TAILORx Trial 
 
Appendix XII 
Ancillary Study EL112LAB 
North American Breast Cancer Groups Biospecimen Bank for Determinants of 
Late Relapse in Operable Breast Cancer 
Study PI:  Joseph Sparano, MD 
Study Statistician:  Robert Gray, Ph.D.  
Patients registered to treatment on E5103 or PACT1 who meet the criteria outlined in section 
XII.6 are eligible to participate in this ancillary study. Patients must provide written signed 
consent, additional to that from participation in the treatment trial, to participate in this ancillary 
study.  
Guidelines for enrollment and submission of data and specimens are outlined below in Section 
XII.6. A model consent for this ancillary study is provided as a sub-appendix (Appendix I-A) to 
the model consent of the respective treatment trial. 
XII.1 
Hypothesis and Specific Aims 
Late relapse (defined as occurring 5 or more years after diagnosis) accounts for up to 
one-half of all breast cancer recurrences, and is difficult to study because of the lack of 
adequate biospecimens linked to clinical data with sufficiently long follow-up. In addition, 
recurrence may be driven by dynamic rather than static host factors that may wax or 
wane with time. We propose that our current paradigm of assessing and 
counseling solely at diagnosis may need to be reconsidered to include a second 
evaluation point 5 or more years after diagnosis when patients continue to be at 
risk for recurrence, and needs to include an evaluation of both tumor and host-
related factors in the context of competing risks. We hypothesize that tumor and 
host-related factors contributing to recurrence that may be identified and 
potentially modifiable via pharmacologic or nutritional or other lifestyle 
interventions.  
Our specific aims include:  
1. To create a biospecimen repository including plasma, serum and CellSearch™ 
cassettes containing circulating tumor cells (CTC) for evaluating determinants of 
late relapse, including candidate biomarkers reflecting occult tumor burden 
(e.g., CTCs and plasma tumor DNA) and host factors  (e.g., estrogen, insulin-IGF 
axis, inflammation, etc).  
2. To create a biorepository of metastatic tumor samples in patients who have had 
a late relapse.  
3. To determine body mass index (BMI) and comorbidity burden in patients with 
operable breast cancer five or more years after diagnosis.  
4. To determine whether there is a relationship between late relapse and BMI at 
diagnosis and at 5 years after diagnosis, and whether BMI-associated 
inflammatory and/or metabolic biomarkers are associated with early and late 
recurrence.  

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XII.2 
Background and Significance 
Late relapse occurring after 5 years or more after a diagnosis of operable breast cancer 
is a major clinical problem accounting for up to one-half of all relapses in ER-positive 
disease, but also may occur unpredictably in other breast cancer subtypes.[1,2] For 
example, when evaluating patterns of recurrence in 4950 eligible patients enrolled in the 
E1199 trial who received adjuvant chemotherapy (plus endocrine therapy if ER-
positive)[3], the annual hazard rate (HR) of recurrence within the first 5 years of diagnosis 
was about 3-fold higher for patients with triple negative breast cancer (TNBC) and 2-fold 
higher for HER2/neu-positive (HER2+) breast cancer compared with ER- and/or PR 
positive, HER2-negative disease (ER+/PR+), but was higher for ER+/PR+ disease 
compared with other subtypes beyond 5 years and remained consistent over time 
(Figure 1A, left).[4] In addition, host factors such as body mass index (BMI) at diagnosis 
may contribute to late relapse, especially in ER+/PR+ disease (Figure 1B, right). Two 
prior reports have found a similar association.[5] [6]  
Figure 1A 
 
 
 
 
 
Figure 1B 
0.00
0.03
0.06
0.09
0.12
0.15
Recurrence hazard rate
0
1
2
3
4
5
6
7
8
9
10
Time (years)
TN
ER+/PR+
HER2+
Recurrence hazard rate by cancer subtype
0.00
0.03
0.06
0.09
0.12
0.15
Recurrence hazard rate
0
1
2
3
4
5
6
7
8
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10
Time (years)
TN, non-obese
TN, obese
ER+/PR+, non-obese
ER+/PR+,obese
HER2+, non-obese
HER2+,obese
Recurrence hazard rate by cancer subtype and obesity
 
