GCC 1366: A Prospective Study of Neoadjuvant Non-Steroidal Aromatase Inhibitors to Evaluate Anti-Proliferative Response in Obese and Overweight Patients
Phase: NA
Conditions: Breast Cancer
Sponsor: University of Maryland, Baltimore

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GCC1366- A PROSPECTIVE STUDY OF NEOADJUVANT NON-STEROIDAL AROMATASE INHIBITORS IN 
POSTMENOPAUSAL WOMEN WITH OPERABLE HORMONE RECEPTOR-POSITIVE BREAST CANCER TO 
EVALUATE THE ANTI-PROLIFERATIVE RESPONSE IN OBESE AND OVERWEIGHT PATIENTS 
 
 
 
 
Coordinating Center: 
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer 
 
Center 
 
Principal Investigator: 
Suliat M. Nurudeen, MD, MPH 
University of Maryland Greenebaum Comprehensive Cancer 
Center 
29 S Greene Street, Suite 600 
Baltimore, MD 21201 
Telephone: (410) 328-7320 
Fax:  (410) 328-5919 
 
 
E-mail:  snurudeen@som.umaryland.edu  
 
Clinical Co-Investigators: 
John Olson, MD, PhD 
University of Maryland Greenebaum Comprehensive Cancer 
Center 
29 S Greene Street, 6th Floor 
Baltimore, MD 21201 
Telephone: (410) 328-7320 
Fax:  (410) 328-5919 
E-mail:  jolson@smail.umaryland.edu 
 
Katherine Tkaczuk, MD 
University of Maryland Greenebaum Comprehensive Cancer 
Center 
Telephone: (410) 328-2567 
Fax: (410) 328-6896 
E-mail: ktkaczuk@umm.edu 
 
Paula Rosenblatt, MD 
University of Maryland Greenebaum Comprehensive Cancer 
Center 
Telephone: (410) 328-6373 
Fax: (410) 328-6896 
E-mail: prosenblatt@umm.edu 
 
Laboratory Co-Investigators: 
          Joanne Dorgan, PhD, MPH 
University of Maryland School of Medicine 
660 W. Redwood St, HH 102E 
Baltimore, MD 21201 
Telephone: (410) 706-1602 
Email: JDorgan@som.umaryland.edu 
 
Olga B. Ioffe, MD Department of Pathology 
University of Maryland School of Medicine 
22 S. Greene Street 
Baltimore, MD 21201 
Telephone: (410) 328-5525 
Fax: (410) 328-5508 
E-mail: oioffe@umm.edu 
 
Tonya Webb, PhD 
University of Maryland School of Medicine 
685 West Baltimore Street 
Baltimore, MD 21201 
Telephone: (410) 706-4109 
Email: TWebb@som.umaryland.edu 
 
 
 

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Statistician: 
Olga Goloubeva, PhD, MSc 
UMM Department of Epidemiology and Public Health 
660 W. Redwood street, Howard Hall Rm 111 Baltimore, 
MD 21201 
Telephone: (410) 706-8502 
E-mail address: ogoloubeva@som.umaryland.edu 
Study Coordinators: 
Nancy Tait 
University of Maryland Greenebaum 
Comprehensive Cancer Center  
22 S. Greene Street 
Baltimore, MD 21201 
Telephone: (410) 328-3546 
Fax: (410) 328-8616 
E-mail address: ntait@umm.edu 
 
 
 
 
Pharmacy Contact: 
Myounghee Lee 
Investigational Drug Services (IDS) 
University of Maryland Greenebaum Comprehensive 
Cancer Center  
22 S. Greene Street 
Baltimore, MD 21201 
Telephone: (410) 328-5468 
Fax: (410) 328-7326 
E-mail address: Mlee1@umm.edu 
 
 
Version #9 / Version Date: December 16, 2019

GCC 1366 December 16, 2019 Version 9
 
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SCHEMA 
 
GCC1366 - A PROSPECTIVE STUDY OF NEOADJUVANT NON-STEROIDAL AROMATASE INHIBITORS IN 
POSTMENOPAUSAL WOMEN WITH OPERABLE HORMONE RECEPTOR-POSITIVE BREAST CANCER TO 
EVALUATE THE ANTI-PROLIFERATIVE RESPONSE IN OBESE AND OVERWEIGHT PATIENTS 
 
Patient population: Postmenopausal women with operable stage I, II, III hormone receptor-positive breast cancer 
• 
Cohort 1: Patients with BMI 
< 25.0 
kg/m2 treating with anastrozole 
• 
Cohort 2: Patients with BMI 
≥ 25.0-29.9 
kg/m2 treating with anastrozole 
• 
Cohort 3: Patients with BMI 
≥ 30 
kg/m2 treating with anastrozole 
• 
Cohort 4: Patients with BMI 
< 25.0 
kg/m2 treating with letrozole 
• 
Cohort 5: Patients with BMI 
≥ 25.0-29.9 
kg/m2 treating with letrozole 
• 
Cohort 6: Patients with BMI 
≥ 30 
kg/m2 treating with letrozole 
 
Sample size:  15 patients in each cohort (total of 90 patients) 
 
Schema: 
 
 
 
 
 
 
 
aA patient may continue anastrozole or letrozole beyond 4 weeks prior to surgery, if in the opinion of the treating 
physician, the patient will benefit from extended endocrine therapy.  These patients will have a core biopsy performed 
at 2-4 weeks after initiation of therapy to assess cellular response by Ki-67 measurement to determine if they are 
responding to endocrine therapy.  Biopsies obtained for this purpose will be used in the analysis for primary endpoint. 
 
Diagnostic (DS) & Correlative (CS) studies: 
*Tissue biopsy/collection 
1. 
ER, PR, HER2, and Ki67 expression (DS) 
2. 
Oncotype Dx in pre-treatment samples (DS) 
3. 
GP88 (CS) 
 
Optional if feasible 
4. 
Infiltrating immunoregulatory cells (IRC): 
Myeloid suppressor cells (MDSC), T cells, NK 
cells, and NK-T cells (CS) 
5. 
Local pro-inflammatory cytokines; Leptin, IL-6, 
IL-8, TNF-α, VEGF (CS) 
 
** Blood collection 
1. 
Estradiol level, FSH (DS) 
2. 
Serum GP88, Estradiol level (sensitive measure) (CS) 
Optional if feasible 
3. 
Metabolomic profiling (CS) 
4. 
Circulating pro-inflammatory cytokines:   
Leptin, IL-6, IL-8, TNF-α, VEGF, IFNγ, IL-
4, GM-CSF, IL-10, IL-17A (CS) 
5. 
Circulating immunoregulatory cells (IRC): 
Myeloid suppressor cells (MDSC), T cells, NK 
cells, and NK-T cells (CS)
Tissue Biopsy* 
Tissue Collection* 
Surgery 
Within 36 hrs after the 
last dose of anastrozole 
or letrozole 
Blood Collection** 
 
2-4 weeksa 
Blood Collection** 

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TABLE OF CONTENTS 
1. 
OBJECTIVES ....................................................................................................................................................... 6 
1.1. 
Primary Objectives .................................................................................................................................... .6 
1.2. 
Secondary Objectives ................................................................................................................................. 6 
1.3. 
Exploratory Objectives ................................................................................................................................ 6 
2. 
BACKGROUND ................................................................................................................................................... 6 
2.1 
Neoadjuvant Endocrine Therapy for Breast Cancer .................................................................................... 6 
2.2 
Biomarkers of response to neoadjuvant AI therapy……………………………………………………………...7 
2.3 
Obesity and Breast Cancer ......................................................................................................................... 7 
2.4 
Correlative Study Background .................................................................................................................... 8 
3. 
PATIENT SELECTION ......................................................................................................................................... 9 
3.1 
Inclusion Criteria ......................................................................................................................................... 9 
3.2 
Exclusion Criteria ........................................................................................................................................ 9 
4. 
REGISTRATION PROCEDURES ...................................................................................................................... 10 
4.1 
General Guidelines ................................................................................................................................... 10 
4.2 
Registration Process ................................................................................................................................ 10 
4.3 
Pretrial Screening. .................................................................................................................................... 10 
5. 
TREATMENT PLAN ........................................................................................................................................... 10 
5.1 
Agent Administration................................................................................................................................. 10 
5.2 
Study Plan ................................................................................................................................................ 11 
5.3 
General Concomitant Medication .............................................................................................................. 12 
5.4 
Duration of Therapy .................................................................................................................................. 12 
5.5 
Surgical Considerations ............................................................................................................................ 12 
5.6 
Postoperative Treatments ......................................................................................................................... 13 
5.7 
Duration of Follow..................................................................................................................................... 13 
5.8 
Criteria for Removal from Study ............................................................................................................... 13 
6. 
DOSING DELAYS .............................................................................................................................................. 13 
7. 
PHARMACEUTICAL INFORMATION ................................................................................................................ 14 
7.1 
Anastrozole .............................................................................................................................................. 14 
7.2 
Letrozole ................................................................................................................................................... 14 
8. 
CORRELATIVE STUDIES ................................................................................................................................. 14 
8.1 
Tumor Tissue Samples ............................................................................................................................. 14 
8.2 
Blood Samples ......................................................................................................................................... 15 
 
9. 
STUDY CALENDAR AND VISIT SCHEDULE……………………………………………………………………...18 
9.1 
Registration .............................................................................................................................................. 19 
9.2 
Pre-treatment............................................................................................................................................ 19 
9.3 
Study Days ............................................................................................................................................... 20 
9.4 
End of Study (Treatment) / Withdrawal ..................................................................................................... 20 
10. MEASUREMENT OF EFFECT .......................................................................................................................... 20 
10.1 
Pathologic Response Determination ......................................................................................................... 20 
10.2 
Clinical Response Determination .............................................................................................................. 20 
11. STATISTICAL CONSIDERATIONS ................................................................................................................... 21 
11.1 
Study Design/Endpoints ........................................................................................................................... 21 
11.2 
Sample Size/Accrual Rate ........................................................................................................................ 21 
12. ADVERSE EVENT REPORTING AND DATA SAFETY AND MONITORING PLAN .............................................22 
12.1 
Adverse Events (AEs).............................................................................................................................. 22 
12.2 
Expedited reporting of serious adverse events (SAEs) ............................................................................. 22 
12.3 
 Data Management………………………………………………………………………………………………….22 
12.4 
Compliance with Laws and Guidance’s…………………………………………………………………………..23 
12.5 
Institutional Review Board…………………………………………………………………………………………23 
 

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13. 
REFERENCES……………………………………………………………………………………………………………..23 
APPENDIX A: ECOG PERFORMANCE STATUS SCALE .......................................................................................... 25 
APPENDIX B: AMERICAN JOINT COMMITTEE ON CANCER STAGING (AJCC) ..................................................... 26 
   APPENDIX C: STUDY DRUG DIARY ...................................................................................................................... 28 
   APPENDIX D: TISSUE ACQUISITION FORM ................................................................................................... …....30 
   APPENDIX E: CYTOKINE, IRC, ESTRADIOL AND METABOLOMIC PROFILING SPECIMEN LOG....................... 31 
  
    APPENDIX F: REGISTRATION WORKSHEET……………………………………….……………………………………32

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1. 
OBJECTIVES 
1.1. Primary Objectives 
1. 
To evaluate the percent change in proliferative index (Ki67) in the primary breast tumor after neoadjuvant 
treatment with standard dose anastrozole or letrozole in normal, overweight, and obese patients with ER 
positive breast cancer (T1-3, N0/1, M0). 
1.2. Secondary Objectives 
 
1. 
To assess estradiol levels at baseline and after treatment with standard dose anastrozole or letrozole in 
normal, overweight, and obese patients. 
2. 
To evaluate differences in baseline GP88 level and Oncotype Dx® assay in primary ER positive breast 
tumors from normal, overweight, and obese patients. 
3. 
To evaluate the association of AI-induced Ki67 response with baseline and posttreatment GP88 level and 
baseline Oncotype Dx® assay in normal, overweight, and obese patients. 
 
