Testing for Atypia in Random Periareolar Fine Needle Aspiration (RPFNA) Cytology After 12 Months Metformin (1, 1-Dimethylbiguanide Hydrochloride) Chemoprevention Versus Placebo Control in Premenopausal Women
Phase: PHASE3
Conditions: Atypical Ductal Breast Hyperplasia, BRCA1 Mutation Carrier, BRCA2 Mutation Carrier, Ductal Breast Carcinoma in Situ, Lobular Breast Carcinoma in Situ
Sponsor: Alliance for Clinical Trials in Oncology

 
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Update #07 
 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A211102 
 
TESTING FOR ATYPIA IN RANDOM PERIAREOLAR FINE NEEDLE ASPIRATION (RPFNA) CYTOLOGY 
AFTER 12 MONTHS METFORMIN (1, 1-DIMETHYLBIGUANIDE HYDROCHLORIDE) CHEMOPREVENTION 
VERSUS PLACEBO CONTROL IN PREMENOPAUSAL WOMEN 
 
For any communications regarding this protocol, 
please call the protocol resource person on the following page. 
 
 
Study Chairs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Co-chairs:  
 
 
 
 
 
Primary Statistician 
Secondary Statistician 
 
 
 
 
 
 
 
Drug Availability IND Exempt (IND #122334) 
Supplied Investigational Agents: Placebo for metformin supplied and compounded by Pharm Ops, Inc., in 
Phillipsburg, NJ. 
Commercial Agents:  Metformin will be purchased through the McKesson Clinical Research Services.  
 
*Investigator having NCI responsibility for this protocol 
Study contributor(s) not responsible for patient care. 
 
Participating NCTN Groups: Alliance/Alliance for Clinical Trials in Oncology (lead); ECOG-ACRIN/ECOG-
ACRIN Cancer Research Group; NRG/NRG Oncology; SWOG/SWOG 

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Data Manager 
Protocol Coordinator 
 
 
 
 
 
 
 
Study Resources: 
 
Expedited Adverse Event Reporting 
 
 Medidata Rave iMedidata portal 
 
OPEN (Oncology Patient Enrollment Network) 
 
 Biospecimen Management System 
 
 
Protocol Contacts: 
A211102 Nursing Contacts 
 
 
   
 
A211102 Pharmacy Contact 
 
 
 
 
Alliance Biorepository at Ohio State 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox 
 
Questions regarding specimens/specimen 
submissions: 
Appropriate Alliance Biorepository  
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
 (Sign in at 
, and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
 
to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 
 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
 
 
Contact the CTSU Help Desk 
with any OPEN related questions 
by phone or email : 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (
). Access 
to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-IAM) registration system and requires log in with a CTEP-
IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
 
For clinical questions (i.e. patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 
All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 

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SCHEMA 
 
 
Pre-registration 
 
 
 
 
 
 
 
 
 
RPFNA1 samples to be collected and submitted to 
lab to determine 
eligibility (atypia on RPFNA and Masood Score 14-17), see Section 6.5. 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
Metformin 
850 mg  p.o. daily for 4 weeks, then 
850 mg p.o. b.i.d. for months 2-12  
 
Placebo 
850 mg  p.o. daily for 4 weeks, then 
850 mg p.o. b.i.d. for months 2-12 
 
 
 
 
 
 
 
At 12 months (+/- 30 days), all patients will undergo repeat RPFNA2 and all patients will be unblinded. 
Patients randomized to metformin will continue metformin; and patients randomized to placebo may opt to 
crossover to metformin or discontinue protocol treatment. See Section 7.3. 
 
 
 
 
 
 
Continue Metformin 
850 mg p.o. b.i.d. for months 13-24 
 
Crossover to Metformin 
850 mg  p.o. daily for 4 weeks, then 
850 mg p.o. b.i.d. for months 14-24 
 
Discontinue 
protocol 
treatment* 
 
 
 
 
 
 
RPFNA2 at 24 months (+/- 30 days)  
RPFNA is optional for patients who were randomized to placebo and opted not to cross 
over to metformin treatment. 
 
 
 
 
 
Observation3 
 
 
*     Placebo is discontinued; however, assessments continue per protocol. 
1 
For patients undergoing initial RPFNA at surgery, only the unaffected/non-operated breast should be aspirated. 
This applies to patients undergoing surgery for DCIS and/or any atypical lesions. Only the contralateral breast 
can be aspirated in patients with DCIS. Aspiration of the unaffected breast is at the discretion of the subject’s 
treating surgeon. 
2 
Only the breast(s) originally aspirated prior to randomization will undergo follow-up RPFNA.  
3 
Follow up visits will be performed at 36 and 48 months after the start of treatment. 
 