 
Figure 1A (left): Annual hazard rate (HR) for recurrence for patients with operable breast cancer treated 
with adjuvant sequential doxorubicin/cyclophosphamide-taxane therapy in trial E1199, including patients 
with ER- and/or PR-positive, HER2 negative disease (ER+PR+), triple negative disease (TN) and 
HER2/neu positive disease (since there was limited information beyond 8-9 years, the confidence 
intervals are wide at the tails of these curves) 
Figure 1B (right): HR of recurrence in obese (BMI >/= 30 kg/m2) vs. non-obese patients at diagnosis.  
There are no clinical or pathologic features predictive of late relapse; gene expression 
assays predict earlier recurrences.[7] [8] Although extended adjuvant therapy with an 
aromatase inhibitor given for up to 5 years after 2-5 year course of tamoxifen therapy 
has been shown to reduce the risk of recurrence in ER-positive disease, the absolute 
benefits are low, resulting in many patients receiving unnecessary therapy.[9] 
XII.3 
Candidate Biomarkers for Late Recurrence: Plasma Tumor DNA, Insulin/IGF Axis, 
and Inflammation 
Plasma Tumor DNA and Circulating Tumor Cells (CTCs). Several assays are 
available that may detect occult tumor burden, but their clinical utility has not been 
established. Detection of circulating tumor DNA in the blood of cancer-free patients is 
one such assay, although the sensitivity, specificity, and positive/negative predictive 
value for predicting recurrence is currently unknown.[10] Enumeration of CTCs in the 
blood (≥ 1 CTC in 7.5 ml blood) has also shown to be associated with recurrence when 

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detected in patients with operable breast cancer who have not yet had surgery[11], but 
has not been evaluated as a predictor of recurrence in patients who are cancer free for 
at least 5 years after surgery. Measurement of both plasma tumor DNA and CTC in 
the same patients at the same time offers an excellent opportunity to evaluate and 
directly compare these two technologies. Although the CTC enumeration must be 
done in real time, the results will not be provided to the clinician or patient for clinical 
decision making. CellSearch™ cassettes containing the CTC will be dried and stored for 
future analysis. Plasma will be evaluated at a future date when the technology has been 
optimized, and when the sample collection has been completed and there is sufficient 
clinical follow-up and events to permit an analysis.    
Insulin-IGF Axis. As described above, obesity at diagnosis is associated with late 
relapse in ER+PR+ disease. Obesity is associated with hyperinsulinemia, and higher 
fasting insulin levels have been associated with increased breast cancer risk[12] and 
breast cancer recurrence.[13-15] The relation of obesity with insulin resistance, metabolic 
syndrome, and cardiovascular disease has been shown to vary. The concept of the 
“healthy obese” – a subset of patients who demonstrate few pernicious effects related to 
their obesity – has been described and increasingly studied.[16] This could apply as well 
to cancer risk in obese patients. Thus, risk stratification by relevant “pernicious 
biomarkers” could potentially be important in identifying which obese patients are at 
increased risk of recurrence and would therefore benefit from specific interventions. 
Insulin shares substantial amino acid sequence homology, downstream signaling 
pathways, and mitogenic/anti-apoptotic activity with insulin-like growth factor (IGF)-1, a 
peptide hormone that mediates many of the growth effects of growth hormone. Insulin 
receptors are expressed at high levels in breast cancer cell lines[17] and human breast 
cancer specimens.[18] Insulin decreases levels of sex hormone binding globulin (thereby 
increasing free estradiol)[19], upregulates androgen secretion by the ovaries[20], increases 
HR expression and binding capacity[21], and induces proliferation in normal and 
dysplastic breast epithelial cells. [21,22] Moreover, higher expression of activated IGF-
1/insulin receptors has been associated with higher risk of recurrence[23], and IGF 
signaling has been associated with resistance to paclitaxel.[24] Elevated HOMA 
(homeostasis model assessment) scores and low levels of adiponectin (both associated 
with obesity) were associated with increased breast cancer mortality in women enrolled 
in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a prospective cohort study of 
women with stage I-IIIA breast cancer.[25] The HOMA score is a method for assessing ß-
cell function and insulin resistance ([insulin µ/mL X glucose mmol/L]/22.5).[26] In addition, 
chronic hypergylcemia (reflected by an elevated Hemoglobin A1C level) has been 
associated with a higher risk of breast cancer recurrence and death.[27] Finally, a 
systematic review and meta-analysis examining the effect of pre-existing diabetes on 
breast cancer-related outcomes found that diabetics had a greater risk of death and 
present with more advanced stage disease. [28] The IGF-axis also includes and IGF-2, a 
related growth factor, and six IGF binding proteins (IGFBPs) which have both IGF-
dependent and independent effects. In addition to their levels in circulation, IGF-axis 
proteins are produced locally in tissues with autocrine and paracrine activity. HR-positive 
breast cancers exhibit significantly higher gene expression of the IGF pathway.[29] 
Widespread gene expression alterations have been described in breast tumors from 
obese patients as compared to other tumors, which resulted in identification of a 662 
gene signature; this signature correlated in publicly available datasets with a gene 
signature for IGF signaling, and in one cohort was associated with a shorter time to 
recurrence.[30]  