1.3. Exploratory Objectives 
 
1. 
To assess circulating and infiltrating immunoregulatory cells (IRC) at baseline and after treatment with 
standard dose anastrozole or letrozole in normal, overweight, and obese patients. (optional when feasible) 
2. 
To evaluate local and circulating pro-inflammatory cytokines at baseline and after treatment with standard 
dose anastrozole or letrozole in normal, overweight, and obese patients. (optional when feasible) 
 
2. 
BACKGROUND 
 
Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Approximately three- 
quarters of all breast cancer patients present with hormone receptor-positive disease.  Endocrine therapies, particularly 
tamoxifen and aromatase inhibitors (AIs), are one of the mainstays of treatment for patients with hormone receptor-
positive breast cancer. Due to their superior efficacy and favorable side effect profile, AIs have become the standard 
treatment for postmenopausal women with hormone receptor-positive breast cancer.1 
 
2.1 Neoadjuvant Endocrine Therapy for Breast Cancer 
 
In patients with hormone receptor-positive tumors, endocrine therapy has also been evaluated in the neoadjuvant setting 
in three large phase III randomized trials. These trials include the P024 trial, the Immediate Preoperative Anastrozole, 
Tamoxifen or Combined with Tamoxifen (IMPACT) trial, and the Preoperative “Arimidex” compared to Tamoxifen 
(PROACT) trial.2-4 Letrozole, a non-steroidal AI, was studied in comparison to tamoxifen in the P024 trial.2 This trial was 
a randomized, double blind, multi-center study, in which three hundred and thirty-seven postmenopausal women with ER 
and/or PR-positive (ER/PR expression > 10%) breast cancer were treated with either tamoxifen or letrozole for 4 months 
prior to surgery. The study met its primary endpoint and demonstrated that letrozole was superior to tamoxifen with a 
clinical response rate of 55% vs. 36% (p < 0.001).  The rates of breast conserving surgery (BCS) were also higher in the 
letrozole arm compared to tamoxifen (45% vs. 35%; p = 0.022).  In contrast to tamoxifen, the overall response rate 
with letrozole was comparable in both EGFR/HER2-positive and negative subsets in the subsequent biomarker analysis.  
Letrozole was also more effective in suppressing the proliferative index, Ki67, than tamoxifen (p=0.0009). Despite the  
impressive  response  rates  with  letrozole  in  the  P024  trial,  anastrozole,  another  non-steroidal  AI,  failed  to demonstrate 
superior response rates compared to tamoxifen in both the IMPACT and PROACT trials.3 , 4 The IMPACT trial enrolled 
330 postmenopausal women with ER-positive (ER expression > 1%) breast cancer who were randomly assigned to either 
anastrozole (A), tamoxifen (T), or the combination (C) for 3 months prior to surgery.3 There was no statistically significant 
difference in response rates measured by both clinical exam (A 37%, T 36%, and C 39%) and ultrasound (A 24%, T 
20%, and C 28%). However, there was a trend toward improvement in BCS with anastrozole in 124 women who were 
not initially deemed to be candidates for BCS (44% vs. 31%; p = 0.23). Among HER2-positive breast cancer, the 
response rate also appeared to be higher in the anastrozole group but this was not statistically significant (58% vs. 22%; 
p = 0.18). The PROACT trial included 451 postmenopausal women with ER/PR-positive breast cancer who were 
randomly assigned to anastrozole or tamoxifen for 12 weeks.4   In contrast to the IMPACT trial, concurrent chemotherapy 
was allowed in this trial.  The objective responses were similar in both the anastrozole and tamoxifen groups measured 
by both clinical exam (50% vs. 46.2%) and ultrasound (39.5% vs. 35.4%).  However, in patients who received endocrine 
therapy alone, there was a statistically significant improvement in BCS rate in the anastrozole group (43% vs. 30.8%; 
p = 0.04).   Data are more limited with exemestane which is a steroidal AI. A single phase II trial with 115 postmenopausal 
women with ER-positive breast cancer demonstrated an impressive clinical response rate of 76.3% with exemestane 
compared to 40%  with tamoxifen (p=0.05).  The rate of BCS was also significantly higher in the exemestane group 

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(36.8% vs. 20%; p = 0.05). 5 Meta-analysis of these four clinical trials (P024, IMPACT, PROACT, and exemestane trials) 
confirmed the benefit of AIs over tamoxifen in all aspects including objective response rate by clinical exam (relative risk 
(RR), 1.29; 95% CI, 1.14–1.47; p < 0.001), objective response rate by ultrasound (RR, 1.29; 95% CI, 1.10–1.51; p = 0.002), 
and BCS rate (RR, 1.36; 95% CI, 1.16–1.59; p < 0.001). Toxicities seem to be comparable between AIs and tamoxifen, 
particularly hot flashes, nausea, and fatigue. The only significant difference was more headaches in the AI group (p = 
0.011) but this toxicity was easy to manage. The ACOSOG Z1031 trial, which compared letrozole, anastrozole, and 
exemestane in the neoadjuvant setting, also demonstrated significant improvements in surgical outcomes.6   Over 50% of 
patients who were eligible only for mastectomy at the start of treatment were able to undergo BCS, and 83% of patients 
who were marginal candidates for BCS at the start of treatment were able to have BCS. Therefore, treatment of 
hormone receptor-positive patients with neoadjuvant AI therapy appears to significantly increase patient eligibility for BCS. 
In addition, the overall BCS rate of 68% in the ACOSOG Z1031 trial is similar to that observed in other trials using 
neoadjuvant chemotherapy.7,8 
 
2.2  Biomarkers of response to neoadjuvant AI therapy 
 
ER/PR:  Estrogen receptor (ER) and progesterone receptor (PgR) are hormone receptors that are expressed in 
approximately 75% of breast cancers in postmenopausal women.  ER and/or PR expression have traditionally been 
considered the most important biomarkers in the management of breast cancer patients and have been utilized to determine 
the use of adjuvant endocrine therapy.  Estrogen receptor expression is the most important predictor of response to 
endocrine therapy.9,10  It has been shown that patients with ER and PgR negative breast cancers derive no benefit from 
adjuvant endocrine therapy11, although there may be a small benefit in patients with ER negative and PgR positive breast 
cancers.9  In patients with higher quantitative levels of ER expression, the benefit of endocrine therapy in the neoadjuvant, 
adjuvant and metastatic setting also appears to be greater.12,13  Progesterone receptor expression, on the other hand, is 
primarily prognostic and not predictive.9,11  Patients with ER positive, PgR negative tumors have a worse prognosis than 
those with ER and PgR positive tumors, however, both groups of patients appear to derive a similar benefit from endocrine 
therapy. 
 
Ki67:  Ki67 protein is a cellular marker for proliferation. Ki67 labeling has been reported to be a good prognostic 
marker and to correlate well with the S phase fraction14  and mitotic index.14,15  A change in expression of Ki67 after 
short-term exposure to an investigational agent is frequently used to determine the efficacy, particularly in the neoadjuvant 
setting.  For neoadjuvant chemotherapy, two previous studies16,17 showed a significant correlation between a reduction in 
Ki67 of more than 25% and a longer disease-free survival. However, subsequent studies18-20 on the reproducibility of Ki67 
measurements in the core needle biopsy suggested that a change in Ki67 score of at least 32-50% between two 
determinations is required to be considered statistically significant and attributable to treatment effect for an individual 
patient. For neoadjuvant endocrine therapy, Dowsett et al.21 reported that a reduction in Ki67 could be observed 2 
weeks after initiation of neoadjuvant endocrine therapy and was largely maintained  after  12  weeks  of  treatment  in  
the  majority  of  patients  in  the  Immediate Preoperative  “Arimidex” (anastrozole), Tamoxifen, or Arimidex Combined 
with Tamoxifen (IMPACT) trial. In this study, postmenopausal women with previously untreated ER-positive breast 
cancer were randomized to receive daily treatment with anastrozole, tamoxifen, or the combination of anastrozole and 
tamoxifen for 12 weeks before surgery. Biomarkers were measured in the core-cut biopsied specimens taken before and 
after 2 weeks of treatment, as well as in surgical specimens after 12 weeks of treatment. The geometric means of reduction 
in Ki67 at 2 and 12 weeks for anastrozole were 76% and 82% respectively. In their subsequent publication22, Ki67 
expression after 2 weeks of treatment, depending on the tertiles of tumor Ki67 expression, was more strongly associated 
with recurrence free survival (log-rank P = .008) than tumor Ki67 expression at baseline (log-rank P = .07). However, there 
was no correlation made between the percentage change in the Ki67 expression and recurrence free survival.  A drop in 
Ki67 levels after 2 weeks of neoadjuvant AI treatment has been shown to be indicative of response to neoadjuvant AI therapy 
in several clinical trials.  Therefore, biopsy and evaluation of Ki67 levels in tumors after 2 weeks of neoadjuvant endocrine 
therapy is considered a standard approach for assessing therapeutic response and guiding a decision for continuing 
neoadjuvant therapy or proceeding to immediate surgery.23 
 
 
2.3  Obesity and Breast Cancer 
 
Obesity 
 
Obesity is an emerging global health problem.  According to the National Institute of Health (NIH) and World Health 
Organization (WHO) classification, normal weight is defined as body mass index (BMI) ≥18.5 to 24.9 kg/m2, overweight as 
BMI ≥25.0 to 29.9 kg/m2 and obesity as BMI ≥30 kg/m2.24 The WHO estimates that 1.5 billion people are overweight and 
more than 500 million are obese worldwide.25  The incidence of overweight and obese adults and children has been 
steadily increasing during the last two decades, and it is estimated that one third of US adults are obese.26  Several studies 
demonstrate a strong correlation between obesity and increased incidence 
of and/or mortality from several types of 
cancer.27,28  In the US, up to 20% of all cancer deaths in women and 14% in men are attributable to obesity.27 
 
 
Purpose for Current Study:  Assessment of Aromatase Inhibitors in Overweight and Obese Patients 
 
It has been long established that obesity is a risk factor for the development of breast cancer in postmenopausal 

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women.29-31 While the relationship between obesity and breast cancer is intricate, a major factor is the increased 
production of estrogen in excess adipose tissue in obese women after menopause.31 Aromatase or CYP19 is a 
member of the cytochrome  P450  superfamily  that is involved  in  the  conversion  of  androgens to  estrogens  via 
aromatization.32  In postmenopausal women, the sole source of estrogens comes from this peripheral conversion of 
androgens by aromatase. This enzyme is present in multiple organs including adipose tissue, brain, blood vessels, skin, 
bone, endometrium, and breast tissue.32 Given the fact that one of the main sources of aromatase is from adipose 
tissue, it is hypothesized that overweight and obese women have higher levels of aromatase and therefore, may have 
poorer outcomes when using the standard dose of AI.  It has been previously observed that obese patients have increased 
risk of recurrence and mortality, including breast cancer-specific mortality, compared to normal weight women.33,34 More 
recent studies also support this observation that obese patients have poor outcomes, particularly with AI treatment. 
Two adjuvant clinical trials in hormone receptor-positive breast cancer comparing AI and tamoxifen demonstrated reduced 
efficacy of AIs in women with higher BMI compared to normal weight patients.35,36  However, this difference in outcome 
between normal and obese patients was not apparent with tamoxifen.  The first clinical trial was the Arimidex, Tamoxifen, 
Alone or in Combination (ATAC) trial.  This trial included a total of 5,172 postmenopausal hormone receptor–positive 
women who were randomly assigned to receive either anastrozole, tamoxifen, or the combination.35 In this study, 
women with high BMI (> 35 kg/m2) at baseline had more recurrences compared to women with low BMI (< 23 kg/m2) 
with an adjusted HR of 1.39 (p 0.03), and significantly more distant recurrences (HR 1.46; p 0.01). The second study 
was the Austrian Breast and Colorectal Cancer Study Group trial 12 (ABCSG-12).36 This trial compared the outcomes of 
anastrozole and tamoxifen in premenopausal women undergoing ovarian suppression with the gonadotropin-releasing 
hormone agonist goserelin. Similar to the ATAC trial, the ABCSG-12 trial also demonstrated a significant increase in the 
risk of disease recurrence in overweight patients (HR 1.60; p 0.02) and more than a doubling in the risk of death (HR 
2.14; p 0.01) compared to normal weight patients. More intriguing, the outcome was even worse when comparing 
treatment within the overweight group alone; patients treated with anastrozole had almost a 50% increase in risk of disease 
recurrence (HR, 1.49; p 0.08) and a three-fold increase in risk of death (HR, 3.03; p 0.004) compared to patients treated 
with tamoxifen. Taken together, these studies suggest that higher levels of peripheral  aromatase  in overweight and obese  
women  might  reduce the efficacy of the standard dose of anastrozole and that higher doses or more complete inhibition of 
aromatase might be more effective in such women. In line with prior studies, a recent clinical trial also demonstrated 
that overweight and obese patients have higher levels of both estradiol and estrone at both baseline and after AI treatment. 
When comparing letrozole and anastrozole, letrozole appeared to provide greater suppression of both estrogen types. 
Furthermore, unlike anastrozole, there was no difference in the benefit of letrozole observed among obese vs. normal 
weight patients in the subset analysis of the breast international group 1-98 (BIG 1-98) trial.37 Nevertheless, it remains 
unclear whether this small difference in the estrogen levels in overweight /obese and normal weight patients will result in 
less anti-tumor activity that can explain the poor outcomes previously observed in the ATAC and ABCSG-12 trials. 
Therefore, this protocol addresses a significant unanswered question in the management of breast cancer patients, whether 
specific aromatase inhibitors work as effectively in overweight and obese individuals as they do in normal weight patients.  
The information that is obtained from this study has the potential to change the management of breast cancer patients and 
may lead to improvements in outcomes. 
 
