Conditions: Breast Cancer Invasive Breast Cancer
Keywords: aromatase inhibitor breast cancer estrogen receptor progesterone receptor endocrine-targeted therapy Anti-estrogen therapy HR+ HER2-negative Neoadjuvant Treatment
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is an exploratory interventional study that initiates standard-of-care anti-estrogen treatment preoperatively for four weeks.

Detailed description:
STUDY RATIONALE: Patients with hormone receptor (HR)+, HER2- node-negative breast cancers generally undergo surgical resection upfront, followed by adjuvant chemotherapy, if needed, in addition to adjuvant endocrine therapy. Because endocrine therapy is primarily delivered in the postoperative setting, the ability to assess the tumor response to this treatment modality is lost and very difficult to assess. This study offers the unique opportunity to assess the responsiveness of breast tumors to endocrine therapy while the tumors are still in vivo by treating patients with endocrine therapy before surgery and assessing molecular changes with treatment. By comparing pre- and post-treatment levels of molecular markers in individual tumors, the team expects to identify predictors of responsiveness to existing agents and identify new candidate therapeutic targets.

PRIMARY OBJECTIVE: The primary objective is to determine the frequency of increased HER family of receptor tyrosine kinases protein expression in tumors, following treatment with neoadjuvant endocrine therapy and their correlation with Ki-67 tumor responses. The team will measure cancer cell protein levels of growth factor receptors of the human epidermal growth factor receptor (HER) family before and after neoadjuvant endocrine therapy. The data will be used to inform a future randomized trial of combined endocrine and the most promising anti-HER targeted therapy.

Arms:
arm 1: Once enrolled, patients would be treated with the current standard-of-care endocrine therapy. Choice of endocrine therapy (aromatase inhibitors or tamoxifen) would be decided by medical oncologist, following a review of the patient's medical history and menstrual status. The patient would be treated with endocrine therapy in a neoadjuvant setting for four weeks, with dosing continuing until surgery.

Interventions: intervention 1: Anastrozole intervention 2: Letrozole intervention 3: Exemestane intervention 4: Tamoxifen
Intervention descriptions: intervention 1: 1 mg once daily. intervention 2: 2.5mg once daily. intervention 3: 25 mg once daily. intervention 4: 20 mg once daily.

Protocol document:
Prot_SAP_000.pdf: 
Protocol Title:  An Exploratory Study of Neoadjuvant Endocrine Therapy in Hormone 
Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to Assess 
Responses and Mechanisms of Endocrine Resistance 
 
NCT:  NCT03219476 
 
Document Date:  11/27/18 


1 
PRO 30178 IIT-Chaudhary-Endocrine  
 
 
 
CLINICAL STUDY PROTOCOL 
 
An Exploratory Study of Neoadjuvant Endocrine Therapy  
in Hormone Receptor-Positive HER2-Negative Node-Negative Breast 
Cancer Patients to Assess Responses and  
Mechanisms of Endocrine Resistance 
   
 
 
Lubna Chaudhary, MD, MS 
 
Version 6 – 11/27/18 
Version 5 – 4/3/2018 
Version 4 – 6/29/17 
Version 3 – 1/10/17 
Version 2 – 10/21/16 
Version 1 – 8/24/16 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential and 
may not be disclosed to others except to the extent necessary to obtain 
Institutional Review Board approval and informed consent, or as required by 
federal and state laws. Persons to whom this information is disclosed should be 
informed that this information is privileged and confidential and that it should not 
be further disclosed. 
 
 
 


 
 
2 
 
PRINCIPAL INVESTIGATOR 
 
Lubna Chaudhary, MD, MS 
Assistant Professor 
Department of Medicine 
Division of Hematology/Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, Wis. 53226 
lchaudhary@mcw.edu 
414-805-4600 
 
SUB-INVESTIGATORS 
 
Radiation Oncology 
Carmen Bergom, MD, PhD 
Assistant Professor 
Department of Radiation Oncology 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
cbergom@mcw.edu 
414-805-4400 
 
Medical Oncology 
Christopher Chitambar, MD 
Professor 
Department of Medicine 
Division of Hematology and Oncology 
9200 W. Wisconsin Ave 
Milwaukee, WI 53226 
cchitambar@mcw.edu 
414-805-4600 
 
Pathology  
Hallgeir Rui, MD, PhD 
Professor 
Department of Pathology  
Medical College of Wisconsin  
8701 W. Watertown Plank Road  
Milwaukee, WI 53226  
414-805-8454  
hrui@mcw.edu  
 
 
 
 
 


 
 
3 
 
Julie Jorns, MD  
Associate Professor 
Department of Pathology  
Medical College of Wisconsin  
8701 W. Watertown Plank Road  
Milwaukee, WI 53226  
414-805-6974  
jjorns@mcw.edu  
 
Yuri Sheinin, MD 
Assistant Professor 
Department of Pathology 
Medical College of Wisconsin 
8701 W. Watertown Plank Road 
Milwaukee, WI 53226 
414-805-7049  
ysheinin@mcw.edu 
 
Surgery 
Amanda Kong, MD, MS  
Associate Professor 
Department of Surgery 
Division of Surgical Oncology  
Medical College of Wisconsin  
8701 W. Watertown Plank Road  
Milwaukee, WI 53226  
akong@mcw.edu  
414-805-5815  
 
 
Radiology 
Mary Beth Gonyo, MD 
Associate Professor 
Department of Radiology 
Chief, Breast Imaging 
Medical College of Wisconsin  
8701 W. Watertown Plank Road 
Milwaukee, WI 53226  
414-805-8454  
mbgonyo@mcw.edu 
 
 
 
 
 
 


 
 
4 
 
Statistician 
Anjishnu Banerjee, PhD 
Assistant Professor 
Institute for Heath and Society 
Division of Biostatistics 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
abanerjee@mcw.edu 
414-955-8358 


 
 
5 
 
PROTOCOL SUMMARY 
Title 
An Exploratory Study of Neoadjuvant Endocrine Therapy in 
Hormone Receptor-Positive HER2-negative Node-Negative Breast 
Cancer Patients to Assess Responses and Mechanisms of 
Endocrine Resistance 
Protocol Number 
FP00011093; PRO 30178. 
IND Sponsor 
N/A 
Principal Investigator  
Lubna Chaudhary, MD, MS 
Study Sites 
 
St. Joseph’s Hospital, West Bend 
Community Memorial Hospital, Dr. Chaudhary 
Froedtert Memorial Lutheran Hospital 
 
Clinical Trial Phase 
Exploratory 
Study Disease 
Hormone receptor-positive (HR+), HER2-negative (Her2-), node-
negative pre and postmenopausal breast cancer patients. 
Study Rationale 
Patients with HR+ HER2- node-negative breast cancers generally 
undergo surgical resection upfront, followed by adjuvant 
chemotherapy, if needed, in addition to adjuvant endocrine 
therapy. Because endocrine therapy is primarily delivered in the 
postoperative setting, the ability to assess the tumor response to 
this treatment modality is lost and very difficult to assess. This 
study offers the unique opportunity to assess the responsiveness 
of breast tumors to endocrine therapy while the tumors are still in 
vivo by treating patients with endocrine therapy before surgery and 
assessing molecular changes with treatment. By comparing pre- 
and post-treatment levels of molecular markers in individual 
tumors, we expect to identify predictors of responsiveness to 
existing agents and identify new candidate therapeutic targets.  
Primary Objectives 
Our primary objective is to determine the frequency of increased 
HER family of receptor tyrosine kinases protein expression in 
tumors, following treatment with neoadjuvant endocrine therapy 
and their correlation with Ki-67 tumor responses. We will measure 
cancer cell protein levels of growth factor receptors of the HER 
family before and after neoadjuvant endocrine therapy. The data 
will be used to inform a future randomized trial of combined 
endocrine and the most promising anti-HER targeted therapy. 
Secondary Objectives 
- 
To determine changes in additional selected molecular markers 
(CK5+/ER- progenitor cells, PD-L1, PD-L2, BTK, iron-related 
proteins) and correlate with KI-67 responsiveness to endocrine 
therapy in our pre- and post-treatment tumor specimens. 


 
 
6 
 
- 
Assess changes in tumor size on radiographic images with 
neoadjuvant endocrine therapy and correlate with changes in 
biomarkers and Ki-67.  
Endpoints 
Primary endpoints are: 
- 
Change in cancer cell protein levels of HER family members 
(HER1-4) with neoadjuvant endocrine therapy and association 
with Ki-67. We hypothesize that the expression of one or more 
HER proteins (HER1-4) will be upregulated in at least 50% of 
tumors after four weeks of neoadjuvant endocrine therapy and 
this upregulation will correlate with Ki-67 expressed in more 
than 10% of cancer cells. 
Secondary end points are: 
- 
Determine whether an increased proportion of therapy-
resistant CK5+ progenitor cells are negatively correlated with 
Ki-67 response and tumor volume reduction, in response to 
neoadjuvant endocrine therapy.  
- 
Assess changes in the % expression of ER and PR in pre- 
and post-treatment breast cancer tumor specimens and their 
correlations with Ki-67 and radiographic responses. 
- 
Assess changes in BTK protein expression with neoadjuvant 
endocrine therapy and correlation with responses. 
- 
Changes in iron-related protein expression, i.e., transferrin, 
ferritin, ferroportin and ribonucleotide reductase with 
neoadjuvant endocrine therapy and correlation with responses.  
- 
Changes in PD-L1 and PD-L2 protein expression with 
neoadjuvant endocrine therapy and correlation with responses. 
- 
Assess changes in tumor size on radiographic images with 
neoadjuvant endocrine therapy and correlate with changes in 
biomarkers and Ki-67.  
Chart review planned at about five years from completion of 
study to assess patient outcomes, i.e., ipsilateral, contralateral 
or distant recurrences. 
 
Study Design 
Exploratory study.  
Study Agent/
Intervention 
Description 
This is an exploratory interventional study that initiates standard-of-
care anti-estrogen treatment preoperatively for four weeks, +/- 1 
week.  
Number of Subjects 
37 
Subject Participation 
Duration 
Patients to be treated C1D1 for four weeks +/- 1 week.  


 
 
7 
 
Duration of Follow up 
Within 30 days after completion of study treatment 
Long term Follow up 
As standard of care, patients will be followed by oncology 
provider(s) at least annually from surgery (+/- 3 months). Cancer 
outcomes up to five years post-treatment will be collected by chart 
review.  
Estimated Time to 
Complete Enrollment: 
2 years 
Statistical 
Methodology: 
 
We hypothesize that expression of one or more HER proteins 
(HER1-4) will be upregulated in at least 50% of tumors after four 
weeks of neoadjuvant endocrine therapy and this upregulation will 
correlate with Ki-67 expressed in more than 10% of cancer cells, 
as compared to upregulation in 30% or less of tumors without the 
therapy. The change in Ki-67 expression will be dichotomized, as a 
categorical variable with ≥10% increase coded as high and <10% 
coded as low.  
- 
For the primary outcome: An exact binomial one sample 
test of proportions will be used for to test the hypothesis 
that proportion of upregulated HER proteins will be at least 
50% after therapy versus the null hypothesis that the 
proportion of upregulated HER proteins is not greater than 
30%. 
- 
For analyzing - the differences in proportion of upregulated 
HER proteins between the high difference in Ki-67 and low 
difference in Ki-67 groups, two sample tests of proportions 
will be used.  
- 
Similarly, appropriate two sample tests will be used to test 
differences in biomarkers between the high difference in Ki-
67 and low difference in Ki-67 groups. We will use the 
appropriate kind of regression instead of two sample tests, 
to test differences in biomarkers between the high 
difference in Ki-67 and low difference in Ki-67groups if we 
need to adjust for covariates. 
- 
Additionally, regression analysis will also be done to 
evaluate the changes in the biomarkers and their 
association with patient specific covariates, such as age, 
race and other relevant predictors of interest.  
Radiographic responses will be assessed by WHO criteria. We will 
use logistic regression (and other generalized linear models as 
appropriate) to measure association between the response rates 
and patient specific covariates such as age, race and other 
relevant predictors of interest.  


 
 
8 
 
To achieve at least 80% power at significance level of 0.05, when 
testing the one sided one sample hypothesis that the proportion of 
tumors with HER protein upregulation with neoadjuvant endocrine 
therapy is at least 50% versus the null hypothesis that the 
proportion is no larger than 30%, the minimum number of 
patients required is 37.  
 