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Inflammation. There is also compelling evidence that obesity produces a systemic 
inflammatory state[31], which in some settings may promote neoplastic transformation or 
growth.[32] In both dietary and mouse genetic models of obesity, necrotic adipocytes 
surrounded by macrophages form crown-like structures (CLS) in the mammary glands 
and visceral fat, and are associated with activation of NF-kappaB, proinflammatory 
mediators, and elevated levels of aromatase.[33] Indeed, it has been shown that the 
relative benefit of the aromatase inhibitor (AI) anastrozole versus tamoxifen tends to be 
better in leaner women compared to overweight women in the ATAC trial.[34] It is 
conceivable therefore, that CLS may serve as biomarker for AI resistance, and such 
patients may require tamoxifen or higher than conventional AI dosing in order to 
adequately suppress the estrogen signaling. 
Given the important role that each of these factors described above, a late relapse 
biospecimen bank will facilitate evaluation of tumor and host factors that may 
contribute to recurrence. Potential candidate biomarkers therefore include 
biomarkers reflecting occult tumor burden (plasma tumor DNA  and CTCs) and 
host factor (possibly including but not limited to estrogens and their metabolites, 
inflammatory markers, and multiple components of the insulin/IGF-axis ligand and 
receptor levels in circulation and in tissues). Moreover, an ongoing NCI-sponsored 
clinical trial (MA32) is evaluating the role of metformin to prevent early recurrence within 
5 years, and will attempt to identify predictive biomarkers of benefit (similar to those 
being evaluated in this proposal). Should that trial prove to be positive, this will provide a 
foundation whether metformin or other strategies may be useful in preventing late 
relapse. 
XII.4 
Comorbidities and Competing Risks in Operable Breast Cancer 
From 2004-2008, the median age at diagnosis for cancer of the breast was 61 years of 
age, and approximately 16% were 70 years of age or older (including 15.5% between 75 
and 84 and 5.6% 85+ years of age) 
(http://seer.cancer.gov/statfacts/html/breast.html#references). Comorbidities are 
common in the elderly and pose a competing risk that attenuates the potential benefit of 
adjuvant therapy. For women with early stage ER-positive breast cancer, the risk of 
death enrolled in the ATAC trial from causes other than breast cancer at 10 years 
ranges from 20-60%. [35] Given our focus on factors contributing to late relapse, it 
will be critical to evaluate competing risks in this patient population who will be 
on average at least 5 years older than at presentation.  
XII.5 
Research Plan 
We propose to evaluate patients enrolled on two ECOG-ACRIN-coordinated adjuvant 
trials, including: (1) E5103: This trial accrued 4994 patients with node-positive (or high 
risk node-negative), HER2/neu negative operable breast cancer between 11/2/07 and 
2/28/11.  All patients received sequential doxorubicin/cyclophosphamide-paclitaxel 
chemotherapy alone or in combination with bevacizumab, plus endocrine therapy for 
patients with ER-positive disease (2) TAILORx: This trial enrolled 10,273 patients with 
ER-positive, HER2/neu negative, node negative breast cancer between 4/7/06 and 
10/6/10, of whom 1629 with a Recurrence Score (RS) < 11 were assigned to endocrine 
therapy alone, 1737 with an RS > 25 were assigned to chemotherapy plus endocrine 
therapy, and 6907 were randomized to endocrine therapy vs. chemoendrocrine therapy.  
Consenting trial participants in both trials had banking of tumor, germ-line DNA, and 
serum/plasma at baseline. This proposal will be accomplished by amending the 
current protocols. Sites will be notified about potentially eligible subjects by the 
ECOG-ACRIN Operations Office – Boston.  
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We will identify patients who meet the following criteria: (1) alive and disease-free 
between 4.5-7.5 years after registration in the parent trial, (2) willingness to sign 
informed consent and donate blood specimens annually x 5 years after registration. In 