2.4 Correlative Study Background 
 
GP88 or PC cell-derived growth factor (PCDFG): GP88 is a novel biomarker that was discovered by Dr. Ginette 
Serrero. GP88 has been shown to be associated with resistance to tamoxifen and aromatase inhibitors.38 Expression 
of GP88 is also associated with invasiveness and VEGF expression.39   More recently, GP88 has been shown to confer 
resistance to anti-HER2 therapy in HER2-overexpressing breast cancer cells.40 
 
Oncotype Dx®: Oncotype Dx® or the 21-gene RT-PCR assay is another gene based approach that quantifies the likelihood 
of distant metastasis in patients with early-stage ER-positive HER2-negative breast cancer.41 This test has also been 
shown to have predictive value to assess the likely benefit from adjuvant chemotherapy.42  Currently, this test is 
recommended for routine standard practice by NCCN guideline version 3.2013 to assist in estimating likelihood of 
recurrence and benefit from adjuvant chemotherapy in patients with ER-positive, HER2-negative breast cancer (category 
2A). 
 
Optional:  Immunoregulatory Cells: In the past few decades the importance of immune surveillance and cancer 
development has been increasingly recognized. Multiple types of patrolling cells of the immune system provide 
continuous surveillance and eliminate cells that undergo malignant transformation. Some tumors may escape the 
immune defense system by masking their tumor antigens. Alternatively, tumors may survive by promoting the production 
of suppressor cells which block effector cells that would normally attack it. 
 
• 
Myeloid-derived suppressor cells (MDSCs): Multiple studies have established that a group of cells derived from 
the bone marrow termed myeloid-derived suppressor cells are directly involved in the suppression of immune 
responses in cancer.43,44 These cells normally express CD33, CD11b, and CD15 but lack expression of 
monocytic differentiation (CD14), dendritic cells (CD11c), and macrophage (CD68). MDSCs exert their 
immunosuppressive effect by both an antigen-specific and nonspecific manner depending on their location and 
tumor type. At the tumor site, the immunosuppressive effect of MDSCs is mediated mainly by the production of 
nitric oxide and high arginase activity. This combination results in not only induction of apoptosis in T cells 
but increased production of reactive oxygen species that suppress T cell function irrespective of the nature of 
the antigens.45 In breast cancer, the adoptive transfer of ex vivo expanded HER2-specific T cells can only 
induce tumor regression when combined with the depletion of MDSCs.46 
• 
Regulatory T cells (Treg cells): Treg cells are a specialized subpopulation of T cells that suppress activation of 
the immune system to maintain the homeostasis and tolerance to self-antigens. This subpopulation of T cells is 
an important "self-check" of the immune system to prevent autoimmunity but is also associated with tolerance 

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of the immune system in cancer. In general, naturally occurring Treg cells are CD4+CD25+ cells and are 
generated in the thymus as part of the normal peripheral T-cell repertoire. Treg can be distinguished from 
activated T cells based on the high expression of CD25, cytotoxic T-lymphocyte antigen 4 (CTLA4), 
and the transcription factor forkhead box P3 (FoxP3).47 
• 
Natural Killer cells (NK cells): NK cells are a subtype of cytotoxic lymphocytes that are a major component 
of the innate immune system.  NK cells play a critical role in rejecting cancer cells as well as virally infected cells. 
NK cells are defined as large granular lymphocytes that do not express T-cell markers (T-cell receptor antigen 
or TCR and pan T cell marker CD3) or B cell surface immunoglobulin (Ig) but usually express the surface 
markers CD16 (FcγRIII) and CD56 in humans.  In addition, up to 80% of NK cells also express CD8.48 
 
Optional:  Pro-inflammatory Cytokines: High pro-inflammatory cytokine levels are associated with poor outcomes in 
breast cancer patients. White adipose tissue (WAT) in obese patients is a source of local and circulating pro-inflammatory 
cytokines.49,50 These cytokines also attract and promote differentiation of monocytes to macrophages which results in the 
secretion of additional pro-inflammatory cytokines and pro-angiogenic factors. The result is a chronic inflammatory 
microenvironment which favors tumor cell motility and invasion, promotes epithelial-mesenchymal transition, and enhances 
survival, proliferation and renewal of cancer stem cells (CSCs). These pro-inflammatory cytokines can also activate 
many cancer-related signaling pathways and may increase aromatase expression in mammary tissue, both which may 
lead to progression of breast cancers. 
 
Optional:  Metabolomics profiling: Metabolomics is an emerging field and one of the core areas of system biology research 
that focus on the holistic study of low-molecular-weight organic and inorganic (typically < 1,500 Da) metabolites. These 
metabolites are the building blocks for many biological components and are central in intermediary metabolism. They also 
have an active role in regulating several cellular functions and are involved in cell signaling.51 Metabolomics profiling allows 
unbiased global assessment of metabolites with a small amount of blood.  Currently, there are limited data on the changes 
that occur in the whole metabolomics profiling from aromatase inhibitors, particularly in correlation with the body mass 
index. 
 
3. 
PATIENT SELECTION 
 
3.1 Inclusion Criteria 
 
1. 
Females greater than or equal to 18 years. 
2. 
Postmenopausal status, defined as no menstrual cycle for 12 months or surgical removal of ovaries. 
3. 
Histologically confirmed adenocarcinoma of the breast. 
4. 
Evidence of hormone sensitive, ER rich primary tumor defined by an Allred score of ≥6. 
5. 
HER2 negative in the primary tumor as defined by: 
• 
Grade 0 or 1+ staining intensity (on a scale of 0 to 3) by means of IHC analysis OR 
• 
Grade 2+ staining intensity by means of IHC analysis with gene amplification on fluorescence in 
situ hybridization (FISH) < 2.0 OR 
• 
Gene amplification on fluorescence in situ hybridization (FISH) < 2.0. 
6. 
Eastern Cooperative Oncology Group (ECOG) performance status < 3 (Appendix A). 
7. 
Unresected operable breast cancer stage I, II, III with primary tumor > 1.0 cm (Appendix B). 
8. 
Ability to understand and willingness to sign a written informed consent document. 
9. 
Patients must not have received any prior chemotherapy, radiation therapy, or endocrine therapy for their 
current breast cancer.  Patients who received tamoxifen or raloxifene or another agent for prevention of 
breast cancer may be included as long as the patient has discontinued the treatment at least one month 
prior to baseline study biopsy. 
10. Patients must have an adequate tumor tissue sample prior to enrollment available for correlative studies as 
defined below: Core needle biopsy or incisional biopsy samples that can provide ≥ 5 unstained sections 
of 5 micron thickness. Fine needle aspiration (FNA) sample alone is not sufficient. 
11. Patients must have adequate organ function as defined below: 
• 
Total bilirubin within normal institutional limits 
• 
AST(SGOT)/ALT(SGPT) < 2.5 x institutional upper limit of normal 
• 
Creatinine clearance ≥ 10 mL/min/1.73 m2 
 
3.2 Exclusion Criteria 
 
1. 
Previous or current systemic malignancy within the past 3 years other than breast cancer or adequately 
treated cervical carcinoma in situ or basal/squamous carcinoma of the skin. 
2. 
Patients may not be receiving any other investigational agent. 
3. 
History of allergic reactions or hypersensitivity to compounds of similar chemical or biologic composition to 
anastrozole or letrozole. 
 
 
 
 

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10 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 General Guidelines 
 
Upon signing consent, sites will sequentially assign a three digit screening number with an “S” prefix. University of Maryland 
Greenebaum Cancer Center will be identified as site #1, therefore their screening numbers will begin with “S101” followed 
by “S102” etc. The Cancer Institute at St. Joseph Medical Center will be identified as site #2, therefore their screening 
numbers will begin with “S201” followed by “S202” etc. These screening numbers will be used on all samples as described 
in section 8 of this protocol.  Eligible patients will be registered onto the study by the lead site study coordinator. Following 
registration, patients should begin protocol treatment within 5 business days. All of the patients’ documents will be 
kept confidential in a secured area. 
 
4.2 Registration Process 
 
To register a patient, the following documents should be completed by a research team member and sent to study 
coordinators, Nancy Tait or Cheryl Young, via fax, (410) 328-1741, or e-mail, ntait@umm.edu or 
Cheryl.Young@umm.edu 
 
• 
Copy of required laboratory tests 
• 
Signed patient consent form 
• 
HIPAA authorization form 
• 
BMI determination 
• 
Other appropriate forms (e.g., Eligibility Screening Worksheet, Documentation of Pathology and 
Diagnosis) 
 
To complete the registration process, the Coordinator will 
 
• 
Assign the patient a four digit study number according to the Registration Worksheet (Appendix F). NOTE: 
this number is different than the assigned site screening number.  
• 
Register the patient into the appropriate cohort as determined by BMI 
• 
Communicate the cohort assignment back to the requestor using email 
 
4.3 Pretrial Screening 
 
Patients will be screened before entry to establish eligibility. The following assessments must be obtained within 3 
weeks of trial entry: 
 
• 
Medical history including all significant conditions. 
• 
Concomitant therapy before entry documented to establish eligibility. 
• 
ECOG performance status. 
• 
Physical examination including vital signs, height, weight and BMI determination. 
• 
Clinical tumor assessment by breast examination for palpable tumors including clinical tumor size, 
character, mobility, and location of the breast mass.  For non-palpable tumors, clinical tumor size and 
location will be assessed by imaging studies. 
• 
Laboratory studies: CBC with diff; chemistries including sodium, potassium, chloride, bicarbonate 
(HCO3− or CO2), BUN, creatinine, fasting blood glucose, total bilirubin, calcium, total protein, 
albumin, AST (SGOT), ALT (SGPT), alkaline phosphatase, LDH, phosphorus, magnesium, estradiol 
level, FSH, PT/INR, and PTT. 
 
The following baseline breast imaging can be obtained within 8 weeks of trial entry: 
 
• 
Baseline mammogram, breast ultrasound, and breast magnetic resonance imaging (MRI) as clinically 
indicated. All imaging should be performed as per standard of care. When feasible, breast MRI should 
also be performed in addition to mammogram and breast ultrasound. 
 
 
5. 
TREATMENT PLAN 
 
5.1 Agent Administration 
 
Treatment will be administered on an outpatient basis. No investigational or commercial agents or therapies other than 
anastrozole or letrozole may be administered with the intent to treat the patient's malignancy. 
 
• 
A total of 90 patients will be enrolled with 15 patients in each cohort below. 