Safety Assessments 
- 
Given the short nature of the treatment regimen (3-5 weeks), 
and expected low grades of toxicity, it is considered highly 
unlikely that a large percentage of patients will experience 
adverse events (AEs) from the endocrine treatment.  
- 
Patients would be assessed at beginning and end of treatment 
with neoadjuvant endocrine therapy at their  follow-up visit 
within 30 days after completion of study treatment. 
- 
This study will be reviewed by the Medical College of 
Wisconsin Cancer Center Data and Safety Monitoring 
Committee (MCWCC DSMC). 


 
 
9 
 
SCHEMA 
 
 
 
 
 


 
 
10 
 
STUDY CALENDAR 
Period / Procedure 
Screening1,2 
Neoadjuvant Endocrine Therapy 
Treatment9 
Surgery 
End of 
treatment 
visit10 
Annual 
Follow up11 
Study Day/ Visit Day 
 
Week 
12 
Week 
2 
Week 3 
Week 4 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Adverse Event 
Assessment 
X 
 
 
 
 
 
X 
 
Current Medications 
X 
 
 
 
 
 
X 
 
Treatment / Drug Administration 
Aromatase Inhibitor 
OR Tamoxifen 
 
X 
X 
X 
X 
 
 
 
Calendar Collection 
 
 
 
 
 
 
X 
 
Imaging 
Unilateral diagnostic 
mammogram and 
ultrasound3 
X 
 
 
 
 
X 
 
 
Clinical Procedures 
Physical Exam 
X 
X 
 
 
 
 
X 
 
Vital Signs 
X 
X 
 
 
 
 
X 
 
Medical History 
X 
X 
 
 
 
 
X 
 
Performance Status 
X 
X 
 
 
 
 
X 
 
Recurrence Status 
 
 
 
 
 
 
 
X 
Laboratory Procedures 
CBC w/ Diff4 
X 
 
 
 
 
 
 
 
Blood Chemistry5 
X 
 
 
 
 
 
 
 
Fasting Lipid Panel6 
X 
 
 
 
 
 
 
 
Pregnancy Test 
(HCG)7 
X 
 
 
 
 
 
 
 
Study Biomarkers8 
X 
 
 
 
 
X 
 
 
 
1. A patient can be screened and have status of week one on the same day. 
2. Screening procedures and drug administration to be done within 28 days of enrollment. 


 
 
11 
 
3. Unilateral diagnostic mammogram and ultrasound to be done within 60 days prior to enrollment and within 5 days prior to surgery. 
4. Including CBC with differential and platelet count. 
5. Including alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, creatinine, potassium, sodium, chloride, and bicarbonate.  
6. Fasting lipid panel to be done once at screening; lipid panel may be performed within the last 12 months. 
o 
This project does not ask Froedtert to bill routine care costs to patient insurance but does ask Froedtert to invoice MCW for the 
following services: 
 
Lipid panel if it needs to be repeated and not obtained as SOC prior to study participation consideration 
7. For premenopausal women only.  
8. Study biomarkers: to be collected on initial core biopsy and on surgical tumor specimens, as described in Table 1. Details on handling and 
preparation of tissue specimen and slides for study evaluations are explained in detail below in section Pathologic Evaluation and 
Handling of Tissue Specimens. 
9. The patient would be treated with endocrine therapy in a neoadjuvant setting for four weeks (+/- 1 week), with dosing continuing until 
surgery (+/- 2 days).  
10. End of treatment visit to be completed within 30 days of surgery. 
11. Long term follow ups are to be done annually (+/- 3 months) from surgery up to 5 years. 


 
 
12 
 
Contents 
PROTOCOL SUMMARY ................................................................................................. 5 
SCHEMA ......................................................................................................................... 9 
STUDY CALENDAR ...................................................................................................... 10 
List of Tables ................................................................................................................. 14 
I. 
BACKGROUND: ............................................................................................. 15 
Advantages of the Neoadjuvant Treatment Approach ....................................................... 15 
Mechanisms of Endocrine Resistance and Biomarkers of Interest ............................... 17 
II. 
HYPOTHESIS AND OBJECTIVES ................................................................. 21 
Hypothesis ....................................................................................................................................... 21 
Primary Objective .......................................................................................................................... 21 
Secondary Objectives and Associative Studies ................................................................... 21 
III. 
ELIGIBILITY CRITERIA .................................................................................. 22 
Inclusion Criteria ............................................................................................................................ 22 
Exclusion Criteria........................................................................................................................... 23 
IV. 
STUDY DESIGN AND TREATMENT PLAN ................................................... 23 
Treatment Plan ............................................................................................................................... 24 
Pathologic Evaluation and Handling of Tissue Specimens .............................................. 26 
Study Drugs .................................................................................................................................... 27 
Definitions of Radiographic Responses ................................................................................. 28 
V. 
STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES .................... 29 
VI. 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .. 32 
Adverse Event (AE) and Serious Adverse Events (SAE) ................................................. 32 
Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) .......................... 32 
AE Attribution and Grading ......................................................................................................... 33 
Unexpected Adverse Events ..................................................................................................... 34 
Expected Adverse Events ........................................................................................................... 35 
Patient Assessments .................................................................................................................... 35 
VII. 
STATISTICAL CONSIDERATIONS................................................................ 36 
Statistical analyses: ...................................................................................................................... 36 


 
 
13 
 
Sample Size and Power Calculation ....................................................................................... 37 
Early Stopping for Futility ............................................................................................................ 37 
VIII. 
PATIENT SAFETY MONITORING AND CONFIDENTIALITY ........................ 38 
IX. 
QUALITY ASSURANCE ................................................................................. 39 
References: ................................................................................................................... 40 
Appendix 1. IIT-Chaudhary-Endocrine: Monthly Intake Diary ........................................ 46 
Appendix 2. Performance Status criteria ....................................................................... 47 
Appendix 3. IIT-Chaudhary-Endocrine:Specimen Submission Form ............................ 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
14 
 
List of Tables 
 
Table 1. Biomarkers to be assess pre- and post-treatment with neoadjuvant endocrine 
therapy .......................................................................................................................... 26 
Table 2. Adverse Event Grading ................................................................................ 33 
Table 3. Adverse Event Attribution ............................................................................ 33 
Table 4. Expected Adverse Events for Aromatase inhibitors .................................. 35 
Table 5. Expected Adverse Events from Tamoxifen ................................................ 35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
15 
 
I. 
BACKGROUND: 
Luminal breast cancers, as defined by estrogen receptor (ER) and/or progesterone 
receptor (PR) expression, account for 75% of all newly diagnosed breast cancers (BC). 
Deprivation of estrogen signaling through endocrine-targeted therapy has become the 
mainstay of treatment in hormone receptor (HR)-positive disease. Anti-estrogen therapy, 
also known as endocrine therapy, provides significant benefit to patients in terms of 
decreasing the risk of recurrence, as well as improving survival. Endocrine therapy is also 
well tolerated with relatively low toxicity. Unfortunately, metastatic recurrences occur in 
about 20–25% of patients and remain a major cause of BC mortality, representing a 
significant issue for optimal clinical management.1 Resistance to endocrine therapy is a 
serious concern and it is extremely important to further understand and characterize the 
underlying molecular features of resistance for more accurate response prediction and 
for selecting the optimal clinical management. Several mechanisms and pathways have 
been explored in the recent years in an attempt to understand the complexity of 
development of endocrine resistance, however, it is unclear if altered levels and changes 
in tumor biomarkers are predictive of aggressiveness of HR+ breast cancers and 
development of endocrine resistance. 
 
Patients with HR+ HER2-negative node-negative breast cancer generally undergo 
surgical resection upfront, followed by adjuvant chemotherapy, if indicated, in addition to 
adjuvant endocrine therapy. The introduction of gene-expression profiling technologies 
has been an important step toward understanding the distinct molecular subtypes of 
breast cancer and their prognostic importance.2 It is unclear whether gene-expression 
profiling tests currently approved to predict the benefit of chemotherapy may be of use to 
determine if patients more likely to experience resistance to endocrine therapy. 
OncotypeDx assay is a validated genomic assay routinely used in clinical practice to 
assess risk of recurrence and benefit of adjuvant chemotherapy.  
 
Endocrine therapy is mostly delivered in the adjuvant setting. However, in some cases, 
endocrine therapy is given in a neoadjuvant setting (treatment before surgery) to reduce 
tumor size and simplify surgery. Investigations involving adjuvant treatment can be 
challenging because the primary tumor has been surgically removed and is thus not 
available for on-treatment molecular analysis. Furthermore, long-term follow-up is 
required for survival and disease recurrence outcomes, which can be difficult to interpret, 
as recurrence may be the result of the inherent cancer aggressiveness, rather than 
acquired resistance to therapy. Additionally, a large sample size is required for such 
studies to produce statistically meaningful results and data collection on relevant 
outcomes takes considerable time and effort to acquire.1 
 
Advantages of the Neoadjuvant Treatment Approach  
 
The neoadjuvant setting presents a number of advantages for investigating the 
characteristics of tumor responsiveness and resistance. The primary tumor remains in 
place during treatment and clinical response can be determined by physical exam, as well 
as with imaging techniques. Furthermore, tumors can be sampled before and after 
neoadjuvant therapy, allowing for assessment of changes in protein or gene transcript 


 
 
16 
 
levels with treatment. These data can be then be correlated to clinical response, allowing 
for a dynamic comparison of clinical and molecular responses in both responsive and 
resistant tumors.1,3,4,5  
 
Neoadjuvant endocrine therapy is a safe and effective strategy for treatment and 
response assessment in both pre- and postmenopausal women with HR+ HER2 negative 
disease. Most of the randomized clinical trials comparing different endocrine agents in 
neoadjuvant setting have involved patients with locally advanced breast cancer (LABC) 
and the duration of treatment has ranged anywhere from two weeks to four months, with 
responses as early as 10 to 14 days. Aromatase inhibitors have shown increased efficacy 
compared with tamoxifen in postmenopausal breast cancer patients, whereas tamoxifen 
alone or with ovarian function suppression are standard treatment options for 
premenopausal women with HR+ breast cancer.6 The P024 trial showed that neoadjuvant 
treatment with letrozole is superior to tamoxifen in terms of clinical response rate (55% 
versus 36%, P = 0.001) and breast conservation rate (45% versus 35%, P = 0.022) in 
postmenopausal women with LABC.7 The IMPACT trial treated 330 postmenopausal 
women with LABC with anastrozole, tamoxifen or a combination of tamoxifen and 
anastrozole for 12 weeks before breast surgery and found no significant differences in 
objective response rates between the three arms (37%, 36%, and 39% respectively, 
p=0.23).8 The STAGE trial showed improved objective response rates, in addition to 
increased rates of breast conservation surgery in premenopausal women with 24 weeks 
of neoadjuvant anastrozole, combined with goserelin, as compared with tamoxifen 
combined with goserelin.9 ACOSOG-Z1031 showed no significant difference in clinical 
responses or surgical outcomes between the three commonly used aromatase inhibitors, 
exemestane, letrozole and anastrozole, in postmenopausal women.10 
 
Given the challenges involved in understanding molecular changes predictive of tumor 
responsiveness and development of endocrine resistance with adjuvant endocrine 
treatment in HR+ HER2-negative breast cancer patients, neoadjuvant endocrine 
therapy in this patient population is a safe and innovative approach to assess changes 
in therapy-relevant tumor biomarkers with treatment and correlated those with changed 
with tumor proliferation and responses. Emerging analytical platforms now become 
available for previously unachievable evaluations of expression patterns in cancer cells. 
Novel marker data can then be correlated with clinical responses, allowing for a dynamic 
comparison of basal pretreatment levels and post-treatment molecular changes in both 
responsive and resistant tumors. We believe that this may result in powerful biomarkers 
of responses to endocrine therapy. 
 
We propose an exploratory interventional study to investigate changes in HER-
protein expression along with other biomarkers of interest and correlations with 
tumor cell proliferation and responses in patients with HR+ HER2 negative early 
stage breast cancer treated with neoadjuvant endocrine therapy. By comparing pre- 
and post-treatment levels of molecular markers in individual tumors, we expect to identify 
predictors of responsiveness to existing agents, in addition to new candidate therapeutic 
targets. Insight gained from this exploratory study is expected to form the basis for a 


 
 
17 
 
phase II randomized trial of a combination of endocrine therapy with a second targeted 
drug for selected patients. 
 
Mechanisms of Endocrine Resistance and Biomarkers of Interest 
 
Endocrine resistance involves both ERα-independent11,12 and ERα-dependent 
mechanisms13,14 that remain to be fully resolved. These mechanisms may differ between 
breast cancer subtypes. Tumor marker-based classification of HR+ breast cancers into 
therapy-relevant subtypes is an ongoing effort.  
 