addition to being followed for recurrence, second primary cancer, and survival in 
accordance with the parent protocol, patients will also be evaluated at 6 time 
points (in E5103) as described in the table below, including 1 CTC measurement at 
baseline. Patients who have a recurrence will be asked to provide a blood specimen 
and specimen from the metastatic tumor (when feasible).  
Serum/plasma samples will be forwarded to the ECOG-ACRIN Central Biorepository and 
Pathology Facility (CBPF). CTC samples will be sent to and analyzed within 96 hours of 
collection in the laboratory of Dr. Katherine Alpaugh at the Fox Chase Cancer Center 
using CellSave tubes and the Veridex CellSearch™ platform, which allows detection of 
as few as 1 CTC/9 ml blood. The Alpaugh lab has considerable expertise in CTC 
measurement in both research and clinical settings. [36-39]The CTC portion of the 
laboratory is CLIA certified to perform the FDA-approved clinical diagnostic testing for 
metastatic breast, prostate and colon cancer and has a CTC research division exploring 
alternative CTC separation methods to obtain single CTC for mutational gene analysis. 
The laboratory has supported two previous ECOG studies (E1104 and E1105) and four 
GOG studies for which samples were shipped for analysis. 
XII.6 
Patient Participation Requirements for Ancillary Study EL112LAB  
The ECOG-ACRIN Operations Office – Boston will provide sites a list of patients who 
have been identified as potential candidates for EL112LAB. The information provided will 
include the date range for which the patients would be eligible to participate which is 
dependent on the date of randomization to treatment.  Routine notifiers will also be 
utililized to serve as reminders to sites regarding the timeline of a patient’s potential 
eligibility. 
The list of potentially eligible patients at your site will be provided via a password 
protected WebPortal.  The location and access information to the WebPortal: 
web link: https://webapps.ecog.org/LabStudyEligible/   
web name: EL112LAB Potential Eligible Patient List 
You access the WebPortal using your CTSU login and password. Access to the listing 
will be based on your site association assignment in RSS, thus it is important that the 
sites' contacts are up to date with CTEP. 
The listing of eligible patient will be rolling, being updated as new patients enter the 
eligibility window.  The list is based on time of registration to treatment on the respective 
parent trial, are alive and recurrence free, and have not withdrawn participation from 
follow-up on the respective trial as reported to ECOG-ACRIN or the CTSU on the 
relevant study forms.  Full eligibility requirements are outlined below.  Actual patient 
eligibility is to be verified by the site prior to registration to EL112LAB and collection of 
the EL112LAB blood specimens. 
XII.6.1 Patient Eligibility 
Patients must meet the following criteria: 
1. Patient was registered to treatment on ECOG trials E5103 or PACT1/ 
TAILORx, at least 4.5 years (54 months) and no more than 7.5 years (90 
months) prior to registration to step 3. It is preferable for patients to be 
registered to step 3 at 5 years (60 months +/- 6 months) after registration 
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to treatment on the relevant clinical trial. Patient must be willing to 
contribute the required information and specimens, 
2. Patient is disease free, with no prior recurrence, at time of registration to 
EL112LAB. 
3. Patient must be willing to contribute the required information and 
specimens.  
4. Previous submission of tumor tissue or blood specimens: 
a. E5103 patients – If primary tumor specimens had not been 
submitted after patient registered to treatment per E5103 Section 
10, tumor tissue must be available for submission within 4 weeks 
following registration to Step 3 
b. PACT1/TAILORx - The primary tumor tissue and peripheral blood 
samples were previously submitted for research studies just prior 
to or following registration to treatment as outlined in 
PACT1/TAILORx Section 10. 
5. Patient must provide written signed consent to participate in the Ancillary 