GCC 1366 March 20, 2018 Version 8  
 
11 
 
o 
Cohort 1: Patients with BMI   < 25.0 
kg/m2 treating with anastrozole 
o 
Cohort 2: Patients with BMI   ≥ 25.0-29.9      kg/m2 treating with anastrozole 
o 
Cohort 3: Patients with BMI   ≥ 30 
kg/m2 treating with anastrozole 
o 
Cohort 4: Patients with BMI   < 25.0 
kg/m2 treating with letrozole 
o 
Cohort 5: Patients with BMI   ≥ 25.0-29.9      kg/m2 treating with letrozole 
o 
Cohort 6: Patients with BMI   ≥ 30 
kg/m2 treating with letrozole 
• 
For each BMI category, the first 15 patients will be treated with anastrozole (cohorts 1, 2 and 3), and the 
following 15 patients will be treated with letrozole (cohorts 4, 5, and 6). Appendix F will be used by the study 
coordinators outlined in section 4.2 to ensure stratification to cohorts is managed appropriately. 
• 
Treatment with anastrozole or letrozole will be administered and continued for a minimum of 14 days and a 
maximum of 28 days (2-4 weeks).  Surgery will be performed between weeks 2-3 of treatment unless there are 
compelling medical or personal reasons that prevent a patient from having surgery during this time.  In those cases, 
patients may continue anastrozole or letrozole up to 4 weeks before surgery. 
• 
Anastrozole will be taken by mouth once daily on a continuous basis at the fixed dose of 1 mg per day in 
cohorts 1, 2, 3 for 2-4 weeks. Surgery should be performed within 36 hours of the last dose of anastrozole.   
• 
Letrozole will be taken by mouth once daily on a continuous basis at the fixed dose of 2.5 mg per day in 
cohorts 4, 5, 6 for 2-4 weeks. Surgery should be performed within 36 hours of the last dose of letrozole. 
• 
A patient may be continued on anastrozole or letrozole beyond 4 weeks (up to 18 weeks) if in the opinion of the 
treating physician, the patient will benefit from extended endocrine therapy.  In this context, patients will have a 
core needle biopsy performed at 2-4 weeks after treatment to assess Ki67 response to AI therapy.  Patients 
with an appropriate response to treatment as determined by a decrease in Ki67 levels (≤10%) will be continued on 
AI treatment.  Patients without an appropriate decrease in Ki67 levels will be recommended to have immediate 
surgery or a switch to neoadjuvant chemotherapy if desired by the patient and treating physician.  This has become 
a standard approach to assessing response to neoadjuvant AI therapy and guiding treatment decisions.23  This is 
currently the treatment approach that is used in the University of Maryland Medical System for patients with ER 
positive breast cancer receiving neoadjuvant endocrine therapy. (personal communication, Dr. Michael Schultz, 
UMMS, St. Joseph Medical Center, Towson, MD) 
 
5.2 Study Plan 
 
• 
A total of 90 patients will be enrolled with 15 patients in each cohort below. 
o 
Cohort 1: Patients with BMI   < 25.0 
kg/m2 treating with anastrozole 
o 
Cohort 2: Patients with BMI   ≥ 25.0-29.9 
kg/m2 treating with anastrozole 
o 
Cohort 3: Patients with BMI   ≥ 30 
kg/m2 treating with anastrozole 
o 
Cohort 4: Patients with BMI   < 25.0 
kg/m2 treating with letrozole 
o 
Cohort 5: Patients with BMI   ≥ 25.0-29.9 
kg/m2 treating with letrozole 
o 
Cohort 6: Patients with BMI   ≥ 30 
kg/m2 treating with letrozole 
• 
Based on the patients’ calculated BMI, patients in each BMI category (normal, overweight, and obese) will be 
enrolled in the different cohorts as described above. The first 15 patients in each BMI category will be treated 
with anastrozole.  After completion of enrollment in cohorts 1, 2, and 3, subsequent patients will be treated with 
letrozole in cohorts 4, 5, and 6. 
• 
Anastrozole 1 mg or Letrozole 2.5 mg oral daily will be administered and continued for a minimum of 14 days 
and a maximum of 28 days (2-4 weeks).  Surgery will be performed between weeks 2-3 of treatment unless 
there are compelling medical or personal reasons that prevent a patient from having surgery during this time.  In 
those cases, patients may continue anastrozole or letrozole up to 4 weeks before surgery.  Surgery should be 
performed within 36 hours of the last dose of anastrozole or letrozole. 
• 
Tumor tissue that is obtained for diagnosis or to assess response to initial AI therapy will be utilized for correlative 
studies.  
• 
A patient may be continued on anastrozole or letrozole beyond 4 weeks (up to 18 weeks) if in the opinion of the 
treating physician, the patient will benefit from extended endocrine therapy.  In this context, patients will have a 
core needle biopsy performed at 2-4 weeks after treatment to assess Ki67 response to AI therapy.  Patients 
with an appropriate response to treatment as determined by a decrease in Ki67 levels (≤10%) will be continued on 
AI treatment.  Patients without an appropriate decrease in Ki67 levels will be recommended to have immediate 
surgery or a switch to neoadjuvant chemotherapy if desired by the patient and treating physician.  This has become 
a standard approach to assessing response to neoadjuvant AI therapy and guiding treatment decisions.23  This is 
currently the treatment approach that is used in the University of Maryland Medical System for patients with ER 
positive breast cancer receiving neoadjuvant endocrine therapy. (personal communication, Dr. Michael Schultz, 
UMMS, St. Joseph Medical Center, Towson, MD) 
• 
Patients on extended AI neoadjuvant treatment having core biopsy at 2-4 weeks for Ki67 determination for clinical 

GCC 1366 March 20, 2018 Version 8  
 
12 
 
decision making will be approached and consented for additional research tissues to be taken at the same time as 
the biopsy for Ki67 determination.  These additional passes (2-4, 14 gauge) are considered minimal risk and have 
been performed in the context of several neoadjuvant AI clinical trials6,52 without adverse outcome reported. 
(personal communication, Dr. John Olson, UMMC, Baltimore, MD) 
• 
Blood samples will be collected prior to starting treatment and within 3 days or on the day of surgery.  Additional 
blood samples will be obtained as clinically necessary. 
• 
Clinical assessment will be performed prior to enrollment and within 3 days or on the day of surgery.  For patients 
who continue neoadjuvant endocrine therapy past 4 weeks, clinical assessment will be performed at the time of 
clinical biopsy and every 4-6 weeks thereafter.  For clinical evidence of progression, patients will be offered 
immediate surgery or switch to neoadjuvant chemotherapy at the discretion of the treating physician. 
• 
Radiological assessment including mammogram, ultrasound, and breast MRI will be performed as per 
standard of care. 
 
5.3 General Concomitant Medication 
 
5.3.1 
Permitted 
 
Thyroid replacement drugs are permitted. Vitamin D, calcium, and bisphosphonates are permitted for patients on this 
study at investigator discretion. 
 
5.3.2 
Not Permitted 
 
Any use of hormone replacement therapy drugs is not permitted (example megace). Please note that raloxifene and 
idoxifene are to be considered as hormone replacement therapy due to their mechanism of action being an estrogen like 
agent. 
 
Topical use of vaginal estrogens is not permitted. 
 
Aromatase inhibitors other than anastrozole or letrozole are not permitted. Tamoxifen and fulvestrant are not permitted. 
 
Concurrent chemotherapy is not permitted. 
 
5.4 Duration of Therapy 
 
For most patients, treatment will be administered for a minimum of 14 days and a maximum of 28 days (2-4 weeks) 
prior to definitive surgery.  Surgery will be performed between weeks 2-3 of treatment unless there are compelling medical or 
personal reasons that prevent a patient from having surgery during this time.  In those cases, patients may continue 
anastrozole or letrozole up to 4 weeks before surgery. 
 
A patient may be continued on anastrozole or letrozole beyond 4 weeks (up to 18 weeks) if in the opinion of the treating 
physician, the patient will benefit from extended endocrine therapy.  In this context, patients will have a core needle biopsy 
performed at 2-4 weeks after treatment to assess Ki67 response to AI therapy.  Patients with an appropriate response to 
treatment as determined by a decrease in Ki67 levels (≤10%) will be continued on AI treatment.  Patients without an 
appropriate decrease in Ki67 levels will be recommended to have immediate surgery or a switch to neoadjuvant 
chemotherapy if desired by the patient and treating physician.  This has become a standard approach to assessing response 
to neoadjuvant AI therapy and guiding treatment decisions.23  This is currently the treatment approach that is used in the 
University of Maryland Medical System for patients with ER positive breast cancer receiving neoadjuvant endocrine therapy. 
(personal communication, Dr. Michael Schultz, UMMS, St. Joseph Medical Center, Towson, MD) 
 
Surgery should be performed within 36 hours of the last dose of anastrozole or letrozole. The treatment should be 
continued until the time of the surgery or until one of the criteria in section 5.8 applies. 
 
5.5 Surgical Considerations 
 
5.5.1 Marker Placement Prior to Initiation of Therapy 
 
A titanium marker or “clip” will be placed at the tumor site(s) prior to starting treatment at the discretion of the treating 
surgeon in women who may be candidates for breast conservation surgery. This marker will identify the tumor location(s) 
for surgical resection. 
 
5.5.2 Breast Surgery and Axillary Staging 
 
Following preoperative treatment, women will undergo breast conserving surgery or mastectomy as well as axillary staging 
at the discretion of the treating surgeon. It is recommended that the definitive surgery take place within 36 hours of the 

GCC 1366 March 20, 2018 Version 8  
 
13 
 
last dose of anastrozole or letrozole. 
 
5.6 Postoperative Treatments 
 
Postoperative treatments including adjuvant chemotherapy, radiation, and endocrine therapy will be at the discretion of 
the treating physicians. 
 
5.7 Duration of Follow-up 
 
Patients will be followed for 30 days on study after the last dose of anastrozole or letrozole prior to surgery. For patients 
who receive extended neoadjuvant therapy with anastrozole or letrozole and for patients who receive other primary 
treatment after anastrozole or letrozole administration prior to surgery, patients will be followed for 30 days on study after 
the last dose of anastrozole or letrozole. Patients continuing to experience adverse events attributable to anastrozole or 
letrozole will be followed as needed until resolution or stabilization of the adverse events. Patients who are either found to 
be ineligible or refuse to start treatment after consenting will not be followed and will be replaced. Their information will 
not be collected.  After 30 days after the last dose of anastrozole or letrozole, if there are no continuing adverse events 
attributable to treatment, patients will be off study. 
 
5.8 Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed below applies.  The reason for study removal and 
the date the patient was removed must be documented in the case report form. 
• 
Evidence of disease progression during treatment at the discretion of the treating investigator. 
• 
Non-compliance with the study protocol; including, but not limited to not attending the majority of 
scheduled visits. The Protocol Chair will determine when non-compliance should lead to removal from 
study. 
• 
Unacceptable major toxicity defined as ≥ grade 3 toxicity related to anastrozole/letrozole. 
Note: Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. 
• 
Concurrent  illness  or  condition  that  would,  in  the  judgment  of  the  treating  investigator,  affect 
assessment of clinical status to a significant degree or require discontinuation of study treatment. 
• 
At subject’s own request. 
Note: The reason for discontinuation from the study must be documented. 
• 
Study is closed for any reason. 
• 
Subject withdraws consent for follow-up. 
• 
Subject is lost to follow-up. 
 
Patients who are removed from the study before completing at least 2 weeks of anastrozole or letrozole will not be counted 
toward accrual and will be replaced with new patients. However, tissue samples from the surgical procedure will be 
collected unless patients withdraw consent. 
 
6. 
DOSING DELAYS 
 
Anastrozole and letrozole are generally well tolerated. The previous study with anastrozole and letrozole in the 
preoperative setting demonstrated only 3.8% grade 3-4 toxicities.53 The following rules will be followed for the 
management of adverse events that are due to anastrozole or letrozole. Toxicity grades are according to the NCI 
CTCAE version 4.0. 
 
There will be no dose reductions in anastrozole or letrozole. 
 
Supportive care measures should be implemented first. Dose interruption should only be implemented when all 
supportive care measures have been exhausted without an improvement of patient status. For unresolved grade 3 or 4 
adverse events or any clinically significant, lower-grade adverse event despite supportive care measures, treatment with 
anastrozole or letrozole can be interrupted for a maximum of 5 days until the patient recovers completely or the adverse 
event reverts to NCI-CTCAE Grade 1 or to baseline grade. 
 
If recurrence of the adverse event after drug holiday or interruptions is observed and patients are unable to resume the 
treatment after 5 days, patients will be removed from the study and should proceed with surgery or other treatment. Patients 
who are removed from the study before completing at least 14 days of anastrozole or letrozole will not be counted toward 
accrual and will be replaced with new patients. However, tissue samples from the surgical procedure will be collected 
unless patients withdraw consent. 
 
 
 
 

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7. 
PHARMACEUTICAL INFORMATION 
 
7.1 Anastrozole 
 
7.1.1 
Description 
 
Anastrozole or Arimidex® is a non-steroidal aromatase inhibitor. It is chemically described as 1,3- 
Benzenediacetonitrile, a, a, a’, a’-tetramethyl 5-(1H-1,2,3-triazol-1-ylmethyl) and the molecular formula C17H19N5, 
with a molecular weight of 293.4. 
 
7.1.2 
Availability 
 
Anastrozole  will  be  prescribed  by the  treating  physician  and  covered  by the  patients  insurance.  Both  
generic anastrozole and Arimidex® are permitted but when possible Arimidex® is preferred. 
 
These tablets should be stored at controlled room temperature 20-25°C (68-77°F). 
 
Additional information regarding the formulation as well as storage and handling instructions can be found in 
the approved package insert. 
 
7.2 Letrozole 
 
7.2.1 
Description 
 
Letrozole or Femara® is a non-steroidal aromatase inhibitor. It is chemically described as 4,4'-(1H-1,2,4-
triazol-1- ylmethylene) dibenzonitrileand the molecular formula C17H11N5, with a molecular weight of 285.302. 
 