HER2/EGFR Family of Receptor Tyrosine Kinases (RTKs) Overexpression 
 
Resistance to endocrine therapy is common in 
HR+ breast cancers that overexpress HER2.15 
Many studies have reported cross-talk between 
ER and receptor tyrosine kinases (RTKs), such 
as HER1 and HER2, which are members of the 
human 
epidermal 
growth 
factor 
receptor 
(HER/EGFR/ERBB) family.16,17 Overexpression 
of these receptors in a subset of ER+ breast 
cancers suggests that tyrosine kinase signaling 
drives  proliferation and evasion of apoptosis in 
these cancers, representing either a primary 
mechanism in the case of innate resistant 
tumors or a switch in driving mechanisms to 
evade the action of endocrine therapy in tumors 
with acquired resistance.18,19 Turnbull et al.20 
studied gene expression changes in breast 
cancer 
tumors 
treated 
with 
neoadjuvant 
aromatase inhibitors to assess association of 
proliferation genes with clinical and molecular 
responses. Proliferation-associated genes were 
significantly 
downregulated 
in 
tumors 
responding 
to 
endocrine 
therapy 
and 
upregulated in nonresponders by as early as 
two weeks. We recently reanalyzed this data 
(Rui H et al; in preparation) to study 53 RTKs 
and to assess changes in mRNA levels at two 
weeks and three months of neoadjuvant 
endocrine therapy. In many tumors, mRNA 
encoding EGFR or HER2 increased fourfold or 
more (note log scale; Figure 1). 
However, it is unknown to what extent such 
increase occurs in patient tumors at the level 
of HER-protein expression. This is important 
since HER-targeted agents work on proteins. 
Figure 1. Changes in mRNA levels in EGFR and 
HER2 at Day 14 and Day 90 of endocrine treatment. 
Figure 2. Patient-derived Luminal B 
MCW2 human breast cancer shows 
upregulation of HER2 protein in Tam-
resistant line, including lung metastases. 


 
 
18 
 
Intriguingly, tamoxifen treatment 
induces increased HER2 protein 
in cancer cells of a patient-
derived breast cancer model 
analyzed in vivo (Figure 2). 
Furthermore, while parental PDX 
model 
is 
unresponsive 
to 
trastuzumab 
(anti-HER2 
antibody), 
the 
tamoxifen-
resistant tumors (TamR) with 
elevated HER2 expression were 
highly 
responsive 
to 
trastuzumab when tested in mice 
(Figure 3). Our study will 
evaluate 
if 
treatment-
associated changes in protein 
expressions in HER family of 
RTKs correlate with tumor responses.  
Reduces Ki-67 is considered a good surrogate of response to treatment. Correlating 
changed in HER protein expression with Ki-67 would be an innovative approach to 
assess the association of HER protein upregulation and tumor responses to endocrine 
therapy.  
 
Cyclin-CDK-RB Pathway 
 
Another potential pathway of interest in HR+ breast cancers is the cyclin-CDK-RB 
pathway (cyclin dependent kinase-retinoblastoma) that can be altered in luminal breast 
cancer and appears to be associated with endocrine resistance.21 High expression of 
cyclin-D1 is associated with activation of cyclin-dependent kinases CDK4 and CDK6 and 
progression to the S-phase of cell cycle. Studies have linked high expression of cyclin-
D1 to tamoxifen resistance and high expression of cyclin-E1 to letrozole resistance.22,23 
Dr. Hallgeir Rui and colleagues at MCW have extensive laboratory experience with 
breast cancer xenograft models and have shown that additional mechanisms of resistant 
ER+ breast cancer may be via the emergence of basal cytokeratin-5 positive (CK5+) 
progenitor cells, which display resistance to chemotherapy and tamoxifen.24 We now 
want to assess CK5+ progenitor cells in breast cancer tumors and determine if an 
increased proportion of therapy-resistant CK5+ progenitor cells is negatively 
correlated with tumor proliferation reduction in response to neoadjuvant endocrine 
therapy. Patients with ER+/CK5+ breast cancer may benefit from emerging BCL6-
inhibitors and may be harmed by prolactin receptor antagonists.24 
 
Bruton’s Tyrosine Kinase (BTK) Expression 
 
Bruton’s tyrosine kinase (BTK) belongs to Tec family tyrosine kinases and causes 
activation of multiple downstream pathways of cell survival and proliferation.25 Recently, 
an alternate isoform of BTK, BTK-C, was identified as a novel survival factor for breast 
Figure 3. Tamoxifen-resistant MCW2-I PDX model with upregulated 
HER2 becomes sensitive to trastuzumab. Note that four of 10 
trastuzumab-treated mice did not have tumor ‘recurrence’ within 90-
day treatment period. 


 
 
19 
 
cancer cells in a large-scale, loss-of-function analysis of human tyrosine kinases, using 
an RNA interference library by Eifert et al.26 That study showed that, although BTK-C is 
expressed at relatively low levels in several human breast cancer cell lines and tumor 
tissues, BTK-C provides an essential function by protecting breast cancer cells from 
apoptosis. BTK expression, in association with endocrine therapy, has not been 
explored. Emergence of BTK expression in tumors after treatment with 
neoadjuvant endocrine therapy may be indicative of development of resistance in 
future. Patients with BTK-expressing breast cancer may benefit from BTK inhibitors, such 
as ibrutinib. 
 
Iron-Related Proteins: 
 
Iron homeostasis deregulation and the role of iron-related proteins in breast cancer 
tumorigenesis and in association with clinicopathological features are another area of 
growing interest. Transferrin receptor (CD71) is involved in the cellular uptake of iron 
and is expressed on proliferating cells. It may be implicated in promoting the growth of 
endocrine-resistant phenotypes within HR+ breast cancers. Habashy et al.27 studied 
CD71 protein expression in patients with breast cancer, as well as in vitro cell models of 
acquired resistance to endocrine therapy. There was significant elevation of transferrin 
receptor in all cell models of acquired resistance. CD71 was found to be an independent 
prognostic factor in the ER+ cohort of patients and was associated with increased tumor 
proliferation, basal CKs, EGFR/HER2 expression and shortened breast cancer-specific 
survival. Changes in other iron-related protein expression, i.e., ferritin, ferroportin and 
ribonucleotide reductase with endocrine therapy, and possible clinical correlation with 
tumor proliferation and responses have not been explored. Our study plans to measure 
changes in iron-related proteins and their correlation with tumor responses. 
Patients with high ribonucleotide reductase expressions may be an indication of 
development of resistance and these patients may benefit from ribonucleotide 
reductase inhibitors.  
 
Programmed Death Receptor 1 (PD-1) Axis 
 
Programmed death receptor 1 (PD-1) is a member of the immunoglobulin superfamily 
and is expressed on activated T cells, B cells, natural killer cells and myeloid cells.28  PD-
1 conveys an inhibitory signal to T cells, and thus, impedes immune responses.29 PD-1 
and its ligands, PD-L1 and PD-L2, interact to downregulate the activation of T cells in 
cancer, as well as in autoimmune conditions and infections. Recently, immune checkpoint 
blockades targeting PD-1 and PD-1 ligands have shown promising therapeutic efficacy in 
several tumor types.30 In breast cancer, the reported frequency of PD-L1 expression by 
carcinoma cells varies considerably between studies (1.7%–58%).31-35 A recent meta-
analysis showed high PD-L1 protein expression to be a negative prognostic factor in 
breast cancer and was associated with high tumor grade, negative ER and PR status, 
positive HER2 status and high Ki-67.36 Although high PD-1 and its ligands expression are 
primarily seen in triple negative and HER2-positive breast cancer subtypes, it is certainly 
seen in some luminal breast cancers, as well. Whether there is an increase or emergence 
of PD-1 protein expression in HR+ breast tumors after treatment with neoadjuvant 


 
 
20 
 
endocrine therapy has not been explored. This would be an important pathway to 
assess in correlation with tumor responses due to the availability and potential 
benefit from PD-1inhibitors (nivolumab and pembrolizumab). 
 
Ki-67 Expression 
 
Expression of the protein Ki-67 is considered a surrogate of cellular proliferation.37 
Iinternational consensus statements, such as those provided by the  European Society of 
Medical Oncology and Saint Gallen International Breast Cancer Conference, do support 
the role of Ki-67 in distinguishing between the two intrinsic subtypes of HR+ BC, namely 
luminal A and B subtypes.38,39 Assuming that the main mechanism of action for endocrine 
therapy in BC is mainly through inducing cell-cycle arrest, an on-treatment Ki-67 read 
out can be considered a surrogate for response to endocrine therapy. Data from the 
STAGE trial support the role of on-treatment Ki-67 measurement for predicting clinical 
responses.9,40 In addition, in ACOSOG-Z1031, on-treatment Ki-67 levels predicted clinical 
responses.10 In the IMPACT trial, Ki-67 was measured as early as two weeks and the 
superiority of anastrozole over tamoxifen in postmenopausal women was confirmed, 
based on a greater reduction in Ki-67 levels after two and 12 week.41 Quantifying levels 
of Ki-67 expression (% positive cells) pre- and post-treatment along with 
radiographic responses to neoadjuvant endocrine therapy will provide measures 
of responses and allow correlation with our study biomarkers. 
 
Future Directions 
 
This project is significant and has the potential to have a strong impact because it poses 
clinically relevant questions. It aims to assess molecular changes with endocrine 
treatment, facilitating recognition of potential targetable resistance mechanisms and 
pathways. Our expectations are that the proposed studies will reveal mechanistic and 
preclinical insight to support novel strategies for improved clinical management of HR+ 
breast cancer patients. Given the small sample size and the exploratory nature of the 
study, we may not have enough responses to reach a statistically significant result. 
However, we expect to determine how frequently the protein levels of HER family of RTKs 
are increased following endocrine therapy. This information would be useful in selecting 
patients for a follow-up trial with targeted HER/EGFR therapy. Likewise, we expect to 
determine the frequency of upregulation in CK5+/ER-negative subpopulation of cancer 
cells, as well as BTK expression in HR+ breast cancer. This information may be used to 
select patients to a follow-up trial with BCL6 inhibitor and BTK inhibitor, respectively. 
Patients with changes in iron-related proteins, such as high ribonucleotide reductase 
expressions, may benefit from ribonucleotide reductase inhibitors and those with 
increased PD-1 expression may benefit from PD-1 inhibitors. Lack of a significant 
radiographic response or change in Ki-67 would potentially be an important prognostic 
indicator of development of early endocrine resistance.  
 
Taken together, these research aims will characterize the changes in tumor 
microenvironment and association with tumor responses to endocrine therapy. 
The knowledge from these studies will help define signaling pathways and 


 
 
21 
 
predictive biomarkers of short and long-term responses to endocrine therapy and 
potential emergence of endocrine resistance in low responding tumors. The results 
from this project would be critical in providing preliminary data for support for a 
follow-up phase II randomized study of endocrine therapy, combined with other 
targeted therapy based on molecular tumor profile. 
 
 
II. 
HYPOTHESIS AND OBJECTIVES 
Hypothesis 
 
We hypothesize that in HR+ HER2 negative tumors of early stage breast cancer patients, 
expression of one or more HER proteins (HER1-4) will be upregulated in at least 50% of 
tumors after four weeks of neoadjuvant endocrine therapy and this upregulation will 
correlate with Ki-67 expressed in more than 10% of cancer cells. 
 
The following objectives are designed to test these hypotheses: 
 
Primary Objective 
 
Determine the frequency of increased HER-protein expression in tumors following 
treatment with neoadjuvant endocrine therapy and their association with tumor Ki-67 
expression. We will measure cancer cell protein levels of growth factor receptors of the 
HER family before and after neoadjuvant endocrine therapy. The data will be used to 
inform a future randomized trial utilizing a combination of endocrine treatment and the 
most promising anti-HER targeted therapy. 
 
Secondary Objectives and Associative Studies 
 
Our secondary objectives are focused on other biomarkers and pathways of interest. Our 
goal is to determine changes in gene expression and/or protein levels of the following 
biomarkers with neoadjuvant endocrine therapy and correlation with tumor responses. 
 