Substudy EL112LAB: North American Breast Cancer Groups 
Biospecimen Bank for Determinants of Late Relapse in Operable Breast 
Cancer.  The model consent for the substudy is provided as Appendix I-A 
of the relevant parent clinical trial. 
XII.6.2 Registration to the Ancillary Study EL112LAB 
Patients are registered to Step 3 as outlined in Section 4 of the parent protocol 
(E5103, section 4.11; PACCT-1/TAILORx section 4.4). 
Regarding timing of Registration to EL112LAB, blood collection and 
sample submission: 
It is understood that blood collection may immediately follow obtaining the 
patient’s consent to participate in EL112LAB, thus registration to EL112LAB may 
follow the blood collection. If this occurs, register the patient to step 3 within 48 
hours following the blood collection. Step 3 registration is required to update the 
consent permission for the specimen collection and use. Note that STS will allow 
logging the samples prior to registration to step 3 and report the actual date of 
blood collection. 
If the blood collection is delayed more than 1 week following time of consent, 
registration to EL112LAB (step 3 registration) is to be delayed until just prior to 
the blood draw. Expectancy timepoints are tagged from date of registration, not 
time of actual collection. A long time frame between registration to EL112LAB 
and the initial EL112LAB blood draw will result in expectancy tracking problems 
for the site and the lab. 
XII.6.3 Data and Specimen Submissions 
NOTE: 
Requirements for EL112LAB do NOT impact or change the 
requirements of the parent protocol. 
A. Comorbidity, BMI and Menstrual History  
EL112LAB Comorbidity Form is to be completed at time of registration to 
EL112LAB. 
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The EL112LAB Menstrual History Form is to be completed at the following 
time points: 
• 
Registration to EL112LAB 
• 
Years 1,2,3,4,5 from time of registration to EL112LAB 
Please refer to the Forms Packet of the relevant parent clinical trial for copies 
of the forms. The E5103 or PACT1/TAILORx Forms Packet may be 
downloaded by accessing the ECOG World Wide Web Home Page 
(http://www.ecog.org) or from the CTSU website. Forms must be submitted to 
the ECOG-ACRIN Operations Office – Boston (ATTN: DATA) at FSTRF, 900 
Commonwealth Avenue, Boston, MA 02215. 
B. Specimen Submissions 
To order the blood collection/submission kits, complete the EL112LAB 
Collection and Shipping Kit Order Form and Fax to Zemotak-International at 
(800) 815-4675. This form may be located in E5103 Appendix XIV or 
PACT1/TAILORx Appendix- VI. 
It is strongly encouraged that blood collections be FASTING blood draws 
and occur at the time the patient attends the clinic for their standard or follow-
up appointments to monitor their health. Trips to the clinic specifically for 
collection of these research samples are not required. If draw is not a fasting 
draw, report the date and time of last caloric intake in STS. 
All sample submissions must be logged and tracked using the ECOG-ACRIN 
Sample Tracking System (STS).  The STS generated shipping manifest is 
to be included with all shipments. If STS is unavailable at time of sample 
submission, follow the instructions in section 10.4 of E5103 or 
PACT1/TAILORx. 
Access to the shipping account for specimen shipments for this project 
can now only be obtained by logging into fedex.com with an account issued 
by the ECOG-ACRIN CBPF. For security reasons, the account number will 
no longer be given out in protocols, over the phone, or via email. If your site 
needs to have an account created, please contact the ECOG-ACRIN CBPF 
by email at eacbpf@mdanderson.org 
Specimen collection and submission requirements are summarized in Table 
2. Collection tubes are listed in order of recommended draw order, however 
follow your institutional draw order requirements.  
All specimens submitted must be labeled with the parent protocol number, 
the ECOG-ACRIN protocol specific patient ID, patient initials, date of 
collection and sample type (e.g. PST, RST, PPT, CTAD, Immunex). 
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Table XII.1 
Specimen Submission Summary 
 