7.2.2 
Availability 
 
Letrozole will be prescribed by the treating physician and covered by the patients insurance. Both generic 
letrozole and Femara® are permitted but when possible Femara® is preferred. 
 
These tablets should be stored at controlled room temperature 20-25°C (68-77°F). 
 
Additional information regarding the formulation as well as storage and handling instructions can be found in 
the approved package insert. 
 
 
8. 
CORRELATIVE STUDIES 
 
Both blood samples and tissue samples will be collected. All samples will be identified using the subject Screening Number -  
“S101” etc. 
 
8.1 Tumor Tissue Samples 
 
8.1.1 
Collections 
 
Tumor tissue samples from the following time points will be obtained: 
 
1. 
Prior to starting treatment; tissue sample from the original diagnostic procedure. (T0) 
2. 
At the time of definitive surgery (i.e., mastectomy or lumpectomy). A separate tumor biopsy is not needed 
on the day of surgery; tissue will be taken from the surgical specimen. (T1) 
3. 
Patients on extended AI therapy will have a core biopsy at 2-4 weeks for Ki67 determination. (T2) 
4. 
Patients on extended AI neoadjuvant treatment having core biopsy at 2-4 weeks for Ki67 determination 
for clinical decision making will be approached and consented for additional research tissues to be taken 
at the same time as the biopsy for Ki67 determination.  These additional passes (2-4, 14 gauge) are 
considered minimal risk and have been performed in the context of several neoadjuvant AI clinical 
trials6,52, without adverse outcome reported. (personal communication, Dr. John Olson, UMMC, 
Baltimore, MD) 
5. 
Hematoxylin and eosin stained sections will be examined by a local pathologist to establish a diagnosis 
and confirm the presence of breast cancer. 
 
The tissue acquisition form in the appendix D should be filled out for each patient sample being shipped. 

GCC 1366 March 20, 2018 Version 8  
 
15 
 
 
8.1.2 
Tissue Sample Processing 
 
8.1.2.1 Immunohistochemistry 
 
Immunohistochemistry (IHC) will be used to determine the pre-treatment and post-treatment expression 
of ER, PR, HER2, Ki67 and GP88 and when feasible IRC (MDSC, CD4/CD8 T cells, NK cells, and NK-
T cells), and pro-inflammatory cytokines (Leptin, IL-6, IL-8, TNF-α, VEGF). The expression of these 
biomarkers will be quantified by Assisted Quantitative Image Analysis. Studies for ER, PR, HER2 and 
Ki67 will be performed by immunohistochemistry technicians in the pathology department at the 
University of Maryland or affiliated study sites.  Studies for GP88 and when possible, IRC and pro-
inflammatory cytokines will be performed by immunohistochemistry technicians in the pathology 
department at the University of Maryland.  The interpretation of IHC studies will be performed by Olga Ioffe, 
M.D., breast pathologist in the Department of Anatomic Pathology, University of Maryland.  The University 
of Maryland laboratory is certified by both Clinical Laboratory Improvement Amendments (CLIA) and 
College of American Pathologists (CAP).  
 
Five-micron sections of formalin-fixed, paraffin-embedded tissue will be tested.  Buffer will replace 
primary antibody for negative controls. All attempts should be made to process tissue specimens within 
1 hour of surgery. 
ONLY baseline or pretreatment samples will be sent for Oncotype Dx®. 
 
Oncotype Dx® will be requested and sent to Genomic Health as per routine clinical practice. This test is 
considered standard of care in these patients according to the current NCCN guidelines. 
 
8.2 Blood Samples 
 
8.2.1 Collections 
 
Blood samples from the following time points will be obtained. These blood samples will be drawn at 2-3 time 
points including: 
 
1. 
Prior to starting anastrozole or letrozole (B0) 
2. 
On the day of surgery or within 3 days of surgery (B1) 
3. 
In patients receiving extended neoadjuvant endocrine therapy beyond 4 weeks, blood samples will be 
obtained 2-4 weeks after initiation of AI therapy (B2) and within 3 days or on the day of surgery (B1). 
 
CBC, CMP, phosphorus, magnesium, PT/INR/PTT, estradiol level, and FSH will be processed per sites usual 
standard of care practices. For research purposes samples for GP88 and estradiol levels (sensitive 
measurements) will be collected. 
 
When feasible, samples for IRC, pro-inflammatory cytokines, and metabolomics profiling should be collected at 
these time points. 
 
For research blood samples, the following venipuncture tubes should be used: 
 
Test 
Amount (ml) 
BD Vacutainer Tubes 
Serum GP88 
6 x 2 
Red top & Na Heparin 
Immunoregulatory cells (IRC) 
 8 
Green-red top (CPT™ Ficoll Tube) 
Pro-inflammatory cytokines 
6 
Lavender top (EDTA anti-coagulant) 
Metabolomic profiling 
10 
Uncoated glass red top 
Estradiol level 
10 
Red top 
 
 
8.2.2 Blood Sample Processing and Storage 
 
8.2.2.1 
Serum GP88 
 
Samples will be labeled with the subject’s screening ID and time point (B0, B1, B2), frozen within 2 hours after 
collection and stored at the research site. Samples will be batched and subsequently shipped to Dr. Ginette 
Serrero.  Dr. Serrero can be contacted via email at gserrero@agpharma.com. 
 

GCC 1366 March 20, 2018 Version 8  
 
16 
 
8.2.2.2 Immunoregulatory Cells (IRC) 
 
IRC sample will be labeled with the subjects screening ID and time point (B0, B1, B2) and collected in 1 tube of 8 
ml green-red top (CPT™ Ficoll Tube). 
 
Please notify contact persons via email and/or telephone PRIOR to sample collection. Transportation 
arrangements will be made via email. Samples must be transported on the day of collection under 
ambient conditions Monday through Friday. 
 
Tonya Webb, PhD 
University of Maryland School of 
Medicine 685 West Baltimore 
Street HSF-I Room 380 
Baltimore, MD 21201 
Telephone: (410) 706-4109 
Email: TWebb@som.umaryland.edu 
 
8.2.2.3 Pro-inflammatory Cytokines 
 
Circulating pro-inflammatory cytokine analysis including Leptin, IL-4, IL-6, IL-8, IL-10, IL-17A, IFNγ, VEGF, 
TNFα, and GM-CSF will be performed at the University of Maryland Cytokine Core Laboratory. Blood 
samples should be collected in an EDTA tube, inverted 8-10 times after collection, centrifuged for 10 minutes 
at 1000xg within 30 minutes of collection. Plasma should be transferred to 2ml aliquots that are labeled with 
the subjects screening ID and time point (B0, B1, B2) and frozen at -80°C. 
 
All attempts should be made to process all specimens within 30 minutes after collection. Samples will be 
batched and subsequently sent to: 
 
Lisa Hester 
Cytokine Core Lab 
University of Maryland, Baltimore 
Bressler Research Bldg 
655 W. Baltimore St. 
7th Floor, Room 07-010, Bay F 
Baltimore, MD  21201 
Telephone:  (410) 706-1508 
Email:  lhester@medicine.umaryland.edu 
 
8.2.2.4 Estradiol levels 
 
Blood for sensitive measurement of estradiol levels should be collected in a 10 ml red top tube, inverted 8-
10 times after collection, centrifuged for 10 minutes at 1000xg within 30 minutes of collection. Plasma should 
be transferred to 2ml aliquots that are labeled with the subjects screening ID and time point (B0, B1, B2) and 
frozen at -80°C. 
 
All attempts should be made to process all specimens within 30 minutes after collection. Samples will be 
sent to an outside laboratory for processing. Details to be provided to the sites prior to shipment. 
 
8.2.2.5 Metabolomic Profiling 
 
Metabolomic profiling will be performed by Dr. Joann Dorgan. Blood samples should be labeled with the 
subjects screening ID and time point (B0, B1, B2), centrifuged at 1500xg for 20 minutes at 4C. Plasma 
should be transferred into 2ml aliquots that are labeled with the subjects screening ID and the timepoint 
(B0, B1, B2)  and frozen at - 80°C. 
  
All attempts should be made to process all specimens within 60 minutes after collection. Samples will be batched 
and subsequently sent to:  
 
Rena Lapidus, PhD 
Director, UMGCC Translational Laboratory 
Bressler Research Building, BRB9-037 
Baltimore, Maryland 21201 
410-328-8092 
Email: rlapidus@som.umaryland.edu 

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17 
 
 
 
A specimen log for IRC, pro-inflammatory cytokines, estradiol levels and Metabolic Profiling (appendix E) should 
be filled out for each patient and retained on site as part of the subject study records. A copy should be provided to 
each lab at the time of sample shipment.

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18 
 
9. 
STUDY CALENDAR AND VISIT SCHEDULE 
 
Baseline evaluations are to be conducted within 3 weeks prior to start of protocol therapy.  However, baseline breast 
imaging may be obtained within 8 weeks of trial entry. 
 
Patients receiving 2-4 weeks of neoadjuvant endocrine therapy. 
 
Procedure 
Pre-
studye 
Week 1-4 
Surgerya,f 
Off Treatmentf 
Treatment: 
Anastrozole 1 mg daily 
 
A 
 
 
Letrozole 2.5 mg daily 
 
A 
 
 
Clinical assessment: 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Current medications 
X 
 
X 
X 
Physical exam 
X 
 
X 
X 
Vital signs 
X 
 
X 
X 
Height 
X 
 
X 
 
Weight 
X 
 
X 
X 
BMI 
X 
 
X 
 
Performance status 
X 
 
X 
 
Adverse event evaluation 
 
 
X 
X 
Tumor measurementb 
X 
 
X 
 
Laboratory test: 
CBC w/diff, plts 
X 
 
* 
* 
Chemistriesc, 
X 
 
* 
* 
PT/INR/PTT 
X 
 
 
 
Estradiol level, FSH 
X 
 
 
 
Correlative studies (Research procedures): 
  Blood samples 
Serum GP88 
 
Xf 
Xg 
 
Estradiol level (sensitive measurement) 
 
Xf 
Xg 
 
IRCd 
 
Xf 
Xg 
 
Pro-inflammatory cytokinesd 
 
Xf 
Xg 
 
Metabolomic profilingd 
 
Xf 
Xg 
 
Tumor Tissue samples 
 
 
X 
 
 
A: Anastrozole 1 mg OR Letrozole 2.5 mg PO daily according to cohort of enrollment (see treatment plan section 5). 
Treatment will be started on day 1 and continue until the day of definitive surgery (lumpectomy or mastectomy). 
Treatment will be continued for a minimum of 14 days and a maximum of 28 days (2-4 weeks).  Surgery will be 
performed between weeks 2-3 of treatment unless there are compelling medical or personal reasons that prevent a 
patient from having surgery during this time.  In those cases, patients may continue anastrozole or letrozole up to 4 
weeks before surgery. 
a: Surgery should be performed within 36 hours of the last dose of anastrozole or letrozole. Clinical assessments, 
laboratory tests, and correlative studies can be performed on the day of surgery or within 3 days prior to surgery. 
b: 
Tumor measurement: clinical tumor size, character, mobility, and location of the breast mass if palpable.  Tumor size will 
also be assessed from surgical specimen. For non-palpable tumors, clinical tumor size and location will be assessed by 
imaging studies. Imaging studies include mammogram, breast ultrasound, and breast magnetic resonance imaging (MRI) 
as clinically indicated. When feasible, breast MRI should also be performed in addition to mammogram and breast 
ultrasound.  
c: Chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, fasting blood glucose, total bilirubin, calcium, 
total protein, albumin, AST (SGOT), ALT (SGPT) , alkaline phosphatase, LDH, phosphorus, and magnesium.   Patients 
need to be fasting at least 9 hours before the test. 
d:  When feasible blood will be collected for IRC, pro-inflammatory cytokines and metabolomic profiling 
e:  Visits are applicable to ALL subjects enrolled, regardless of duration of neoadjuvant endocrine therapy 
f. Collected within 3 days prior to study drug initiation. 
g. Samples may be collected on the day of surgery or within 3 days of surgery. 
 
*Additional blood will be drawn as clinically indicated.

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Patients receiving extended neoadjuvant endocrine therapy, > 4 weeks. 
 