 
1. Determine whether an increased proportion of therapy-resistant CK5+ 
progenitor cells are negatively correlated with a response in Ki-67 and tumor 
volume reduction, in response to neoadjuvant endocrine therapy.  
2. Assess changes in the % expression of ER and PR in pre- and post-treatment 
breast cancer tumor specimens and their correlations with Ki-67 and radiographic 
responses. 
3. Assess changes in BTK protein expression with neoadjuvant endocrine therapy 
and correlation with responses. 
4. Changes in iron-related protein expression, i.e., transferrin, ferritin, 
ferroportin and ribonucleotide reductase with neoadjuvant endocrine therapy 
and correlation with responses.  
5. Changes in PD-L1 and PD-L2 protein expression with neoadjuvant endocrine 
therapy. 


 
 
22 
 
6. Assess changes in tumor size on radiographic images with neoadjuvant endocrine 
therapy and correlate with changes in biomarkers and Ki-67.  
7. Chart review planned at about five years from completion of study to assess patient 
outcomes, i.e., ipsilateral, contralateral or distant recurrences. 
 
 
III. 
ELIGIBILITY CRITERIA 
Inclusion Criteria 
 
1. Unilateral diagnostic breast mammogram and ultrasound within 60 days of enrollment.  
2. Pathologically proven diagnosis of invasive breast cancer, clinical stage I or II.  
3. Patients must be clinically lymph node negative. Lymph node negativity must be 
confirmed by clinical exam and/or ultrasound imaging. 
4. The patient must be female.  
5. Age ≥18 years.  
6. Estrogen and/or progesterone receptor positive tumor defined ≥1% positively staining 
cells by immunohistochemistry, according to the current ASCO/CAP guidelines. 
7. HER2/neu must be negative by immunohistochemistry (IHC) or fluorescence in situ 
hybridization (FISH).  
8. ECOG performance status 0 to 2.  
9. Bilateral breast cancer and/or multifocal, multicentric disease is allowed if all disease 
sites are biopsied. 
10. Appropriate pretreatment evaluations for protocol entry, including no clinical evidence 
for distant metastases, based upon the following minimum diagnostic workup: 
history/physical examination, including breast exam (inspection and palpation of the 
breasts), clinically negative axillary lymph nodes, within 28 days prior to study 
entry. 
11. The patient must qualify for anti-endocrine treatment (treatment of choice), per the 
treating medical oncologist.  
12. The patient must provide study-specific informed consent prior to study entry.  
13. Patients with a prior history of breast cancer will be considered eligible, if they have 
completed all treatment (including endocrine therapy) more than 2 years prior to 
registration. 
14. Patients must not have had a prior treatment for this breast cancer or for any 
malignancy diagnosed or treated within the past 2 years, with the exception of non-
melanomatous skin cancer, carcinoma in situ of the cervix..  
15. Women of child bearing age will be advised to use adequate methods of 
contraception. Adequate methods of contraception for premenopausal women include 
barrier methods and/or non-hormonal methods (Intrauterine devices etc.). 
16. Negative pregnancy test. (if applicable) 


 
 
23 
 
17. Strong CYP2D6 inhibitors will be prohibited with tamoxifen, as it can decrease the 
efficacy of tamoxifen. There are no known strong interactions with aromatase 
inhibitors. 
18. Adequate organ function with baseline lab values.  
 
Absolute neutrophil count (ANC) ≥ 1500/µL 
 
Hemoglobin (Hb) ≥ 9g/dL 
 Platelet count ≥ 100,000/µL 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x upper 
limit of normal (ULN) 
 Serum bilirubin within ≤ 1.5 x ULN 
Exclusion Criteria 
 
1. AJCC clinical T4, N1-3 or M1, breast cancer. 
2. Synchronous non-breast malignancy (exceptions include non-melanomatous skin 
cancer, carcinoma in situ of the cervix).  
3. Purely noninvasive breast cancer (i.e., ductal carcinoma in situ, lobular carcinoma in 
situ). 
4. Men with breast cancer. Male breast cancer is a rare event and it is unclear if 
neoadjuvant endocrine treatment approach is safe in men.  
5. Medical, psychiatric or other condition that would prevent the patient from receiving 
the protocol therapy or providing informed consent. 
6. Pregnant or lactating women are ineligible. 
 
IV. 
STUDY DESIGN AND TREATMENT PLAN 
General description: This is an exploratory interventional study to investigate changes 
in HER-protein expression along with other biomarkers of interest and correlations with 
tumor cell proliferation and responses in patients with HR+ HER2 negative early stage 
breast cancer treated with neoadjuvant endocrine therapy. 
Number of subjects: 37 
Primary End point: Determine the frequency of increased protein expression of HER 
family of receptor tyrosine kinases in tumors, following treatment with neoadjuvant 
endocrine therapy and their correlation with Ki-67 tumor responses. 
Secondary End points:  
• To determine changes in additional selected molecular markers (CK5+/ER- 
progenitor cells, PD-L1, PD-L2, BTK, iron-related proteins) and correlate with Ki-


 
 
24 
 
67 responsiveness to endocrine therapy in our pre- and post-treatment tumor 
specimens. 
• Assess changes in tumor size on radiographic images with neoadjuvant endocrine 
therapy and correlate with changes in biomarkers and Ki-67. 
Study Timeline: 
Primary completion: We expect that the study will reach primary completion 24 months 
from the time the study opens to accrual. 
Study completion: We expect that the study will reach study completion 36 months from 
the time the study opens to accrual. 
Treatment Plan 
 
1. At MCW, all patients undergo diagnostic mammogram and ultrasound of the breast 
(standard of care) to further evaluate an abnormal breast finding and to obtain core 
biopsies for diagnostic purposes. If the tumor is visualized on both imaging 
modalities, at least the largest bidimensional measurements will be recorded. If 
possible, three-dimensional measurements of tumors will be obtained. 
2. Patients with a diagnosis of ER and/or PR positive, HER2 negative node negative 
invasive breast cancer would be screened for this study (refer to the schema).  
3. Node negativity will be established by clinical exam and/or ultrasound 
4. After the informed consent is obtained with the patient’s signature, the eligibility 
process begins. If the patient is deemed eligible, then the patient can participate in 
any study related procedures.  
5. Interested patients must meet with a medical oncologist prior to study entry to 
determine if Oncotype Dx testing is recommended. If recommended and the 
patient is amenable to the possibility of receiving chemotherapy, there must be 
adequate biopsy tissue for testing. If adequate tissue is not available for the 
Oncotype Dx testing, patients may undergo additional biopsies. If a patient plans 
to decline chemotherapy, regardless of a high Oncotype Dx results, and elects to 
forgo the test, they will still be eligible for enrollment. If the patient elects to undergo 
an additional biopsy, but no residual tumor is found, then, the patient is not eligible 
for the study. 
6. The Oncotype Dx assay is obtained initially in order to know which patient would 
benefit from the addition of adjuvant chemotherapy after her surgery, so that all 
patients undergo the appropriate standard-of-care postsurgical treatment. 
Treatment with neoadjuvant endocrine therapy is likely to induce changes within 
tumor biology and Oncotype Dx assay done after surgery in this setting may not 
provide reliable results, and thus, will not be performed after surgery.  
7. Once enrolled, patients would be treated with the current standard-of-care 
endocrine therapy. Choice of endocrine therapy (aromatase inhibitors or 
tamoxifen) would be decided by medical oncologist, following a review of the 
patient’s medical history and menstrual status. The patient would be treated with 


 
 
25 
 
endocrine therapy in a neoadjuvant setting for four weeks (+/- 1 week), with dosing 
continuing until surgery (+/- 2 days).  
8. Patient compliance would be monitored by providing a calendar sheet to the 
patients to log in their daily use of prescribed endocrine therapy (Appendix.1). This 
calendar sheet will be returned to our clinical trial staff upon completion of the  four-
week (+/- 1 week) period of neoadjuvant endocrine treatment.  
9. Core biopsy specimens from the initial biopsy at diagnosis would be used for 
OncotypeDx assay, as well as for study biomarkers assessments. One 
hematoxylin and eosin slide and up to 15 to 20 unstained charged slides cut at 4 
microns thick would be obtained from pathology blocks with residual tumor. These 
specimens will be reserved for study labs/biomarkers for pre- treatment after the 
Oncotype has been completed (if applicable). Biomarkers to be assessed pre- and 
post-treatment are shown in Table 1. Details on handling and preparation of tissue 
specimen and slides for study evaluations are explained in detail below in section 
Pathologic Evaluation and Handling of Tissue Specimens. 
10. If adequate tissue is not available for all study biomarkers to be done, additional 
biopsies will be requested. However, if the patient declines an additional biopsy 
and enough tissue is available to obtain some but not all study biomarkers, the 
patient would still qualify and be enrolled to the study.  
11. Patients would undergo unilateral diagnostic mammogram and ultrasound within 
five days prior to surgery to assess radiographic responses to the pretreatment 
imaging obtained at diagnosis. The CRC/CRN should notify Dr. Gonyo in 
Radiology prior to surgery. Diagnostic mammogram and the US are to be 
assessed using WHO criteria for response. 
12. Patients would undergo surgery as planned at the end of the four-week (+/- 1 
week) period of neoadjuvant endocrine treatment. 
13. Surgical specimen would be use for post-treatment assessments. Changes in 
proliferation marker Ki-67 between pre- and post-treatment tumor specimens 
would be assessed by our breast pathologists. One hematoxylin and eosin slide 
and up to 15 to 20 unstained charged slides cut at 4 microns thick would be 
obtained from pathology blocks with residual tumor. These specimens will be 
reserved for study labs/biomarkers for post-treatment. Biomarkers to be assessed 
pre- and post-treatment are shown in Table 1. Details on handling and preparation 
of tissue specimen and slides for study evaluations are explained in detail below 
in section Pathologic Evaluation and Handling of Tissue Specimens. 
14. Any remaining tumor tissue would be banked in MCW Tissue Bank according to 
the MCW Tissue Bank quality control measures. Specimens would be deidentified. 
A separate consent form would be used for tissue banking. Patients who do not 
participate in the Tissue Banking are still eligible. 
15. Patients would be treated per standard-of-care guidelines following surgery. The 
initial Oncotype Dx assay, if done, would be used by the treating medical 
oncologist to decide if adjuvant chemotherapy is indicated.  
16. A follow-up visit would be scheduled within 30 days from surgery. Further follow-
up visits would be per the discretion of the patient’s treating physicians, who will 
follow NCCN guidelines.  


 
 
26 
 
17. As standard-of-care treatment, patients will be followed by oncology provider(s) at 
least annually (+/- 3 months). Cancer outcomes up to five years post-treatment will 
be collected annually (+/- 3 months) by chart review. 
18. Given the short course of study treatment (~3-5 weeks) and none-few low-grade 
toxicities expected, we expect most of our study patients to complete the 4-week 
study treatment. Patients should be treated for at least 2 weeks with neoadjuvant 
endocrine therapy to be considered evaluable for the study end points. All dosed 
patients with at least 2 weeks of neoadjuvant endocrine therapy received would be 
included in the analyses. 
19. All adverse events grade 3 and above, regardless of attribution, will be collected 
and reviewed at the required timepoints (screening and/or week 1, and end of 
treatment visit). 
 
 
Table 1. Biomarkers to be assess pre- and post-treatment with neoadjuvant endocrine therapy 
Biomarkers 
End Points 
Ki-67 
Assess change in proliferation with treatment. 
HER tyrosine kinase 
receptor expression 
Assess frequency of increased protein levels of HER1-4 
and correlation with response to treatment. 
ER% / PR% 
Assessment of pre- and post-treatment changes and 
response to treatment.  
CK5+/ER- progenitor 
cells 
Assess proportion of CK5+/ER- cancer cells and correlation 
with response to treatment. 
Iron related proteins 
Assess changes in protein expression and correlation with 
responses. 
BTK expression 
Assess changes in protein expression and correlation with 
responses. 
PD-L1/PD-L2 
Assess changes or emergence of protein expression with 
treatment and correlation with responses. 
 
Pathologic Evaluation and Handling of Tissue Specimens 
 
1. The surgical specimens will be subject to routine pathological analysis. Routine 
hematoxylin and eosin (H&E) stain will be used for morphological analysis and for 
the determination of carcinoma diagnosis. The samples will be assessed by our 
breast pathologists.  
2. One H&E slide and up to 15 to 20 unstained slides charged and cut at 4 microns 
thick will be reserved for study labs/biomarkers for pre and post-treatment 
assessments. These will be sent to Dr. Hallgeir Rui’s laboratory (suite C4980) at 
the Medical College of Wisconsin Translational and Biomedical Research 
Center (TBRC). 
3. Protein 
expression 
will 
be 
quantified 
on 
slides, 
using 
optimized 
immunohistochemical protocols for planned study biomarkers. 