Specimen Type 
Collection type 
Protocol: Time points 
Submit to: 
 
Plasma1,2 + 
residual cells 
(WBC+RBC) 
CTAD (sodium citrate, theophylline, 
adenosine, dipyridamole;light blue 
top) 
E5103 
• 
Registration to 
EL112LAB 
• 
Years 1,2,3,4,5 
• 
Recurrence 
PACT1/TAILORx 
• 
Registration to 
EL112LAB 
• 
Recurrence 
ECOG-ACRIN 
Central 
Biorepository and 
Pathology Facility 
(CBPF) 
 
Serum1,2 
Rapid Serum Tube (RST – no 
anticoagulant, orange top) 
 
Plasma1,2 
Plasma Separator Tube (PST – 
lithium heparin, green top), 
 
Plasma1,2 
Plasma Preparation Tube (PPT - 
EDTA, pearl white top) 
 
Peripheral 
Blood1 
CellSave® 
E5103 
• 
Registration to 
EL112LAB 
Fox Chase Cancer 
Center 
Clinical Protocol 
Support Lab, 
P2011 
 
 
Rev. 10/13 Tumor Tissue 
Block 
Primary Tumor 
E5103 
Required if not 
previously submitted 
ECOG-ACRIN 
Central 
Biorepository and 
Pathology Facility 
(CBPF) 
 
Recurrence, diagnostic biopsy 
All patients 
1. FASTING DRAWS STRONGLY ENCOURAGED. Date and time of specimen 
collection and last caloric intake is to be provided, via STS, with submission of the 
blood specimens. 
2. If a kit is not available at time of sample collection, institutional supplies may be 
utilized. If the equivalent tube types cannot be obtained, the following standard tubes 
may be substituted:  RST = SST or red top, PST = heparin (green top) tube, PPT = 
EDTA (purple top) tube, CTAD = citrate (light blue top). For E5103 patients, there are 
no substitutions for the CellSave® vacutainers. 
I. 
Submission to the FCCC Clinical Protocol Support Laboratory (LAB015) 
Peripheral Blood (Veridex CellSave Tubes): Draw 9 mL of blood into each 
tube. Sample must be shipped day of collection at ambient temperature. DO 
NOT REFRIGERATE SAMPLE 
FASTING DRAWS STRONGLY ENCOURAGED. Provide date and time of 
last caloric intake in STS. 
Samples must be sent by overnight courier at ambient temperature on the 
day of collection to address below. Questions may be directed to Kathy 
Alpaugh at (215) 214-1634 or email (rk_alpaugh@fccc.edu).  Samples must 
be sent to arrive Monday through Friday. The laboratory is CLOSED on 
Saturdays, Sundays and holidays. IF DRAWN ON A FRIDAY mark the 
waybill “FOR MONDAY DELIVERY”. If to be drawn on a DAY BEFORE A 
HOLIDAY, telephone the Fox Chase Laboratory to receive alternative 
shipping instructions. 
Rev. 10/13 
Rev. 10/13 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
162 
Ship Veridex tubes only to: 
Fox Chase Cancer Center 
Clinical Protocol Support Lab, P2011 
Attn: Kathy Alpaugh 
333 Cottman Avenue 
Philadelphia, PA 19111-2497 
II. 
Submissions to the ECOG-ACRIN Central Biorepository and Pathology 
Facility (CBPF) 
Questions are to be directed to the ECOG-ACRIN CBPF at 
eacbpf@mdanderson.org or call 844-744-2420. 
a. Plasma and Serum Samples 
• 
FASTING DRAWS STRONGLY ENCOURAGED. Provide date and 
time of last caloric intake in STS.  
• 
Peripheral blood should be collected into each vacutainer. 
• 
Immediately invert tube several times: CTAD, 3-4 times; RST, 5-6 
times; PPT and PST, 8-10 times. 
• 
For the RST tube, allow to clot for at least 5 minutes. If an SST or 
standard red top tube is used, allow to clot for 30 minutes. 
• 
Centrifuge, within two hours of draw, at room temperature at 1100g – 
1300g for 10 minutes in a swing bucket or 15 minutes for a fixed angle 
centrifuge 
• 
Aliquot serum and plasma into 2 cryovials for each vacutainer 
collected.  CLEARLY LABEL CRYOTUBES WITH RST, PPT, PST or 
CTAD or institutional tube types utilized. 
• 
For the CTAD vacutainer – DO NOT DISCARD RESIDUAL CELLS. 
Restore the cap to the plastic vacutainer tube and store with the 
plasma and serum samples. If the vacutainer is glass, transfer cells to 
a vryovial prior to freezing.  
• 
Freeze cryovials at –70ºC. Batch ship overnight on dry ice. 
b. Tumor tissue specimens 
The required representative tumor blocks (see table XII.1) are to be 
submitted within 4 weeks of registration to EL112LAB (primary tumor) or 
collection (recurrence.) If a block is not available, contact the ECOG-
ACRIN CBPF at 844-744-2420 to discuss possible alternative submission 
guidelines. 
The following forms are to be submitted with the tumor tissue: 
• 
ECOG-ACRIN Generic Specimen Submission Form (#2981). Please 
identify the clinical status of the submitted material. 
• 
Copy of the Pathology Report 
Samples are to be shipped Monday through Thursday only. Pathology 
materials are to be submitted at ambient within one month of collection. 
Plasma & Serum   
 
 
 