Procedure 
Week 2-4 bx to 
assess responsea 
Week 5-18 
q4-6 wks 
Anastrozole 1 mg daily 
A 
A 
Letrozole 2.5 mg daily 
A 
A 
Current medications 
X 
X 
Physical exam 
X 
X 
Vital signs 
X 
X 
Height 
X 
 
Weight 
X 
X 
BMI 
X 
X 
Performance status 
X 
X 
Adverse event evaluation 
X 
X 
Tumor measurementb 
X 
X 
CBC w/diff, plts 
* 
* 
Chemistriesc 
* 
* 
Serum GP88 
X 
 
Estradiol level (sensitive measurement) 
X 
 
IRCd 
X 
 
Pro-inflammatory cytokinesd 
X 
 
Metabolomic profilingd 
X 
 
Tumor Tissue samples 
X 
 
 
A: Anastrozole 1 mg OR Letrozole 2.5 mg PO daily according to cohort of enrollment (see treatment plan section 5). 
Treatment will be started on day 1 and continue until the day of definitive surgery (lumpectomy or mastectomy). 
Treatment will be continued for a minimum of 14 days. 
a:  A biopsy to assess response to treatment and blood samples will be obtained 2-4 weeks after initiation of treatment. 
b:  Tumor measurement: clinical tumor size, character, mobility, and location of the breast mass for palpable tumors. Tumor size 
will also be assessed from surgical specimen. For non-palpable tumors, clinical tumor size and location will be assessed by 
imaging studies. Imaging studies include mammogram, breast ultrasound, and breast magnetic resonance imaging (MRI) as 
clinically indicated. When feasible, breast MRI should also be performed in addition to mammogram and breast ultrasound. 
c: Chemistries: sodium, potassium, chloride, bicarbonate, BUN, creatinine, fasting blood glucose, total bilirubin, calcium, 
total protein, albumin, AST (SGOT), ALT (SGPT) , alkaline phosphatase, LDH, phosphorus, and magnesium.  Patients 
need to be fasting at least 9 hours before the test. 
d:  When feasible blood will be collected for IRC, pro-inflammatory cytokines and metabolomic profiling. 
 
*Additional blood will be drawn as clinically indicated. 
 
VISIT SCHEDULE 
 
The study consists of a maximum 21-day (3 weeks) screening phase prior to registration, start of study drug 
administration within 5 business days of registration. The follow up will last 30 days after the last dose of anastrozole or 
letrozole prior to surgery. 
 
9.1 Registration 
 
Registration will take place once the consented patient has completed the necessary screening procedures and is 
deemed eligible for study entry by the investigator or designee. Each registered patient will be assigned a unique 
identification number. Treatment should begin within 5 business days after registration. Please see registration 
process in more detail in section 4.2. 
9.2 Pre-treatment 
 
These following procedures and tests are to be conducted within 3 weeks prior to starting treatment except baseline 
imaging studies can be performed within 10 weeks. 
 
• 
Informed consent (signed and dated by patient) 
• 
Medical history and demographics 
• 
Inclusion/Exclusion Criteria 
• 
Concomitant medications and treatments will be recorded from 1 month prior to the start of study 

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treatment. 
• 
Physical examination including examination of major body systems, height, body weight, BMI, ECOG 
performance status, and vital signs (temperature, blood pressure, heart rate, respiratory rate) 
• 
Clinical tumor assessment by breast examination for palpable tumors including clinical tumor size, 
character, mobility, and location of the breast mass. The patient will be examined by one of the 
treating investigators or his/her designee at each specified time point and after the final dose of 
treatment. 
• 
Laboratory studies: CBC with diff; chemistries including sodium, potassium, chloride, bicarbonate 
(HCO3− or CO2), BUN, creatinine, fasting blood glucose, total bilirubin, calcium, total protein, albumin, 
AST (SGOT), ALT (SGPT),  alkaline phosphatase, LDH, phosphorus, magnesium, estradiol level, 
FSH, and PT/INR/PTT. 
• 
Baseline mammogram, breast ultrasound, or breast magnetic resonance imaging (MRI) as indicated. 
• 
Collection of research blood samples: Serum GP88 and sensitive estradiol measurements and 
when feasible IRC, pro-inflammatory cytokines, and metabolomics profiling 
• 
Collection of tumor sample: Paraffin blocks and/or unstained slides 
9.3 Study Days 
 
9.3.1 Patients receiving 2-4 weeks of neoadjuvant endocrine therapy. 
 
The period called “Study Days” begins when the patient receives the initial dose of anastrozole or letrozole (Week 
1 Day 1). Assessments are scheduled as defined in the study calendar.  However, assessments may be 
repeated more often, as clinically indicated. A maximum 5-day delay for resolution of study drug-related toxicities 
is allowed. A patient should be discontinued from the study if a greater than 5-day delay occurs. 
 
9.3.2 Patients receiving extended neoadjuvant endocrine therapy > 4 weeks. 
 
The period called “Study Days” begins when the patient receives the initial dose of anastrozole or letrozole (Week 
1 Day 1). Assessments are scheduled as defined in the study calendar.   However, these assessments may be 
repeated more often, as clinically indicated. A maximum 5-day delay for resolution of study drug-related toxicities 
is allowed. A patient should be discontinued from the study if a greater than 5-day delay occurs. 
 
9.4 End of Study (Treatment) / Withdrawal 
 
All patients must continue to be observed for 30 days after the last dose of anastrozole or letrozole. At the end of 
the study treatment, the following procedures should be performed within 4 weeks after surgery. 
 
• 
Assessment of Concomitant Treatments including medication use 
• 
Physical examination including examination of major body systems, body weight, ECOG performance 
status, and vital signs (temperature, blood pressure, heart rate, respiratory rate) 
• 
Adverse event assessment 
 
10. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be evaluated at the start of treatment and at the time of surgery.  
Patients on extended neoadjuvant endocrine therapy will be reevaluated every 4-6 weeks until surgery.  
Measurements of effect are not in the specific objectives of this study and not part of the formal statistical plan; 
however, we will collect these data for descriptive purposes. 
 
10.1 Pathologic Response Determination 
 
Pathological response in the breast, and when appropriate, in the axilla will be assessed. 
 
• 
Pathologic Complete Response (pCR): No viable invasive cancer in pathologic specimen, as 
determined by histological examination. We will report whether in situ disease only was present in the 
specimen versus no disease. We will also report for each woman whether she had a pCR in the breast 
only, in the lymph nodes only, or in both. 
• 
Nodal Disease: We will report the number of women who had positive lymph node prior to starting study 
drugs, or at the time of surgery: 0, 1-3, 4-9, or ≥10 lymph nodes. 
 
10.2 
Clinical Response Determination 
 
Clinical response in the breast will be evaluated, and when appropriate, in the axilla, infraclavicular, supraclavicular 

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regions, and skin. At the time of study enrollment, patients will have a breast examination. Physical examination 
findings will be documented including clinical tumor size, character, mobility, and location of the breast mass for 
palpable tumors. The patient will be examined by one of the treating investigators or his/her designee at each specified 
time point and at the time of the surgery. 
 
Endpoint Definitions for Clinical Response (UICC criteria) 
 
• 
Complete response (cCR) in the breast on physical exam will be defined as the absence of any 
palpable abnormality: i.e., no skin or breast thickening, mass, or associated skin or nipple changes. CR will 
be recorded separately for the breast and axilla. 
• 
Partial response (cPR) in the breast will be defined as a 50% or greater decrease in the product of 
biperpendicular diameters as measured with a ruler, compared with the pretreatment measurement. 
• 
Stable disease (cSD) in the breast will be a defined as palpable disease which does not fit the definition of 
PR or PD. 
• 
Progressive disease (cPD) will be defined as an increase in the product of biperpendicular diameters of 25% 
or greater compared to the original measurement. 
• 
Inevaluable disease (cID) is defined as breast cancer that is not palpable in two dimensions. 
 
11. STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design/Endpoints 
 
Patients will enter the study according to their BMI. There are a total of 6 cohorts in this study as described below: 
 
• 
Cohort 1: Patients with BMI 
< 25.0 
kg/m2 treating with anastrozole 
• 
Cohort 2: Patients with BMI 
≥ 25.0-29.9 
kg/m2 treating with anastrozole 
• 
Cohort 3: Patients with BMI 
≥ 30 
kg/m2 treating with anastrozole 
• 
Cohort 4: Patients with BMI 
< 25.0 
kg/m2 treating with letrozole 
• 
Cohort 5: Patients with BMI 
≥ 25.0-29.9 
kg/m2 treating with letrozole 
• 
Cohort 6: Patients with BMI 
≥ 30 
kg/m2 treating with letrozole 
 
The first 15 patients in each BMI category will be treated with anastrozole. After completion of the enrollment in 
cohort 1, 2, and 3, the following patients will be treated with letrozole in cohort 4, 5, and 6. The primary endpoint that 
will be used to assess treatment efficacy is percent reduction in Ki67. Sample size calculations are based on the power 
of the rank test under Lehmann’s alternative hypothesis using a Monte Carlo resampling procedure.54 
 
We expect a sufficiently higher  percent reduction in Ki67 in the control, i.e.,  normal weight group compared to 
overweight and obese patients. With a sample size of 15 patients per group, and odds parameters of 2 and 3, 
respectively, indicating that the odds are 2:1 and 3:1 that a patient in overweight and obese groups, respectively, will 
have lower Ki67 percent reduction than a patient in a control group. There will be above 80% power of the rank sum 
statistic under the Lehmann alternative. Testing will be done at the 0.05 one-sided level of significance, using the 
Jonckheere-Terpstra test statistic. (Please note: if odds parameter is 3, it indicates that the odds are 3:1 that a patient 
from the control group (normal BMI) has the greater percent reduction in Ki67 level than a patient in obese group.) 
We used the Jonckheere-Terpstra statistic because it provides more power than the Kruskal-Wallis statistic under the 
ordered alternatives. We stated the hypothesis that the odds of Ki76 reduction between patients’ group is proportional 
to their BMI. 
 
Secondary objectives: Secondary objectives include a number of correlative studies. The expression of ER, PR, 
HER2, GP88 as well as the levels of local pro-inflammatory cytokines (when possible) and the percentage of 
infiltrating IRC (when possible), will be assessed in tumor samples and compared between three cohorts of patients, 
including normal weight, overweight, and obese patients as well as between patients taking anastrozole vs. letrozole. 
We will also evaluate and compare estradiol, serum GP88, circulating pro-inflammatory cytokines (when possible), 
circulating IRC (when possible) and metabolomics profiling (when possible) in peripheral blood among normal weight, 
overweight, and obese cohorts as well as between patients taking anastrozole vs. letrozole. Comparing between pre-
treatment and post-treatment specimens, effects of anastrozole or letrozole treatment in these parameters in tumor 
tissue and peripheral blood will be estimated. All patients’ characteristics will be compared between patients’ cohort 
using BMI. We expect this aspect of the study to be exploratory and hypotheses generating. Statistical analysis 
will be done in S-plus (v. 8.0, TIBCO) and in R using bioconductor package. All required analyses will be conducted 
by the GCC Biostatistic Shared Service. 
 
 
11.2 
Sample Size/Accrual Rate 
 

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This trial will enroll a total of 90 patients. At an estimated accrual rate of 2-3 patients per month, we expect that this 
trial will need to accrue patients for anywhere from 30-45 months. 
 
12. ADVERSE EVENT REPORTING, DATA SAFETY AND MONITORING PLAN 
 
12.1 
Adverse Events (AEs) 
 
An Adverse Event is any untoward occurrence reflecting a change from baseline state after signing informed consent and 
up to 30 days from last administration of the study medication.  A Serious Adverse Event (SAE) is any AE that is 
1) Fatal, 2) Life Threatening 3) Requires or prolongs hospital stay, 4) Results in a persistent or significant disability or 
incapacity. 5) Results in a congenital anomaly or birth defect 6) Is considered by the Investigator as an important 
medical event. 
 
12.1.1 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 (Available through http://ctep.cancer.gov) will be utilized for AE reporting. AEs of 
any grade will be documented in the case report form. 
 
12.1.2 
AEs can be “Expected” if described in the Informed Consent or “Unexpected”. The attribution of the AE 
is Definite if the AE is clearly related to study treatment; Probable if it is likely related to the study treatment; Possible 
if it is equally likely related to study treatment or to some other circumstance, and Unlikely if most probably some other 
event was responsible for the adverse event, and Unrelated if the Adverse Event is entirely explained by circumstances 
not caused by the study medication. 
 
12.1.3 
Data Safety Monitoring Board (DSMB). DSMB oversight will be conducted in accordance with the 
Greenebaum Cancer Center DSMB standard operating procedures. It is the responsibility of the Principal Investigator to 
oversee the safety of the study. This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above.  
 