 
 
27 
 
4. Ki-67 assessment on pre- and post-treatment specimens would include 
assessment by manual counting of stained tumor cells by our pathologists (dual 
stain CD45/Ki-67 to differentiate between lymphocytes and tumor cells and allow 
accurate 
counting 
of 
stained 
tumor 
cells), 
as 
well 
as 
quantitative 
immunohistochemistry. 
5. Any residual tissue from pretreatment biopsy specimens and post-treatment 
surgical specimens would be stored at MCW Tissue Bank according to the MCW 
Tissue Bank quality control measures. The stored specimens would be 
deidentified.  
 
Study Drugs 
 
• Aromatase inhibitors: Anastrozole, Letrozole, Exemestane 
• Tamoxifen  
 
All agents are FDA approved for use in breast cancer patients and are similarly priced. 
Commercial stock will be used for this exploratory study.  
 
Anastrozole 
Anastrozole is a potent and selective nonsteroidal aromatase inhibitor.  
Route of administration: Oral 
Dose: 1 mg once daily. May be administered with or without food. 
Dose adjustments: No dosage adjustment necessary in any degree of renal or hepatic 
impairment. 
 
Letrozole 
 
Letrozole is a potent and selective nonsteroidal aromatase inhibitor.  
Route of administration: Oral 
Dose: 2.5mg once daily. May be administered with or without food. 
Dose adjustments:  
• Renal impairment: No dosage adjustment necessary. 
• Hepatic impairment:  
o Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment 
necessary. 
o Severe impairment (Child-Pugh class C) and cirrhosis: 2.5 mg every other day 
o Non-cirrhotic patients with elevated bilirubin: There are no dosage adjustments 
provided in the manufacturer’s labeling (effect has not been determined). 
 
Exemestane 
Exemestane is an irreversible, steroidal aromatase inhibitor. 
Route of administration: Oral 
Dose: 25 mg once daily. Administer after a meal. 


 
 
28 
 
Dose adjustments: No dosage adjustment necessary in any degree of renal or hepatic 
impairment. 
 
Tamoxifen 
Tamoxifen is a selective estrogen receptor modulator. Tamoxifen competitively binds to 
estrogen receptors on tumors and other tissue targets, producing a nuclear complex that 
decreases DNA synthesis and inhibits estrogen effects producing cytostatic effects.  
Route of administration: Oral 
Dose: 20 mg once daily. May be administered with or without food. 
Dose adjustments: No dosage adjustment necessary in any degree of renal or hepatic 
impairment. 
Food interaction: Grapefruit juice may decrease the metabolism of tamoxifen. Avoid 
grapefruit juice. 
  
 
 
 
Prohibited Medications 
The following agents must be stopped at least one week prior to registration and must not 
be administered during the study intervention. 
 
• Any agent with estrogenic properties, including herbal preparations. This also 
includes hormone replacement therapy of any type, or raloxifene. 
• Strong CYP2D6 inhibitors will be prohibited with tamoxifen, as it can decrease the 
efficacy of tamoxifen.  
• Any other anti-neoplastic approach, such as chemotherapy or radiation, must not 
be administered while the patient is receiving study treatment. 
 
Concomitant Medications 
All three aromatase inhibitors and tamoxifen are generally safe to administer with other 
medicines. Concomitant use of agents and herbal products that alter ER function are 
specifically not allowed, as mentioned in the prohibited medications.  
 
Definitions of Radiographic Responses 
 
If a tumor is visualized on both imaging modalities, at least the largest bidimensional 
measurements will be recorded. If possible, three-dimensional measurements of tumors 
will be obtained. If a tumor is visualized on only one imaging modality (only a mammogram 
or only an ultrasound), at least the largest bidimensional measurements will be recorded. 
If possible, three dimensional measurements of tumors will be obtained. 
The ultrasound images will be acquired such that the largest dimensions of the tumor in 
at least two of four planes (radial, anti-radial, sagittal, or transverse) are recorded. 


 
 
29 
 
• WHO criteria will be used to assess tumor response to drug therapy. Complete 
Response (CR): The disappearance of all known disease, based on a comparison 
between the measurements at baseline and after four weeks of treatment with 
neoadjuvant therapy.  
• Partial Response (PR): A 50% or greater decrease in the product of the 
bidimensional measurements of the lesion (total tumor size), based on a 
comparison between the measurements at baseline and after four weeks of 
treatment with neoadjuvant therapy.  
• No Change (NC): A 50% decrease in total tumor size cannot be established nor 
has a 25% increase in the size of the lesion been demonstrated. 
• Progressive Disease (PD): A 25% or greater increase in the total tumor size of 
the measurable lesions (calculated on the smallest diameter recorded over time). 
 
 
V. 
STUDY ENTRY AND WITHDRAWAL; STUDY PROCEDURES 
Required Preregistration Screening Tests and Procedures 
The study-specific assessments are detailed in this section and are outlined in the study 
calendar. Screening assessments must be performed within 28 days prior to enrollment. 
Any results falling outside of the reference ranges may be repeated at the investigator’s 
discretion. Treatment or visit delays for public holidays or weather conditions do not 
constitute a protocol violation. 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A separate consent form for tissue banking of residual tumor 
specimens would be used. Signed copies of the study consent forms would be given to 
the subject. and a copy will be filed in the medical record. The original study consent will 
be kept on file with the study records.  
All patients who are consented will be registered in OnCore®, the MCW Cancer Center 
clinical trial management system. The system is password protected and meets HIPAA 
requirements. 
Registration Procedures 
Registration and Monitoring of Patients 
1. Patients will be screened for eligibility and registered by a certified research 
associate/certified research coordinator (CRC/CRA) in the Clinical Trials Office of 
the Froedtert & the Medical College of Wisconsin Clinical Cancer Center.  
2. Patients will be registered in the institutional OnCore® web-based system under 
the CRA console.  


 
 
30 
 
3. Registration of patients and information regarding consenting, eligibility review, on-
study status, treatment status and follow-up will be monitored, using the OnCore® 
calendar system.  
4. Serious adverse events (SAEs) and protocol deviations will be reported through 
the OnCore® reporting system.  
5. Questions regarding OnCore systems and data reporting should be reported to 
OnCore® data management.  
6. Questions regarding patient eligibility and registration procedures should be 
directed 
to 
the 
principal 
investigator, 
Lubna 
Chaudhary, 
MD, 
MS 
(lchaudhary@mcw.edu, pager 414-318-8288, office 414-805-4600).  
7. Subject Withdrawal. Given the short nature of the treatment regimen (three to five 
weeks), and none or few low-grade toxicities are expected, it is not considered 
likely that a large percentage of patients will withdraw from the study, once 
endocrine treatment has begun. However, subjects have the right to withdraw from 
the study at any time. In the rare case that a patient withdraws from the protocol 
after the initiation of treatment, only the data collected up until the date of 
withdrawal will be used in analysis. 
8. A subject may be withdrawn from the study, if she wishes to decline treatment on 
the study. Subjects may also be withdrawn if there is a violation of the protocol 
inclusion and exclusion criteria, as deemed relevant by the treating physician and 
the principal investigator. As these patients would be withdrawn prior to delivery of 
study-related treatment, they will then be replaced on the study and not counted 
toward the total accrual goal of 39 patients. Similarly, patients withdrawing for any 
other reason prior to delivery of treatment will be replaced on the study and not 
counted toward the total accrual goal. 
9. Patients who withdraw from the study should be treated in accordance with normal 
standard of care. Follow-up will be per the discretion of the patient’s treating 
physicians, but at a minimum be in accordance with NCCN guidelines.  
Pretreatment Period 
Screening Assessments  
 
Once the informed consent is signed, proceed with the screening procedures and 
assessments which must be completed within 28 days of prior to enrollment. 
 Physical examination 
 Vital signs 
 Complete medical history 
 Performance status (ECOG, KPS, etc.) (Appendix.2) 


 
 
31 
 
 Adverse event assessment  
 Current medications  
 Blood chemistry assessment, including 
 Complete blood count (CBC) with differential and platelet count 
• Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase - 
(ALT/AST)  
• total bilirubin  
• calcium  
• phosphorus,  
• creatinine,  
• potassium,  
• sodium,  
• chloride,  
• bicarbonate,  
• fasting lipid panel (low-density lipoprotein [LDL], total cholesterol, triglycerides) -
within the past 12 months.  
 Serum or urine pregnancy test for premenopausal women 
 Specimen collection for Oncotype Dx  and study biomarkers once enrolled. 
 Unilateral diagnostic breast mammogram and ultrasound within 60 days of 
enrollment 
 
Study Procedures during Treatment 
Patients must have met eligibility criteria on Day 1 to be treated. The clinic visit can be 
the same for screening, eligibility assessment and if enrolled, to start treatment with 
endocrine therapy for week 1. Patient will get treatment for 4 weeks (+/-1 week) before 
their surgery. No additional clinic follow ups are planned during this period, however can 
be scheduled per discretion of treating physician. 
 
Surgery 
 Diagnostic mammogram and ultrasound are required within 5 days prior to surgery 
 Surgical specimen collection for study biomarkers 
 
End of Treatment Visit 
 
The end of treatment visit would be scheduled within 30 days from surgery.  
 
 Physical examination 
 Vital signs 


 
 
32 
 
 Complete medical history 
 Performance status (ECOG, KPS, etc.) 
 Current medications  
 Adverse event assessment 
 
Long-term/Outcomes Follow-Up Procedures 
As standard of care, patients will be followed by oncology provider(s) at least annually 
after surgery (+/- 3 months). Cancer recurrence outcomes up to five years post-treatment 
will be collected by chart review annually.  
 
VI. 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS 
Adverse Event (AE) and Serious Adverse Events (SAE) 
The investigator and team will follow the Medical College of Wisconsin policies related to 
adverse event reporting. Common Terminology Criteria for Adverse Events (CTCAE) 
version 5 would be used. This information may be found on the Human Research 
Protection Program website.  
Serious AE (SAE) means any untoward medical occurrence: 
• Death. Results in death. 
• Life threatening. Is life threatening (refers to an AE in which the patient was at 
risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe). 
• Hospitalization. Requires inpatient hospitalization or prolongation of an existing 
hospitalization 
• Disability/incapacity. Results in persistent or significant disability or incapacity. 
(Disability is defined as a substantial disruption of a person’s ability to conduct 
normal life functions). 
• Medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
or require medical or surgical intervention to prevent one of the outcomes listed 
above. 
Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 


 
 
33 
 
The investigator and team will follow the Medical College of Wisconsin policies related to 
unanticipated problems involving risks to subjects or others. This information may be 
found on the Human Research Protection Program website.  
AE Attribution and Grading 
 
Table 2. Adverse Event Grading 
Grades 
Description 
0 
No AE (or within normal limits) 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate; minimal, local or noninvasive intervention; limiting age-
appropriate instrumental ADL* 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL* 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; ADL: activities of daily living. 
* Instrumental ADLs include preparing meals, shopping, using the telephone, managing money. Self-care ADLs include 
bathing, dressing, using the toilet, taking medications.  
Adverse Event Attribution 
Attribution is an assessment of the relationship between the AE and the medical 
intervention 
Table 3. Adverse Event Attribution 
Relationship 
Attribution 
Description 
Unrelated to study 
drug/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related 
to 
study 
drug/intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 


 
 
34 
 
Relationship Assessment:  In-Depth Definitions 
For all collected AEs, the clinician who examines and evaluates the subject will determine 
the adverse event’s causality, based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories 
below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
pharmacologically definitive, with use of a satisfactory rechallenge procedure, if 
necessary.  
Probably Related: There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time sequence to administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (dechallenge). Rechallenge information is not 
required to fulfill this definition.  
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, the influence of other factors may have contributed to the event (e.g., the 
subject’s clinical condition, other concomitant events). Although an adverse drug event 
may rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) 
and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the subject’s clinical condition, other concomitant treatments).  
Unrelated: The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.  
Unexpected Adverse Events 
Review all unexpected grade 3, and all grade 4, and 5 adverse events, as well as any 
others requiring expedited reporting as defined in this protocol. (Grades 4 and 5 events 


 
 
35 
 
must be reported to the DSMB within five calendar days of study staff’s knowledge.)  
 