CTAD RBC+WBC 
 
Rev. 12/14 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
163 
Plasma and serum samples are to be shipped on dry ice quarterly.  Multiple 
patient samples may be batched shipped together, however each plastic bag 
must contain samples from a single patient only.   
Ship with the relevant documentation to: 
ECOG-ACRIN Central Biorepository and Pathology Facility 
MD Anderson Cancer Center 
Department of Pathology, Unit 085 
Tissue Qualification Laboratory for ECOG-ACRIN, Room G1.3586 
1515 Holcombe Blvd 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International 
Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
XII.7 
References 
1. Davies C, Godwin J, Gray R, et al: Relevance of breast cancer hormone receptors 
and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of 
randomised trials. Lancet 378:771-84, 2011 
2. Peto R, Davies C, Godwin J, et al: Comparisons between different 
polychemotherapy regimens for early breast cancer: meta-analyses of long-term 
outcome among 100,000 women in 123 randomised trials. Lancet 379:432-44, 2012 
3. Sparano JA, Wang M, Martino S, et al: Weekly paclitaxel in the adjuvant treatment of 
breast cancer. The New England journal of medicine 358:1663-71, 2008 
4. Sparano JA, Strickler HD: Breast cancer patients who are obese at diagnosis: alea 
iacta est? or "is the die cast"? Oncology 25:1002, 1004, 1007, 2011 
5. de Azambuja E, McCaskill-Stevens W, Francis P, et al: The effect of body mass 
index on overall and disease-free survival in node-positive breast cancer patients 
treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the 
experience of the BIG 02-98 trial. Breast Cancer Res Treat 119:145-53, 2010 
6. Majed B, Moreau T, Senouci K, et al: Is obesity an independent prognosis factor in 
woman breast cancer? Breast Cancer Res Treat 111:329-42, 2008 
7. Sparano JA, Paik S: Development of the 21-gene assay and its application in clinical 
practice and clinical trials. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 26:721-8, 2008 
8. Mook S, Schmidt MK, Weigelt B, et al: The 70-gene prognosis signature predicts 
early metastasis in breast cancer patients between 55 and 70 years of age. Annals 
of oncology : official journal of the European Society for Medical Oncology / ESMO 
21:717-22, 2010 
9. Jin H, Tu D, Zhao N, et al: Longer-term outcomes of letrozole versus placebo after 5 
years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment 
crossover. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology 30:718-21, 2012 
10. Shaw JA, Page K, Blighe K, et al: Genomic analysis of circulating cell-free DNA 
infers breast cancer dormancy. Genome research 22:220-31, 2012 
Rev. 12/14 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
164 
11. Lucci A, Hall CS, Lodhi AK, et al: Circulating tumour cells in non-metastatic breast 
cancer: a prospective study. The lancet oncology, 2012 
12. Kabat GC, Kim M, Caan BJ, et al: Repeated measures of serum glucose and insulin 
in relation to postmenopausal breast cancer. Int J Cancer 125:2704-10, 2009 
13. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early-stage 
breast cancer: results of a prospective cohort study. J Clin Oncol 20:42-51, 2002 
14. Duggan C, Irwin ML, Xiao L, et al: Associations of insulin resistance and adiponectin 
with mortality in women with breast cancer. J Clin Oncol 29:32-9 
15. Irwin ML, Duggan C, Wang CY, et al: Fasting C-peptide levels and death resulting 
from all causes and breast cancer: the health, eating, activity, and lifestyle study. J 
Clin Oncol 29:47-53 
16. Wildman RP: Healthy obesity. Curr Opin Clin Nutr Metab Care 12:438-43, 2009 
17. Milazzo G, Giorgino F, Damante G, et al: Insulin receptor expression and function in 
human breast cancer cell lines. Cancer Res 52:3924-30, 1992 
18. Frittitta L, Vigneri R, Papa V, et al: Structural and functional studies of insulin 
receptors in human breast cancer. Breast Cancer Res Treat 25:73-82, 1993 
19. Pugeat M, Crave JC, Elmidani M, et al: Pathophysiology of sex hormone binding 
globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol 40:841-9, 1991 
20. Barbieri RL, Smith S, Ryan KJ: The role of hyperinsulinemia in the pathogenesis of 
ovarian hyperandrogenism. Fertil Steril 50:197-212, 1988 
21. Panno ML, Salerno M, Pezzi V, et al: Effect of oestradiol and insulin on the 
proliferative pattern and on oestrogen and progesterone receptor contents in MCF-7 
cells. J Cancer Res Clin Oncol 122:745-9, 1996 
22. Elias JJ, Armstrong RC: Brief communication: Hyperplastic and metaplastic 
responses of human mammary fibroadenomas and dysplasias in organ culture. J 
Natl Cancer Inst 51:1341-3, 1973 
23. Law JH, Habibi G, Hu K, et al: Phosphorylated insulin-like growth factor-i/insulin 
receptor is present in all breast cancer subtypes and is related to poor survival. 
Cancer Res 68:10238-46, 2008 
24. Huang GS, Brouwer-Visser J, Ramirez MJ, et al: Insulin-like growth factor 2 
expression modulates Taxol resistance and is a candidate biomarker for reduced 
disease-free survival in ovarian cancer. Clin Cancer Res 16:2999-3010, 2010 
25. Duggan C, Irwin ML, Xiao L, et al: Associations of insulin resistance and adiponectin 
with mortality in women with breast cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 29:32-9, 2011 
26. Matthews DR, Hosker JP, Rudenski AS, et al: Homeostasis model assessment: 
insulin resistance and beta-cell function from fasting plasma glucose and insulin 
concentrations in man. Diabetologia 28:412-9, 1985 
27. Erickson K, Patterson RE, Flatt SW, et al: Clinically defined type 2 diabetes mellitus 
and prognosis in early-stage breast cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 29:54-60, 2011 