This study will be monitored by the UMGCC Data and Safety Monitoring and Quality Assurance Committee and will follow the 
Data Safety and Monitoring Plan as outlined in the Clinical Investigator Handbook of the UMGCC Clinical Research Office. 
Monitoring will be conducted as per the plan on file with the University of Maryland IRB (also available in the UMGCC Clinical 
Investigator Handbook found at http://www.umgcc.org/research/clinical_research.htm). 
 
 
12.1.4 
Clinical Trial Monitoring.  Data safety and verification monitoring will be conducted in accordance with the 
Greenebaum Cancer Center Sponsor-Investigator Monitoring Standard Operating Procedure (SOP), the Code of Federal 
Regulations (CFR), and FDA and International Counsel on Harmonization (ICH) E6 Guidelines. 
 
12.2 
Expedited reporting of serious adverse events (SAEs) 
 
The University of Maryland IRB requires the expeditious reporting (within 5 business days) of SAEs that are 
unexpected and probably related to the study intervention (See reportable new information policy available from  
http://www.hrpo.umaryland.edu/default.asp). All other SAEs are collected in the UMGCC clinical research database 
(ONCORE) and are reviewed by the UMGCC DSM/QAC as per their SOP and summarized for the IRB in the annual 
renewal. 
 
For those events that require a change to the informed consent, the data entry staff who input these data will 
immediately notify the appropriate research coordinator and regulatory coordinator of this change. 
In the event of overdoses and secondary malignancies, the reporting requirements will be the same as for serious 
adverse event. 
 
12.3 
Data Management 
 
Clinical data will be entered into the OnCore® database by the designated data manager at the University of Maryland 
Marlene and Stewart Greenebaum Cancer Center (UMGCC). Oncore® is 21CRF11.10 (electronic medical records) compliant 
and is equipped for HIPAA-compliant internet-based entry of protocol tracking and review information. 
All study data will be collected by the research team at each and every study visit and recorded in the research record. This data 
will then be entered in to the OnCore® study database. 
 
Remote VPN access will be provided for each participating site along with Oncore® training. This access and training will occur 
prior to enrollment of the first patient at the site, to ensure staff are adequately trained and able to enter data within 5 days of the 
visit occurring. All study data will be collected by the research team at each and every study visit and recorded in the research 
record. This data will then be entered in to the OnCore® study database. 
 
All source documents will be obtained and retained along with any study forms, and placed into the patient’s research folder 
according to the policies around record retention in place at each site. 

GCC 1366 March 20, 2018 Version 8 n6
 
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12.4 
Compliance with Laws and Guidance’s 
 
This study will be conducted in accordance with current U.S. Food and Drug Administration (FDA) Regulations, Good 
Clinical Practices (GCPs) and International Counsel on Harmonization (ICH) E6 Guidelines. 
12.5 
Institutional Review Board (IRB) 
This protocol will be submitted to the University of Maryland IRB. Study procedures will begin once local IRB approval is 
secured. All amendments, instances of reportable new information (i.e. unanticipated problems, data breaches, etc.) and 
continuing review reports will be submitted to the University of Maryland IRB. 
13. REFERENCES: 
 
 
 
 
1. 
Burstein HJ, Prestrud AA, Seidenfeld J, et al: American Society of Clinical Oncology clinical practice guideline: 
update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol 28:3784-96, 2010 
 
2. 
Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of postmenopausal breast cancer 
patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12:1527-32, 2001 
 
3. 
Smith IE, Dowsett M, Ebbs SR, et al: Neoadjuvant treatment of postmenopausal breast cancer with 
anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with 
Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23:5108-16, 2005 
 
4. 
Cataliotti L, Buzdar AU, Noguchi S, et al: Comparison of anastrozole versus tamoxifen as preoperative 
therapy in postmenopausal women with hormone receptor-positive breast cancer: the Pre-Operative "Arimidex" Compared to 
Tamoxifen (PROACT) trial. Cancer 106:2095-103, 2006 
 
5. 
Semiglazov V, Kietsel, A., Semiglazov, V., Zhiltzova, E., Ivanov, V., Dashyan, G., Bozhok, A., Melnikova, O., 
Paltuev, R., and Berstein, L. : Exemestane vs. tamoxifen as neoadjuvant endocrine therapy for postmenopausal women with 
ER+ breast cancer. J Clin Oncol 23:abstract 530, 2005 
 
6. 
Olson JA, Jr., Budd GT, Carey LA, et al: Improved surgical outcomes for breast cancer patients receiving 
neoadjuvant aromatase inhibitor therapy: results from a multicenter phase II trial. J Am Coll Surg 208:906-14; discussion 915-6, 
2009 
 
7. 
Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with 
operable breast cancer. J Clin Oncol 16:2672-85, 1998 
 
8. 
von Minckwitz G, Raab G, Caputo A, et al: Doxorubicin with cyclophosphamide followed by docetaxel every 
21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the 
GEPARDUO study of the German Breast Group. J Clin Oncol 23:2676-85, 2005 
 
9. 
Dowsett M, Houghton J, Iden C, et al: Benefit from adjuvant tamoxifen therapy in primary breast cancer 
patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol 17:818-26, 2006 
 
10. 
Byar DP, Sears ME, McGuire WL: Relationship between estrogen receptor values and clinical data in 
predicting the response to endocrine therapy for patients with advanced breast cancer. Eur J Cancer 15:299-310, 1979 
 
11. 
Early Breast Cancer Trialists' Collaborative G: Effects of chemotherapy and hormonal therapy for early breast 
cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687-717, 2005 
 
12. 
Early Breast Cancer Trialists' Collaborative G, Davies C, Godwin J, 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 
 
13. 
Kim C, Tang G, Pogue-Geile KL, et al: Estrogen receptor (ESR1) mRNA expression and benefit from 
tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol 29:4160-7, 2011 
 
14. 
Spyratos F, Ferrero-Pous M, Trassard M, et al: Correlation between MIB-1 and other proliferation markers: 
clinical implications of the MIB-1 cutoff value. Cancer 94:2151-9, 2002 
 
15. 
Weidner N, Moore DH, 2nd, Vartanian R: Correlation of Ki-67 antigen expression with mitotic figure index and 
tumor grade in breast carcinomas using the novel "paraffin"-reactive MIB1 antibody. Hum Pathol 25:337-42, 1994 
 
16. 
Bottini A, Berruti A, Bersiga A, et al: Relationship between tumour shrinkage and reduction in Ki67 expression 
after primary chemotherapy in human breast cancer. Br J Cancer 85:1106-12, 2001 
 
17. 
Billgren AM, Rutqvist LE, Tani E, et al: Proliferating fraction during neoadjuvant chemotherapy of primary 
breast cancer in relation to objective local response and relapse-free survival. Acta Oncol 38:597-601, 1999 
 
18. 
Urruticoechea A, Smith IE, Dowsett M: Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 23:7212-
20, 2005 
 
19. 
Assersohn L, Salter J, Powles TJ, et al: Studies of the potential utility of Ki67 as a predictive molecular marker 
of clinical response in primary breast cancer. Breast Cancer Res Treat 82:113-23, 2003 
 
20. 
Ellis PA, Smith IE, Detre S, et al: Reduced apoptosis and proliferation and increased Bcl-2 in residual breast 
cancer following preoperative chemotherapy. Breast Cancer Res Treat 48:107-16, 1998 
 
21. 
Dowsett M, Smith IE, Ebbs SR, et al: Short-term changes in Ki-67 during neoadjuvant treatment of primary 
breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res 
11:951s-8s, 2005 
 
22. 
Dowsett M, Smith IE, Ebbs SR, et al: Prognostic value of Ki67 expression after short-term presurgical 
endocrine therapy for primary breast cancer. J Natl Cancer Inst 99:167-70, 2007 
 
23. 
Goncalves R, Ma C, Luo J, et al: Use of neoadjuvant data to design adjuvant endocrine therapy trials for 
breast cancer. Nat Rev Clin Oncol 9:223-9, 2012 
 
24. 
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The 

GCC 1366 March 20, 2018 Version 8 n6
 
24 
 
Evidence Report. National Institutes of Health. Obes Res 6 Suppl 2:51S-209S, 1998 
 
25. 
Organization WH:  Obesity and Overweight - Fact Sheet #311, 2011,  
 
26. 
Flegal KM, Carroll MD, Ogden CL, et al: Prevalence and trends in obesity among US adults, 1999-2008. 
JAMA 303:235-41, 2010 
 
27. 
Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a 
prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-38, 2003 
 
28. 
Bergstrom A, Pisani P, Tenet V, et al: Overweight as an avoidable cause of cancer in Europe. Int J Cancer 
91:421-30, 2001 
 
29. 
van den Brandt PA, Spiegelman D, Yaun SS, et al: Pooled analysis of prospective cohort studies on height, 
weight, and breast cancer risk. Am J Epidemiol 152:514-27, 2000 
 
30. 
Trentham-Dietz A, Newcomb PA, Storer BE, et al: Body size and risk of breast cancer. Am J Epidemiol 
145:1011-9, 1997 
 
31. 
Key TJ, Appleby PN, Reeves GK, et al: Body mass index, serum sex hormones, and breast cancer risk in 
postmenopausal women. J Natl Cancer Inst 95:1218-26, 2003 
 
32. 
Simpson ER, Mahendroo MS, Means GD, et al: Aromatase cytochrome P450, the enzyme responsible for 
estrogen biosynthesis. Endocr Rev 15:342-55, 1994 
 
33. 
Protani M, Coory M, Martin JH: Effect of obesity on survival of women with breast cancer: systematic review 
and meta-analysis. Breast Cancer Res Treat 123:627-35, 2010 
 
34. 
Kwan ML, Chen WY, Kroenke CH, et al: Pre-diagnosis body mass index and survival after breast cancer in 
the After Breast Cancer Pooling Project. Breast Cancer Res Treat 132:729-39, 2012 
 
35. 
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 
 
36. 
Pfeiler G, Konigsberg R, Fesl C, et al: Impact of body mass index on the efficacy of endocrine therapy in 
premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol 29:2653-9, 2011 
 
37. 
Ewertz M, Gray KP, Regan MM, et al: Obesity and risk of recurrence or death after adjuvant endocrine 
therapy with letrozole or tamoxifen in the breast international group 1-98 trial. J Clin Oncol 30:3967-75, 2012 
 
38. 
Tangkeangsirisin W, Hayashi J, Serrero G: PC cell-derived growth factor mediates tamoxifen resistance and 
promotes tumor growth of human breast cancer cells. Cancer Res 64:1737-43, 2004 
 
39. 
Tangkeangsirisin W, Serrero G: PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates 
migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis 25:1587-92, 2004 
 
40. 
Kim WE, Serrero G: PC cell-derived growth factor stimulates proliferation and confers Trastuzumab resistance 
to Her-2-overexpressing breast cancer cells. Clin Cancer Res 12:4192-9, 2006 
 
41. 
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 351:2817-26, 2004 
 
42. 
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 24:3726-34, 2006 
 
43. 
Nagaraj S, Gabrilovich DI: Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer 
Res 68:2561-3, 2008 
 
44. 
Paulos CM, Kaiser A, Wrzesinski C, et al: Toll-like receptors in tumor immunotherapy. Clin Cancer Res 
13:5280-9, 2007 
 
45. 
Bronte V, Zanovello P: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5:641-
54, 2005 
 
46. 
Morales JK, Kmieciak M, Graham L, et al: Adoptive transfer of HER2/neu-specific T cells expanded with 
alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor 
cells. Cancer Immunol Immunother 58:941-53, 2009 
 
47. 
Le NT, Chao N: Regulating regulatory T cells. Bone Marrow Transplant 39:1-9, 2007 
 
48. 
Newman KC, Riley EM: Whatever turns you on: accessory-cell-dependent activation of NK cells by 
pathogens. Nat Rev Immunol 7:279-91, 2007 
 
49. 
Fruhbeck G, Gomez-Ambrosi J: Modulation of the leptin-induced white adipose tissue lipolysis by nitric oxide. 
Cell Signal 13:827-33, 2001 
 
50. 
Trayhurn P, Beattie JH: Physiological role of adipose tissue: white adipose tissue as an endocrine and 
secretory organ. Proc Nutr Soc 60:329-39, 2001 
 
51. 
Dunn WB, Broadhurst D, Begley P, et al: Procedures for large-scale metabolic profiling of serum and plasma 
using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc 6:1060-83, 2011 
 
52. 
Ellis MJ, Suman VJ, Hoog J, et al: Randomized phase II neoadjuvant comparison between letrozole, 
anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and 
biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype--ACOSOG Z1031. J Clin Oncol 
29:2342-9, 2011 
 