The drugs used in this study are FDA approved for the use of women with hormone 
receptive positive breast cancer. The importance of monitoring these drugs used prior to 
surgery is vital therefore any adverse events that are grade 3, 4, or 5 along with 
causality of possibly, probable or definitely should be reported to the institutions IRB as 
per policy. 
Expected Adverse Events 
 
The following tables provides the expected adverse events for aromatase inhibitors: 
Anastrozole, letrozole and exemestane and tamoxifen. 
Table 4. Expected Adverse Events for Aromatase inhibitors 
Likely 
Less Likely 
Rare 
Fatigue 
Hypertension 
Heart disease 
Joint musculoskeletal pain 
Constipation 
Chest pain 
Loss of bone density over time Nausea/Vomiting 
 
 
Weight gain 
 
 
Sweating/Hot flashes 
 
 
Mood alteration (depression, anxiety)  
 
Hair thinning 
 
 
Headaches 
 
 
Table 5. Expected Adverse Events from Tamoxifen 
Likely 
Less Likely 
Rare 
Fatigue 
Difficulty with sleep 
Ischemic 
cardiovascular 
event 
Hot 
flashes/Sweating 
Constipation 
Thromboembolic event 
Decrease in libido 
Nausea/Vomiting 
Uterine cancer 
 
Weight gain 
 
 
Mood 
alteration 
(depression, 
anxiety) 
 
 
Hair thinning 
 
 
Headache 
 
 
Hypertension 
 
 
Patient Assessments 
1. As noted, given the short nature of the treatment regimen (three to five weeks), 
and expected low grades of toxicity, it is considered highly unlikely that a large 
percentage of patients will experience adverse events (AEs) from the endocrine 
treatment.  


 
 
36 
 
2. All grade 3 and above AEs would be recorded regardless of attributions.  
3. Patients would be assessed at beginning and end of treatment with neoadjuvant 
endocrine therapy as well as at their follow up visit within 30 days after completion 
of study treatment. 
4. Expected side effects are minimal. The most commonly reported symptom is 
fatigue. Fatigue is characterized by a state of generalized weakness with a 
pronounced inability to summon sufficient energy to accomplish daily activities.  
5. Other less commonly reported side effects are anti-estrogen symptoms, i.e., hot 
flashes, mood changes and weight changes. Some of the rare but serious side 
effects, such as ischemic cardiovascular event, thromboembolic event or uterine 
cancer with tamoxifen are long-term side effects and are not expected to occur 
during this short course of neoadjuvant treatment. Similarly, decrease in bone 
density with aromatase inhibitors is a slow and long-term side effect, not expected 
to be seen during the four-week study period. 
6. There are no dose modifications or reductions recommended with endocrine 
treatment.  
 
VII. 
STATISTICAL CONSIDERATIONS 
Statistical analyses: 
 
Demographic and baseline characteristics, such as age, race, weight, values of all 
biomarkers pre and post-treatment, response measures will be summarized, using 
means, standard deviations, medians, ranges for continuous variables, and proportions 
for categorical variables. 
 
This is an exploratory study to gather information on how frequently protein levels of HER 
growth factor receptors (HER1-4) are upregulated along with changes in other study 
biomarkers and correlation with Ki-67 in response to short-term neoadjuvant endocrine in 
early stage HR+ breast cancer. We hypothesize that expression of one or more HER 
proteins (HER1-4) will be upregulated in at least 50% of tumors after four weeks of 
neoadjuvant endocrine therapy and this upregulation will correlate with Ki-67 expressed 
in more than 10% of cancer cells, as compared to upregulation in 30% or less of tumors 
without the therapy. The change in Ki-67 expression will be dichotomized, as a categorical 
variable with ≥10% increase coded as high and <10% coded as low.  
a) For the primary outcome: An exact binomial one sample test of proportions will be 
used for to test the hypothesis that proportion of upregulated HER proteins will be 
at least 50% after therapy versus the null hypothesis that the proportion of 
upregulated HER proteins is not greater than 30%. 
b) For analyzing - the differences in proportion of upregulated HER proteins between 
the high difference in Ki-67 and low difference in Ki-67 groups, two sample tests 
of proportions will be used.  
c) Similarly, appropriate two sample tests will be used to test differences in 
biomarkers between the high difference in Ki-67 and low difference in Ki-67 
groups. We will use the appropriate kind of regression instead of two sample tests, 
to test differences in biomarkers between the high difference in Ki-67 and low 


 
 
37 
 
difference in Ki-67 groups if we need to adjust for covariates. 
d)  Additionally, regression analysis will also be done to evaluate the changes in the 
biomarkers and their association with patient specific covariates, such as age, race 
and other relevant predictors of interest.  
 
Radiographic responses will be assessed by WHO criteria. Radiographic response rates 
will be measured as the rate of complete response (CR) or partial response (PR) in 
patients treated with neoadjuvant endocrine therapy. Complete response is defined as 
the resolution of tumor on post-treatment imaging as compared with pretreatment 
imaging, while partial response is defined as 50% reduction in tumor size on post-
treatment imaging, as compared with pretreatment imaging. We will estimate the rates of 
response with 95% confidence intervals. We will use logistic regression (and other 
generalized linear models as appropriate) to measure association between the response 
rates and patient specific covariates such as age, race and other relevant predictors of 
interest. 
 
We will use a family type I error rate of 0.05 significance throughout with 
Bonferroni adjustments for multiple testing wherever appropriate, so that the overall 
family type I error rate is maintained. 
 
Sample Size and Power Calculation 
 
To achieve at least 80% power at significance level of 0.05, when testing the one sided 
one sample hypothesis that the proportion of tumors with HER protein upregulation with 
neoadjuvant endocrine therapy is at least 50% versus the null hypothesis that the 
proportion is no larger than 30%, the minimum number of patients required is 37.  
Early Stopping for Futility 
 
Early stopping for futility and interim analysis in clinical trials are done to ensure safety of 
the patients and prevent any unnecessary intervention. This is an exploratory study to 
understand changes in tumor biology with neoadjuvant endocrine treatment. All study 
biomarkers including changes in HER family of RTKs are being studied to assess 
responses and development of endocrine resistance. In this study, patients are being 
treated with endocrine therapy in the neoadjuvant setting for a short duration of time (4 
weeks +/- 1 week) without causing any significant delay in their surgery. They will be 
treated with the same endocrine therapy in the adjuvant setting for at least 5 years which 
is standard of care. These drugs are routinely used in neoadjuvant setting in patients 
deemed to be poor surgical candidates or requiring a delay in surgery for variety of 
reasons and is considered a safe approach with minimal risk to the patients particularly 
when used for a short duration as done in this study.  
The primary objective of this study is to assess changes/upregulation of one or more 
HER proteins (HER1-4) after neoadjuvant endocrine treatment. Given the exploratory 
nature and small sample size of this study, we may not see enough upregulation of HER 


 
 
38 
 
proteins to meet statistical significance. Up regulation or lack thereof of HER proteins is 
not a known prognostic factor for patient outcomes at this time and will not impact the 
safety or clinical management of these patients. Interim analysis and stopping for futility 
is not indicated in this setting of an exploratory study where the goal is to understand 
changes in tumor microenvironment to learn more about tumor responses or lack thereof 
to endocrine treatment. We expect to get important preliminary data from this exploratory 
study for future follow up clinical trials.  
 
Missing Data management: Observed data will be included in listings, summary tables 
and statistical analysis, with counts and proportions of missing data, if any. The only likely 
source of missing data in our study is the absence of some biomarker information due to 
lack of tissue specimens. As already mentioned, we will attempt to obtain additional 
biopsy tissue to complete the information, but in case this is not feasible, the evaluation 
of these biomarkers will be done dropping the missing samples from the analysis. This 
missed data is likely to be at random and there will be no imputation of missing data. 
 
VIII. 
PATIENT SAFETY MONITORING AND CONFIDENTIALITY 
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and 
Safety Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC 
activities are as follows:  
 
 Review the clinical trial for data integrity and safety  
 Review all grade 3 and higher adverse events, as well as any others requiring 
expedited reporting as defined in this protocol. (Grades 4 and 5 events must be 
reported to the DSMC within five calendar days of study staff’s knowledge.)  
 Review all Data and Safety Monitoring reports.  
 Submit a summary of any recommendations related to study content.  
 Terminate the study if deemed unsafe for patients. 
 
1. A copy of the MCWCC Data and Safety Monitoring Plan and membership roster 
will be maintained in the study research file and updated as membership changes. 
The committee will review reports from the study PI twice annually (or more 
frequently if needed) and provide recommendations on trial continuation, 
suspension or termination as necessary.  
2. Any available DSMC letters will be submitted to the IRB of record as required. 
3. Data on patient information and follow-up information will be collected and entered 
into the password protected OnCore® system. Data will be accessible only by the 
research team and DSMC.  
4. Hard copy forms will be kept in a locked file in offices of the CTO. The forms will 
be linked to patients by a unique identifier and patient initials in the event that the 


 
 
39 
 
identifier is transcribed incorrectly. Access to these forms will be limited to the CRA 
and PI only as the data collected will be entered in to OnCore®. 
 
IX. 
QUALITY ASSURANCE 
This trial has been determined to be an intermediate risk trial by the MCW Cancer 
Center Clinical Trials Office Quality Assurance Team. This will be reviewed by the MCW 
CC CTO Quality Assurance team as follows 
• Intermediate risk trials are reviewed every year. 
• 20% of subject files will be selected randomly for review (a maximum of 10 subjects 
at each monitoring time point). Consent/eligibility and objective-based data will be 
reviewed for those files selected.  
• One file will be selected randomly for a comprehensive review at each monitoring 
time point. 
• Regulatory documents (IRB submissions, reportable events, etc.) will be reviewed 
at each monitoring time point. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
40 
 
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46 
 
Appendix 1. IIT-Chaudhary-Endocrine: Monthly Intake Diary 
 
Institution: 
 
Physician: 
 
Study ID#: 
 
Initials (L, FM): 
 
 
Instructions for the participant: This is a monthly calendar on which you are to record the daily anti-estrogen pill you 
take each day for the 4-week period. If you develop any side effects from the pill, describe side effect on the day that it 
happened on the calendar below. If you ever miss taking a pill, write missed on the date. Please bring your calendars with 
you to your follow up visit after you’ve completed the 4-week period. If you take over the counter medications, for example 
cold & allergies, please write on the day what medication you took. 
 
Special Instructions: Please take 1 anti-estrogen pill, ONCE each day, preferably in the morning with food & a 
glass of water. Tablets MUST be swallowed whole, do NOT crush or chew. AVOID grapefruit & products 
containing grapefruit juice while you are taking tamoxifen. 
 
If you have any questions, please contact: 
 
Phone: 
 
 
Patient Name: 
 
Date: 
 
 
 
 
 
Surgeon: 
 
Surgery Date: 
 


 
 
47 
 
Appendix 2. Performance Status criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity 
Fully active, able to carry on 
all pre-disease performance 
without restriction 
100 
Normal, no complaints, no 
evidence of disease 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease 
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) 
80 
Normal activity with effort; some 
signs or symptoms of disease 
70 
Cares for self, unable to carry on 
normal activity or to do active 
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 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs 
50 
Requires considerable 
assistance and frequent medical 
care 
3 
In bed > 50% of the time 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours 
40 
Disabled, requires special care 
and assistance 
30 
Severely disabled, 
hospitalization indicated 
Death not imminent 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or 
chair 
20 
Very sick, hospitalization 
indicated 
Death not imminent 
10 
Moribund, fatal processes 
progressing rapidly 
5 
Dead 
0 
Dead 
 
 
 
 


 
 
48 
 
Appendix 3. IIT-Chaudhary-Endocrine: Specimen Submission Form 
 
An Exploratory Study of Neoadjuvant Endocrine Therapy in Hormone 
Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to 
Assess Responses and Mechanisms of Endocrine Resistance 
PI: Lubna Chaudhary, MD, MS 
 
 
For Clinical Trials Office to complete: Please send pathology for pre- and post- treatment, One 
H&E slide and 15 to 20 unstained charged slides cut at 4 microns thick, to Dr. Hallgeir Rui’s 
laboratory (suite C4980) at the Medical College of Wisconsin Translational and Biomedical 
Research Center (TBRC). 
 
 
 
 
 
 
Date of Specimen Collection:  
Date of Shipment:  
 
 
(Date found on surgical path report) 
 
 
 
Study Identification Number: 
 
 
 
 
 
 
 
 
 
Shipped From: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact Name: 
 
 
 
Contact Number: 
 
 
Contact Fax: 
 
 
 
Contact Email: 
 
 
 
 
 
 
 
 
 
For Dr. Hallgeir Rui’s laboratory to complete:  Please note any residual tissue from 
pretreatment biopsy specimens and post-treatment surgical specimens are to be stored at MCW 
Tissue Bank. Please submit accordingly and notify Clinical Research team of submission. Please 
sign and send this form to the clinical trials office by fax or email. 
 