ECOG-ACRIN 
PACCT-1 
Cancer Research Group 
Version Date: April 25, 2014 
 
NCI Update Date: December 16, 2014 
165 
28. Peairs KS, Barone BB, Snyder CF, et al: Diabetes mellitus and breast cancer 
outcomes: a systematic review and meta-analysis. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 29:40-6, 2011 
29. Sparano JA, Gray, R., Goldstein L.J., Childs, B.H., Brassard, D., Bugarini, R., 
Rowley, S., Baker, J., Shak, S., Badve, S., Baehner, F.L., Kenny, P., Perez, E.A., 
Shulman, L.N., Martino, S., Sledge, G.W., Davidson, N.E.: Gene Expression Profiling 
of Phenotypically-Defined Hormone-Receptor Positive Breast Cancer: Evidence for 
Increased Transcriptional Activity of the Insulin Growth Factor Receptor Pathway and 
Other Pathways. Breast Cancer Res Treat (abstract 5165), 2009 
30. Creighton CJ, Sada YH, Zhang Y, et al: A gene transcription signature of obesity in 
breast cancer. Breast Cancer Res Treat, 2011 
31. Sinicrope FA, Dannenberg AJ: Obesity and breast cancer prognosis: weight of the 
evidence. J Clin Oncol 29:4-7, 2011 
32. Wang T, Rohan TE, Gunter MJ, et al: A prospective study of inflammation markers 
and endometrial cancer risk in postmenopausal hormone nonusers. Cancer 
Epidemiol Biomarkers Prev 20:971-7, 2011 
33. Subbaramaiah K, Howe LR, Bhardwaj P, et al: Obesity is associated with 
inflammation and elevated aromatase expression in the mouse mammary gland. 
Cancer Prev Res (Phila) 4:329-46, 2011 
34. Sestak I, Distler W, Forbes JF, et al: Effect of body mass index on recurrences in 
tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC 
trial. J Clin Oncol 28:3411-5, 2010 
35. Ring A, Sestak I, Baum M, et al: Influence of comorbidities and age on risk of death 
without recurrence: a retrospective analysis of the arimidex, tamoxifen alone or in 
combination trial. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 29:4266-72, 2011 
36. Behbakht K, Sill MW, Darcy KM, et al: Phase II trial of the mTOR inhibitor, 
temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in 
persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a 
Gynecologic Oncology Group study. Gynecol Oncol 123:19-26, 2011 
37. Cohen SJ, Alpaugh RK, Gross S, et al: Isolation and characterization of circulating 
tumor cells in patients with metastatic colorectal cancer. Clin Colorectal Cancer 
6:125-32, 2006 
38. Urtishak S, Alpaugh RK, Weiner LM, et al: Clinical utility of circulating tumor cells: a 
role for monitoring response to therapy and drug development. Biomark Med 2:137-
45, 2008 
39. Dotan E, Cohen SJ, Alpaugh KR, et al: Circulating tumor cells: evolving evidence 
and future challenges. Oncologist 14:1070-82, 2009