53. 
Baselga J, Semiglazov V, van Dam P, et al: Phase II randomized study of neoadjuvant everolimus plus 
letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2630-7, 
2009 
 
54. 
Heller G: Power calculations for preclinical studies using a K-sample rank test and the Lehmann alternative 
hypothesis. Stat Med 25:2543-53, 2006 
 

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APPENDIX A: ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 

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APPENDIX B: American Joint Committee on Cancer Staging (AJCC) 
 
T – Primary Tumor 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
Tis (DCIS) 
Ductal carcinoma in situ 
Tis (LCIS) 
Lobular carcinoma in situ 
Tis (Paget) 
Paget’s disease of the nipple with no tumor 
Note: Paget’s disease associated with a tumor is classified according to the size of the tumor. 
T1 
Tumor ≤ 2 cm in greatest dimension 
T1mic 
Microinvasion ≤ 0.1 cm in greatest dimension 
T1a 
Tumor > 0.1 cm but not > 0.5 cm in greatest dimension 
T1b 
Tumor > 0.5 cm but not > 1 cm in greatest dimension 
T1c 
Tumor > 1 cm but not > 2 cm in greatest dimension 
T2 
Tumor > 2 cm but not > 5 cm in greatest dimension 
T3 
Tumor > 5 cm in greatest dimension 
T4 
Tumor of any size with direct extension to 
(a) chest wall or 
(b) skin, only as described below 
T4a 
Extension to chest wall, not including pectoralis muscle 
T4b 
Edema (including peau d’orange” or ulceration of the skin of the breast, or satellite skin nodules 
confined to the same breast 
T4c 
Both T4a and T4b 
T4d 
Inflammatory carcinoma 
 
N – Regional lymph nodes 
NX 
Regional lymph nodes cannot be assessed (e.g., previously removed) 
N0 
No regional lymph node metastasis 
N1 
Metastasis in movable ipsilateral axillary lymph node(s) 
N2 
Metastases in ipsilateral axillary lymph nodes fixed or matted, or in clinically apparent ipsilateral 
internal mammary nodes in the absence of clinically evident axillary lymph node metastasis 
N2a 
Metastasis in ipsilateral axillary lumph nodes fixed to one another (matted) or to other structures 
N2b 
Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of 
clinically evident axillary lymph node metastasis 
N3 
Metastasis in ipsilateral infraclavicular lymph node(s), or in clinically apparent ipsilateral internal 
mammary lymph node(s) and in the presence of clinically evident axillary lymph node metastasis; 
or metastasis in ipsilateral supraclavicular lymph node(s) with or without axillary or internal 
mammary lymph node involvement 
N3a 
Metastasis in ipsilateral infraclavicular lymph node(s) and axillary lymph node(s) 
N3b 
Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s) 
N3c 
Metastasis in ipsilateral supraclavicular lymph node(s) 

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APPENDIX B (Continued) 
 
pN – Regional lymph nodes 
pNX 
Regional lymph nodes cannot be assessed (e.g., previously removed or not removed for 
pathologic study) 
pN0 
No regional lymph node metastasis histologically, no additional examination for isolated tumor cells 
pN0(i-) 
No regional lymph node metastasis histologically, negative IHC 
pN0(i+) 
No regional lymph node metastasis histologically, positive IHC, no IHC cluster > 0.2 mm 
pN0(mol-) 
No regional lymph node metastasis histologically, negative molecular findings (RT-PCR) 
pN0(mol+) 
No regional lymph node metastasis histologically, positive molecular findings (RT-PCR) 
pN1mi 
Micrometastasis (> 0.2 mm, none > 2.0 mm) 
pN1 
Mestastasis in one to three axillary lymph nodes and/or in internal mammary nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically apparent 
pN1a 
Mestastasis in one to three axillary lymph nodes 
pN1b 
Metastasis in internal mammary nodes with microscopic disease detected by sentinel lymph node 
dissection but not clinically apparent 
pN1c 
Mestastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with 
microscopic disease detected by sentinel lymph node dissection but not clinically apparent 
pN2 
Metastasis in four to nine axillary lymph nodes, or in clinically apparent internal mammary lymph 
nodes in the absence of axillary lymph node metastasis 
pN2a 
Metastasis in four to nine axillary lymph nodes (at least one tumor deposit > 2.0 mm) 
pN2b 
Metastasis in clinically apparent internal mammary lymph nodes in the absence of axillary lymph 
node metastasis 
pN3 
Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically 
apparent ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary 
lymph nodes; or in more than three axillary lymph nodes with clinically negative microscopic 
metastasis in internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes 
pN3a 
Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit > 2.0 mm), or metastasis 
to the infraclavicular lymph nodes 
pN3b 
Metastasis in clinically apparent ipsilateral internal mammary lymph nodes in the presence of one 
or more positive axillary lymph nodes; or in more than three axillary lymph nodes and in internal 
mammary lymph nodes with microscopic disease detected by sentinel lymph node dissection but 
not clinically apparent 
pN3c 
Metastasis in ipsilateral supraclavicular lymph nodes 
 
 
M – Distant metastasis 
MX 
Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 

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APPENDIX C: Study Drug Diary 
 
Anastrozole 
 
Letrozole 
 
Please complete this diary every time you take your anastrozole or letrozole. You should also use this diary to 
record any side effects that you experience and medications that you take other than your anastrozole or 
letrozole. Please be sure to bring this diary with you to your next doctor’s visit. 
 
You will take one tablet of anastrozole or letrozole by mouth once a day. You should continue anastrozole or 
letrozole until you have your surgery (i.e. lumpectomy or mastectomy). Anastrozole or letrozole is a tablet 
that can be taken with or without food. You should take anastrozole or letrozole at around the same time 
every day. Please contact your study doctor or nurse with any new complaints or symptoms that you have 
after starting to take anastrozole or letrozole. If you have severe symptoms, you may be told to stop taking 
anastrozole or letrozole. Please do not make 
any changes in your anastrozole or letrozole dose without 
speaking with your study doctor or nurse. 
 
 
Dose 
# 
Date 
Taken 
Time 
Taken 
Comments 
(Side effects, other 
medications) 

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Note:  For any time that you did not take your anastrozole or letrozole (Example:  You forgot to take it), 
write the reason that you did not take it in the “Comments” field. 
 
 
Completed by:_________________________ Date:   _______ Signature of Patient 
 
 
Reviewed by: _________________________ Date:   ________ Signature of Study Staff 
Dose 
# 
Date 
Taken 
Time 
Taken 
Comments 
(Side effects, other 
medications) 

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APPENDIX D: Tissue Acquisition Form 
 
Protocol Title: GCC1366 - A PROSPECTIVE STUDY OF NEOADJUVANT NON-STEROIDAL AROMATASE 
INHIBITORS IN POSTMENOPAUSAL WOMEN WITH OPERABLE HORMONE RECEPTOR-POSITIVE BREAST 
CANCER TO EVALUATE THE ANTI-PROLIFERATIVE RESPONSE IN OBESE AND OVERWEIGHT PATIENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Researcher:  Please fill out 
 
Date Samples Received: 
Data entered into database:  Yes   /    No 
Pathologist:  Please fill out 
 
Diagnosis:____________________________________ 
 
Results of IHC staining: 
 
ER 
% PR 
% 
Ki67 
% HER2 
 
by IHC 
HER2 Ratio 
by FISH 
 
Pathologist Name:___________________________   Date:__________ 
 
 
Completed form must be returned to:_____________________________ Fax ____________________ 
Study Coordinator/Research Nurse:  Please fill out and send form as instructed in section 8 of protocol. 
 
Patient Initials ______ Screening ID#: S______ 
Institution:_________ Attending physician: _____________  
Date consented for clinical protocol: 
 
Diagnosis:   
  
Consent to Fresh Surgical Core that is frozen for left over tissue storage for future research? ___Y ___N 
Origin of Tissue: 
 
 
 Date Tissue Obtained:   
 
Type of specimens:   
 
 
 
 
   
Please mark: 
 
 
Prior to starting treatment or original diagnosis procedure (T0)  
 
 
Clinical biopsy week 2-4 (T2) 
 
 
At the time of definitive surgery (T1) 
 
Please mark:   
 Anastrozole 
 Letrozole 
 
Cohort:   
 1 
 2 
 3 
 4 
 5 
 6 

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APPENDIX E: Pro-inflammatory Cytokines, IRC, Estradiol levels and Metabolomic Profiling Specimen Log 
 
 
 
 
Sample 
Date 
Time drawn 
Time processed 
Comment 
Prior to starting 
anastrozole or 
letrozole (B0) 
On the day of biopsy 
to assess clinical 
response (B2) 
On the day of 
surgery or within 3 
days of surgery (B1) 
 
 
 
 
Patient Initials:___ ___ ___                             Patient Screening  ID #: S ___ ___ ___ 
Institution: 
 
Attending physician:   
 
Please mark: 
Anastrozole 
Letrozole 
Cohort: 
1 
2
3
4
5
6

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APPENDIX F: Registration Worksheet 
 
Cohort 1 BMI<25.0 
Anastrozole – Subject # 
Subject Initials and 
Screening # (S101 etc.) 
Confirmed BMI 
Site 
1001 
 
 
 
1002 
 
 
 
1003 
 
 
 
1004 
 
 
 
1005 
 
 
 
1006 
 
 
 
1007 
 
 
 
1008 
 
 
 
1009 
 
 
 
1010 
 
 
 
1011 
 
 
 
1012 
 
 
 
1013 
 
 
 
1014 
 
 
 
1015 
 
 
 
1016 (replacement only) 
 
 
 
1017 (replacement only) 
 
 
 
1018 (replacement only) 
 
 
 
Cohort 2 BMI ≥25.0-29.9 
Anastrazole – Subject # 
 
 
 
2001 
 
 
 
2002 
 
 
 
2003 
 
 
 
2004 
 
 
 
2005 
 
 
 
2006 
 
 
 
2007 
 
 
 
2008 
 
 
 
2009 
 
 
 
2010 
 
 
 
2011 
 
 
 
2012 
 
 
 
2013 
 
 
 
2014 
 
 
 
2015 
 
 
 
2016 (replacement only) 
 
 
 
2017 (replacement only) 
 
 
 
2018 (replacement only) 
 
 
 
Cohort 3 BMI ≥30 
Anastrazole – Subject # 
 
 
 
3001 
 
 
 
3002 
 
 
 
3003 
 
 
 
3004 
 
 
 

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3005 
 
 
 
3006 
 
 
 
3007 
 
 
 
3008 
 
 
 
3009 
 
 
 
3010 
 
 
 
3011 
 
 
 
3012 
 
 
 
3013 
 
 
 
3014 
 
 
 
3015 
 
 
 
3016 (replacement only) 
 
 
 
3017 (replacement only) 
 
 
 
3018 (replacement only) 
 
 
 
Cohort 4 BMI<25.0 
Letrozole – Subject # 
 
 
 
4001 
 
 
 
4002 
 
 
 
4003 
 
 
 
4004 
 
 
 
4005 
 
 
 
4006 
 
 
 
4007 
 
 
 
4008 
 
 
 
4009 
 
 
 
4010 
 
 
 
4011 
 
 
 
4012 
 
 
 
4013 
 
 
 
4014 
 
 
 
4015 
 
 
 
4016 (replacement only) 
 
 
 
4017 (replacement only) 
 
 
 
4018 (replacement only) 
 
 
 
Cohort 5 BMI ≥25.0-29.9 
Letrozole – Subject # 
 
 
 
5001 
 
 
 
5002 
 
 
 
5003 
 
 
 
5004 
 
 
 
5005 
 
 
 
5006 
 
 
 
5007 
 
 
 
5008 
 
 
 
5009 
 
 
 
5010 
 
 
 
5011 
 
 
 
5012 
 
 
 

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34 
 
5013 
 
 
 
5014 
 
 
 
5015 
 
 
 
5016 (replacement only) 
 
 
 
5017 (replacement only) 
 
 
 
5018 (replacement only) 
 
 
 
Cohort 6 BMI ≥30.0 
Letrazole – Subject # 
 
 
 
6001 
 
 
 
6002 
 
 
 
6003 
 
 
 
6004 
 
 
 
6005 
 
 
 
6006 
 
 
 
6007 
 
 
 
6008 
 
 
 
6009 
 
 
 
6010 
 
 
 
6011 
 
 
 
6012 
 
 
 
6013 
 
 
 
6014 
 
 
 
6015 
 
 
 
6016 (replacement only) 
 
 
 
6017 (replacement only) 
 
 
 
6018 (replacement only)