Time Point 
Date 
Received 
Any Residual 
Specimen?  
Residual specimen 
sent to MCW 
Tissue Bank? 
Comments: 
Pre - treatment 
specimen (biopsy) 
 
 
 
 
Post - treatment 
specimen 
(definitive surgery) 
 
 
 
 
 
 
 
Signature of Person Receiving Specimens 
 
Date  

ICF_001.pdf: 
Informed Consent Form Title:  An Exploratory Study of Neoadjuvant Endocrine Therapy 
in Hormone Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to 
Assess Responses and Mechanisms of Endocrine Resistance 
 
NCT:  NCT03219476 
 
Document Date:  01/09/2019 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
Page 1 of 14 
Version: MCW v 11-27-18 
 
EFFECTIVE 
 
1/9/2019 
 
MCW/FH IRB
Medical College of Wisconsin and Froedtert Hospital 
INTRODUCTION TO THE INFORMED CONSENT 
 
Name of Subject: ____________________________ 
 
An Exploratory Study of Neoadjuvant Endocrine Therapy  
in Hormone Receptor-Positive HER2-Negative Node-Negative Breast Cancer Patients to 
Assess Responses and Mechanisms of Endocrine Resistance 
 
Lubna Chaudhary, MD, MS 
Department of Medicine  
414-805-6700 
Medical College of Wisconsin 
8701 Watertown Plank Road 
Milwaukee WI 53226 
 
 
You are invited to take part in this research. You can decide whether to take part in this project 
or not. You are free to say yes or no. If there is anything that you do not understand, please ask 
questions. 
 
 
Definitions 
 
Medical Oncologist – is a physician who specializes in drug-based treatments for 
cancer (for example chemotherapy and hormone therapy). 
Performance status – an assessment of how much you can participate in your activities 
of daily living. 
Principal Investigator - The Principal Investigator is responsible and accountable for 
the research project. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
Page 2 of 14 
Version: MCW v 11-27-18 
 
EFFECTIVE 
 
1/9/2019 
 
MCW/FH IRB
 
Purpose 
This project is being done to assess if tumor-
based biomarkers have a connection to 
disease response with anti-estrogen therapy. 
Length 
 You will be in this research project for 
about 4 weeks (+/- 1 week), depending on 
surgery date.  
 We would also like to follow you annually 
for up to 5 years after your surgery. 
Risks 
This is a brief list of the most commonly seen 
side effects. The full consent form after this 
introduction contains a more complete list of 
potential research risks. 
 
Aromatase Inhibitors risks: 
 
Fatigue 
 
Joint musculoskeletal pain 
 
Loss of bone density over time 
 
Tamoxifen risks: 
 
Fatigue 
 
Sweating / hot flashes 
 
Decreased libido 
 
Procedures 
 
There is no placebo in this project. All patients 
will be treated with anti-estrogen therapy. 
 
List of visits: 
 
Screening Visit 
- Total Number: _1_ 
- Total Time: _1 hour_ 
 
Week 1, Day 1 Visit 
- Total Number: _1_ 
- Total Time: _1 hour_ 
 
End of Treatment Visit 
- Total Number: _1_ 
- Total Time: _30 min_ 
 
Follow up Visits 
- Total Number: _5_ 
- Total Time: _~30 min_ 
 
Procedures that will occur at various 
visits: 
 
Invasive Procedures 
- Additional biopsies for more tissue 
for Oncotype test, if applicable. 
- Blood Sample Collection at 
screening or Week 1, Day 1 visit. 
 
Non-invasive Procedures 
- Physical Exam 
- Vitals: blood pressure, pulse 
- Medical History 
- Performance status 
- Recurrence Status 
- Adverse Event assessment 
- Current Medications assessment 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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My Other Options 
You do not have to join this project. Your other 
options may include: 
 Joining a different project 
 Routine care for this condition 
 Getting no treatment for this condition 
 
Benefits 
We don’t know if this project will help you. Your 
condition may get better but it could stay the 
same or even get worse. 
If you have more questions about this project at any time, you can call Dr. Lubna Chaudhary 
at 414-805-6700. 
 
If you have questions about your rights as a participant, want to report any problems or 
complaints, or offer input, you can call the MCW/Froedtert Hospital Research Subject 
Advocate at 414-955-8844. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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CONSENT TO PARTICIPATE IN RESEARCH 
A1. INTRODUCTION – WHY ARE WE ASKING YOU TO PARTICIPATE? 
You are being invited to participate in this research because you have been diagnosed with 
invasive breast cancer and are a candidate for anti-estrogen (hormonal) therapy. 
 
A total of about 37 people are expected to participate in this research at the Medical College of 
Wisconsin/Froedtert Hospital, St. Joseph’s Hospital, and Community Memorial Hospital. 
 
The Director of the project is Dr. Lubna Chaudhary in the Department of Hematology and 
Oncology. A research team works with Dr. Lubna Chaudhary. You can ask who these people 
are.  
 
Rock River Foundation and the Medical College of Wisconsin Cancer Center are funding the 
study. 
 
A2. DO I HAVE TO PARTICIPATE? 
You can decide whether to take part in this research or not. You are free to say yes or no. If you 
say no, your regular medical care will not change. Even if you join this project, you do not have 
to stay in it. You may stop at any time.  
 
A research project is different from routine medical care in three ways: 1) there are extra risks 
that we will tell you about in this form; 2) you may have some extra medical tests and visits; 3) 
the research procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS PROJECT BEING DONE? 
In this study, we want to see if tumor-based biomarkers have a connection to disease response 
with anti-estrogen therapy. Biomarkers are part of the tumor cells and their levels in the tumor 
tissue may have a relationship with treatment response. We plan to look at your tissue samples 
before and after your anti-estrogen therapy for research purposes. 
 
We would like to see if these biomarker levels might help predict treatment response in the 
future. The purpose is not to discover information that could be used to change your medical 
care or make a change to your diagnosis.  
 
B1. WHAT WILL HAPPEN IF I PARTICIPATE? 
Screening procedures:  
 
If you decide to join, some screening tests will be done first to see if you are eligible.  
 
 
Breast mammogram and ultrasound on the side where your breast cancer is located. These 
exams may have already been done to diagnose your breast cancer.  
 
Medical Oncologist consultation 
 
OncotypeDx testing if recommended 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
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IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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 
Physical exam including measurements of weight and vital signs (blood pressure, pulse) and 
performance status.   
 
Collect information on medications you are taking 
 
Collect information on your medical history and any current symptoms you have 
 
Specimen collection for study biomarkers from archived tumor tissue from your initial cancer 
diagnosis 
 
Blood tests will be obtained (approximately 3 tablespoons will be drawn from your vein) to 
assess your general health and organ function.  
 
Pregnancy test, if applicable 
 
If you are interested in participating in the study, you will also need to meet with a 
medical oncologist prior to enrollment. A medical oncologist is a physician who 
specializes in drug-based treatments for cancer (for example chemotherapy and 
hormone therapy). Patients treated for early stage breast cancer usually see a medical 
oncologist after surgery, so this is a physician you would see regardless of whether you 
participate in the study. 
 
The reason you need to meet with a medical oncologist is to determine whether you 
need to have a special genetic test on your tumor. Typically, this test is called 
Oncotype DX and is used to help determine whether or not you would benefit from 
chemotherapy. If the medical oncologist does not recommend an Oncotype DX be 
performed in your case, or you decide to not receive chemotherapy regardless of the 
results of the Oncotype DX testing, you may then be able to enroll on the study. 
 
If an Oncotype DX test is recommended and you are willing to receive chemotherapy, then the 
doctors treating you will perform that test prior to surgery. The test will be 
performed on the tissue obtained at the time of the biopsy that diagnosed your cancer. 
The reason this needs to be done is that the anti-estrogen therapy you get on the study prior to 
surgery, is likely to induce changes within the tumor biology which could affect the results of the 
Oncotype DX test, and may cause a loss of information that would guide your treatment in the 
future. If there is insufficient tissue from the biopsy to perform the OncotypeDX test, you may be 
ineligible for the study. In that case, you may choose to undergo an additional biopsy to obtain 
additional tissue to perform the OncotypeDX test and thus become eligible for the study. 
However, if you choose that option, you or your insurance company will be charged for that 
additional biopsy.  If you elect to undergo an additional biopsy, but no residual tumor is found, 
then, you would not be eligible for the study. 
 
If the screening information shows that you meet the requirements, then you will be able to start 
the study. If the screening information shows that you cannot be in the research study, the study 
doctors will discuss other options with you and/or refer you back to your regular doctor.  
 
Summary of Procedures: 
 
If you are eligible to be in the study, you will begin your 4-week (+/- 1 week) treatment period of 
anti-estrogen therapy and have the following procedures done, most of which are part of your 
regular care.   
 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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Day 1 of the 4 week treatment period 
(The screening visit and day 1 visit can be the same if performed within 28 days of enrollment) 
 
Physical exam including measurements of weight and vital signs (blood pressure, pulse) 
and performance status.  Performance status is an assessment of how much you can 
participate in your activities of daily living.  
 
Collect information on medications you are taking 
 
Collect information on your medical history and any current symptoms you have 
 
You will take 1 of your prescribed anti-estrogen pills once a day by mouth with a glass of 
water. Tablets must be swallowed whole and not chewed or crushed. 
 
You must immediately inform your study doctor if you begin any new medications while 
on study. 
 
You should record the daily anti-estrogen pill you take each day and any side effects you 
experience on a calendar for the 4-week (+/- 1 week)period.   
 
You should bring your calendar with you to your doctor’s visit prior to your surgery.  
 
If your anti-estrogen pill is Tamoxifen, avoid Grapefruit juice as this may decrease the 
metabolism of the drug.  
 
Breast Cancer Surgery:   
(Scheduled 4 weeks (+/- 1 week) after your first dose of anti-estrogen therapy) 
 
Breast mammogram and ultrasound will be done about 5 days before the surgery 
 
Sometime after your surgery, tests will be performed on your tumor tissue and on the 
tissue from your biopsy to see if the genes expressed in each sample have changed. 
 
End of Treatment Visit  
(Within 1 month after your surgery) 
 
Physical exam including measurements of weight and vital signs (blood pressure, pulse) 
and performance status.  Performance status is an assessment of how much you can 
participate in your activities of daily living.  
 
Collect information on medications you are taking 
 
Collect information on your medical history and any current symptoms you have 
 
Specimen collection for study biomarkers from leftover tissue samples from your breast 
cancer surgery. 
 
Follow- Up 
(Annually (+/- 3 months) from surgery) 
 
Further follow-up visits would be per the discretion of the patient’s treating physicians.   
 
There will be a yearly medical record follow up review for 5 years from your surgery to check on 
how you have been doing. The study team will review your medical records (chart review), for 
appointments you may have had with your cancer care doctors, annually for 5 years to collect 
information on the status of your cancer. 
 
Subjects will be presented with a separate consent form from the MCW Tissue Bank. The MCW 
Tissue Bank consent form will ask subjects if they would consent to bank any residual tissue 
from their initial biopsy as well as final breast cancer surgery after all the study biomarkers have 
been tested. The samples would be stored according to the MCW Tissue Bank quality control 
measures and would be deidentified. If subjects do not consent to have their tissue banked at 
the MCW Tissue Bank, they can participate in the study. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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B2. HOW LONG WILL I BE IN THE PROJECT? 
 You will take the research required anti-estrogen therapy for 4 weeks (+/- 1 week) up to your 
surgery date. 
 You will be in this research project for about 5 years. 
 
B3. CAN I STOP BEING IN THE PROJECT?   
You are free to withdraw from the project at any time. If you leave, your regular medical care will 
not change. If you are thinking about leaving, please tell the research doctor.  
 The research doctor can tell you about the effects of stopping, and you and the research 
doctor can talk about what follow-up care would help you the most. 
 You might be asked to come back for one more visit to check your health. 
 
The research doctor may take you out of this project at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the project rules. 
 
The whole project is stopped. 
If this happens, the research doctor will tell you. 
 
B4. ARE THERE ANY SPECIAL INSTRUCTIONS WHILE I AM IN THE PROJECT?  
Prohibited Medications 
The following agents must be stopped at least one week prior to registration and must not be 
administered during the study intervention. 
 
 
Any agent with estrogenic properties, including herbal preparations. This also includes 
hormone replacement therapy of any type, or raloxifene. 
 
Strong CYP2D6 inhibitors will be prohibited with tamoxifen, as it can decrease the efficacy 
of tamoxifen. Avoid grapefruit juice, as it may decrease the absorption of this drug. 
 
Any other anti-neoplastic approach (cancer treatments), such as chemotherapy or 
radiation, must not be administered while the patient is receiving study treatment. 
 
Concomitant Medications 
 
All three aromatase inhibitors and tamoxifen are generally safe to administer with other medicines. 
Concomitant use of agents and herbal products that alter Estrogen Receptor function are 
specifically not allowed, as mentioned in the prohibited medications.  
 
You should tell your study doctor about all medications (over the counter, herbal, and 
prescription) you are currently taking and check with your study doctor before beginning any 
new medications. 
 
C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE PROJECT? 
There are risks to taking part in any research project. There is a risk that this intervention may 
not help your condition or may make it worse.  There also may be problems (side effects) we do 


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IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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not know about yet, from the intervention itself, or how it combines with other drugs you are 
taking. If we learn about new important side effects, we will tell you.  
 
We watch everyone in the project for problems (side effects). You need to tell the research 
doctor or a member of the research team immediately if you experience any problems, 
side effects, or changes in your health.   
 
C2. RISKS OF AROMATASE INHIBITORS AND TAMOXIFEN 
The anti-estrogen drugs (aromatase inhibitors, tamoxifen) may cause problems (side effects).  
Side effects may be mild or very serious.  Some can last a long time or never go away.   
The anti-estrogen drugs (aromatase inhibitors, tamoxifen) can affect individuals in different 
ways.  
 
The side effects that other people have experienced so far with aromatase inhibitors are:  
 
Likely: 
 
Fatigue 
 
Joint musculoskeletal pain 
 
Loss of bone density over time 
 
Less likely: 
 
Hypertension 
 
Constipation 
 
Nausea/ vomiting 
 
Weight gain 
 
Sweating/ hot flashes 
 
Mood alteration (depression, anxiety) 
 
Hair thinning 
 
Headaches 
 
Rare: 
 
Heart disease 
 
Chest pain 
 
The side effects that other people have experienced so far with Tamoxifen are:  
 
Likely: 
 
Fatigue 
 
Sweating/ hot flashes 
 
Decreased libido 
 
Less likely: 
 
Difficulty with sleep 
 
Constipation 
 
Nausea/ vomiting 
 
Weight gain 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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 
Mood alteration (depression, anxiety) 
 
Hair thinning 
 
Headaches 
 
Hypertension 
 
Rare: 
 
Ischemic cardiovascular event-decreased blood flow & oxygen to the heart 
 
Thromboembolic event- blood clot which may cause swelling, pain, shortness of 
breath  
 
Uterine cancer 
 
C3. OTHER RISKS OF THIS RESEARCH PROJECT 
Other procedures that are part of the research also involve some risks: 
 
 
Blood Draw Risks: 
o The side effects that you might experience because of donating a blood sample 
for this study include possible discomfort and bruising at the needle entry site. 
Rare complications of any venipuncture (drawing blood from a vein) include 
fainting, arterial puncture, peripheral nerve injury, local infection, and local blood 
clot. There may be other unanticipated risks, but every precaution will be taken to 
assure your personal safety and to minimize discomfort. The person drawing 
your blood will observe you for side effects, but please inform him or her if you 
experience any discomfort or feel faint. 
 
 
Mammogram: 
o The benefits of mammography outweigh any possible harm from the radiation 
exposure. Modern machines use low radiation doses to get breast x-rays that are 
high in image quality. On average the total dose for a typical mammogram with 2 
views of each breast is about 0.4 mSv. (A mSv is a measure of radiation dose.) 
o To put dose into perspective, people in the US are normally exposed to an 
average of about 3 mSv of radiation each year just from their natural 
surroundings. (This is called background radiation.) The dose of radiation used 
for a screening mammogram of both breasts is about the same amount of 
radiation a woman would get from her natural surroundings over about 7 weeks. 
  
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant 
 
The anti-estrogen therapy in this project might affect a baby, before or after the baby is born. 
We do not know if the Anti-estrogen therapy can disturb the development of the embryo or fetus 
which causes harm to a baby, so we do not want anyone who might be pregnant to enter the 
project. You should not become pregnant or nurse a baby while in this project. You must tell the 
research doctor right away if you think you are pregnant. You will be asked to have a pregnancy 
test to be sure you are not pregnant at the start of the project. 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
IRB Protocol Number: 30178 
IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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Women who become pregnant or think they might be pregnant must inform their treating 
physician immediately. Pregnancy requires a woman to come off protocol 
treatment immediately. 
 
Birth control methods for all subjects 
Check with the research doctor about the birth control methods needed for this project and how 
long to use them. Some methods might not be good enough for this project. If you are having 
sex that could lead to pregnancy, you should use birth control while you are in this project.   
 
This may include: 
 
Not having vaginal sex (abstinence) 
 
Taking birth control pills orally 
 
Having birth control shots or patches such as Depo-Provera 
 
Surgical sterilization (hysterectomy or tubal ligation) 
 
Use of an intrauterine device (IUD) 
 
Use of diaphragm with contraceptive jelly 
 
Use of condoms with contraceptive foam 
 
Use of diaphragm with condoms (“double barrier”) 
 
Limiting sexual activity to a male partner who has had a vasectomy 
 
You should continue using birth control for 3 months after stopping the anti-estrogen therapy. 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE PROJECT? 
We don’t know if this study will help you. Your condition may get better but it could stay the 
same or even get worse. We hope the information from this study will help us predict patients’ 
responses to anti-estrogen therapy and potentially help doctors choose better treatments for 
their patients. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE PROJECT? 
Most of the medical care that you will receive in this project is considered routine care for your 
condition and would be recommended whether or not you join the project.  Costs for routine 
care will be billed to you or your insurance carrier.  Activities / costs that are part of the project 
will not be billed to you or your insurance company. These are collection, analysis, processing 
of archived tumor samples, and research blood samples. Some insurers will not pay for drugs, 
tests or hospitalization that are part of research, so check with your insurer before you join this 
project. If you have questions regarding costs, please contact Dr. Lubna Chaudhary. 
 
If you participate in this research, the costs of any necessary emergency medical treatment in 
the event of a research-related injury will be billed to you or your health insurance. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE PROJECT? 
There is no payment for being in this project, 
 


Medical College of Wisconsin & Froedtert Hospital 
Informed Consent for Research 
Clinical Interventions template - Version: March 30, 2018 
 
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IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
You do not have to join this project. You are free to say yes or no. If you do not join this project, 
your research doctor can discuss other healthcare choices with you.  
Your other choices may include: 
 
Joining a different research project 
 
The procedure or drug offered to you may also be available without being in any 
research project. 
 
The research doctor can explain both the possible benefits and the risks of other options that 
are available to you. 
 
D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE PROJECT? 
If we learn any important new information about anti-estrogen therapy administered that might 
change your mind about being in the project, we will tell you about it right away.  You can then 
decide if you want to stay in the project. 
 
Clinically relevant results, including individual results, will be disclosed to you. These results will 
be shared by one of your treating physicians when available. 
 
D5. WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THE PROJECT?  
Emergency medical treatment for injuries directly related to your participation in this research 
project will be provided to you. You or your health insurance will be billed for the costs of this 
emergency treatment.  MCW will decide on a case by case basis if they will reimburse you or 
your insurer for emergency treatment costs.  If your research-related injury requires medical 
care beyond this emergency treatment, you or your insurer will be responsible for the costs of 
this follow-up care.  
 
At this time, there is no plan for any additional financial payments. 
 
If you believe that you have been injured because of your participation in this project, contact 
the research doctors right away.  Contact information: Dr. Lubna Chaudhary at 414-805-6700.  
 
Nothing in this consent form affects any legal rights you may have nor does it release the 
investigator, the sponsor, the institution, or its agents from liability for negligence. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE PROJECT? 
 
If you have more questions about this project at any time, you can call Dr. Lubna 
Chaudhary at 414-805-6700. 
 
If you have questions about your rights as a research participant, want to report any 
problems or complaints, or offer input, you can call the MCW/Froedtert Hospital Research 
Subject Advocate at 414-955-8844. 
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 


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E1. What health information will be collected and used for this project? 
To be in this research project, the research team needs your permission to access, collect and 
use some of your health information. If you say no, you cannot be in the project. This 
information may come from questions we ask, forms we ask you to fill out, or your medical 
record, as described below. We will only collect and use information needed for the project. 
 
The protected health information (PHI) originates from services you will or have received at one 
or more of the following locations: the Medical College of Wisconsin (MCW); BloodCenter of 
Wisconsin (BCW); Children’s Hospital of Wisconsin (CHW); any Froedtert Health Affiliate- 
Froedtert Memorial Lutheran Hospital (FMLH), Inc.; Community Memorial Hospital (CMH) 
Menomonee Falls, Inc.;  St. Joseph’s Community Hospital (SJH) West Bend, Inc.;  Froedtert & 
The Medical College of Wisconsin Community Physicians Clinics, Inc. (FMCWCP); the West 
Bend Surgery Center, LLC; and the Froedtert Surgery Center, LLC.  
 
The health information to be collected and used for this project is:  
 Medical records of the care you receive for this project until approximately 5 years after 
your surgery. 
 Medical records dating from when you join this project until the end of your participation 
in the study. 
 
E2. Who will see the health information collected for this project? 
The only MCW/Froedtert Hospital employees allowed to handle your health information are 
those on the research team, those on the Institutional Review Board (IRB) and those who check 
on the research activities to make sure the hospital’s rules are followed. 
 
If the costs of any necessary emergency medical treatment in the event of a research-related 
injury are billed to your health insurance, your health information may need to be disclosed to 
the insurer for billing purposes. 
 
Because this project involves the use of drugs and/or devices, the FDA also has the right to 
inspect all project records. 
 
We may record your research information, including results of tests and procedures done for 
research, in your Froedtert Hospital and/or Medical College of Wisconsin medical record. As a 
result, this research information may be seen by people allowed to see your medical records for 
healthcare operations or treatment, by those you allow to see your medical records by giving 
written permission, and by others when required by law. 
 
We will not use your personal health information for a different project without your permission 
or the permission of a hospital research review board (IRB). Once all personal identification is 
removed from your health information and biospecimens, the information and biospecimens 
may be used for future research or distributed to another investigator for future research without 
additional informed consent from you or your legally authorized representative. The information 
might also be used or released for other purposes without asking you. Results of the project 
may be presented in public talks or written articles, but no information will be presented that 
identifies you. 
  


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E3. What are the risks of sharing this health information? 
One risk of taking part in a research project is that more people will handle your personal health 
information collected for this project. The research team will make every effort to protect the 
information and keep it confidential, but it is possible that an unauthorized person might see it. 
Depending on the kind of information being collected, it might be used in a way that could 
embarrass you or affect your ability to get insurance. If you have questions, you can talk to the 
research doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this project? 
If you sign this form, we plan to keep your information without any end-date in case we need to 
check it again for this project. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health information, you 
need to send a letter to Dr. Chaudhary at 9200 W. Wisconsin Avenue Milwaukee, WI 53226. 
The letter must say that you have changed your mind and do not want the researcher to collect 
and share your health information. At that time, we may decide that you cannot continue to be 
part of the project. We may still use the information we have already collected.  
 
 
F1. FOR MORE INFORMATION ABOUT THE PROJECT 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
 
You can look up this project by referring to the ClinicalTrials.gov number (NCT03219476) or by 
asking the research team for a printed copy.    
 


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IRB Approval Period: 1/9/2019 – 11/27/2019 
 
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CONSENT TO PARTICIPATE 
 
By signing my name below, I confirm the following: 
 
I have read (or had read to me) this entire consent document. All of my questions have been 
answered to my satisfaction. 
 
The project’s purpose, procedures, risks and possible benefits have been explained to me.   
 
I agree to let the research team use and share the health information and other information 
gathered for this project. 
 
I voluntarily agree to participate in this research project. I agree to follow the procedures as 
directed. I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please keep it 
where you can find it easily.  It will help you remember what we discussed today. 
 
 
 
 
Subject's Name please print  
Subject's Signature 
Date    
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 
 
 
 
Name of Witness (if applicable) 
please print  (for short form consent 
process, or consent of blind or 
illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent 
Date 
* A member of the research team trained and authorized by the Principal Investigator to act on 
her/his behalf in obtaining informed consent according to the protocol.  The Principal 
Investigator is responsible and accountable for the research project.