Serum and whole blood samples for mandatory correlative science studies will be collected prior to 
treatment, and at 6, 12, and 24 months (see Section 14.0).  
 
Site RPFNA Credentialing: Sites must either have been previously approved for participation in 
CALGB 70806 or routinely perform RPFNA (> 10 RPFNA per year); OR undergo RPFNA training (see 
Section 6.2.5). 
 
Please refer to the full protocol text for eligibility criteria and a complete description of the 
treatment plan. 
 
 
 

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Table of Contents 
1.0 
BACKGROUND ............................................................................................................................. 7 
1.1 
Background .................................................................................................................................................. 7 
1.2  
Rationale ...................................................................................................................................................... 7 
1.3 
Feasibility and Preliminary Studies .............................................................................................................. 8 
2.0 
OBJECTIVES ............................................................................................................................... 12 
2.1 
Primary objective ....................................................................................................................................... 12 
2.2 
Secondary objectives .................................................................................................................................. 12 
2.3 
Correlative Research .................................................................................................................................. 12 
3.0 
PATIENT ELIGIBILITY ............................................................................................................ 13 
3.1 
Pre-registration - Inclusion Criteria ............................................................................................................ 13 
3.2 
Pre-registration Exclusion Criteria ............................................................................................................. 14 
3.3 
Registration/Randomization Inclusion Criteria .......................................................................................... 15 
4.0 
TEST SCHEDULE ....................................................................................................................... 16 
5.0 
DATA SUBMISSION ................................................................................................................... 17 
5.1 
Data Collection and Submission ................................................................................................................ 17 
6.0 
PRE-REGISTRATION AND REGISTRATION/RANDOMIZATION PROCEDURES ..... 18 
6.1 
CTEP Investigator Registration ................................................................................................................. 18 
6.2 
Cancer Trials Support Unit Site Registration Procedures .......................................................................... 19 
6.3 
Patient Registration Requirements ............................................................................................................. 22 
6.4 
Patient pre-registration (Step 0) procedures ............................................................................................... 22 
6.5 
Central review of RPFNA samples ............................................................................................................ 23 
6.6 
Registration/Randomization (step 1) procedures ....................................................................................... 23 
6.7 
Stratification factors ................................................................................................................................... 24 
6.8 
Procedures for Double-Blinding the Treatment Assignment ..................................................................... 24 
6.9 
Open-label and crossover re-registration (step 2) procedures .................................................................... 25 
7.0 
PROTOCOL TREATMENT ....................................................................................................... 26 
7.1 
Treatment Schedule .................................................................................................................................... 26 
7.2 
Patient Monitoring ..................................................................................................................................... 26 
7.3 
Crossover ................................................................................................................................................... 27 
7.4 
Emergency unblinding ............................................................................................................................... 27 
8.0 
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS ............................................. 28 
8.1 
Summary .................................................................................................................................................... 28 
8.2 
Dose modifications..................................................................................................................................... 28 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE ............................................................... 29 
10.0 
ADVERSE EVENT (AE) REPORTING AND MONITORING .............................................. 30 
10.1 
Adverse Event Characteristics ................................................................................................................... 30 
10.2  
Expected vs. Unexpected Adverse Events (AEs) ....................................................................................... 30 
10.3 
Assessment of Attribution .......................................................................................................................... 31 
10.4 
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: ............................... 32 
10.5  
Other Required Event Reporting ................................................................................................................ 34 
11.0 
TREATMENT EVALUATION ................................................................................................... 35 
11.1 
Primary endpoint ........................................................................................................................................ 35 

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11.2 
Secondary endpoints .................................................................................................................................. 35 
12.0 
DESCRIPTIVE FACTORS ......................................................................................................... 35 
13.0 
TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT .................... 36 
13.1 
Discontinuation due to side effects ............................................................................................................ 36 
13.2 
Diagnosis of breast cancer ......................................................................................................................... 36 
13.3 
Pregnancy ................................................................................................................................................... 36 
13.4 
Ineligible patients ....................................................................................................................................... 36 
13.5 
Protocol deviations ..................................................................................................................................... 36 
13.6 
Cancellations .............................................................................................................................................. 36 
13.7 
Tamoxifen, raloxifene, pyrimethamine, cimetidine, rifampin and cephalexin ........................................... 36 
14.0 
CORRELATIVE STUDIES ......................................................................................................... 37 
14.1 
Summary .................................................................................................................................................... 37 
14.2 
Biospecimen Kits ....................................................................................................................................... 38 
14.3 
Research Biospecimen Collection and Processing ..................................................................................... 38 
14.4 
Biospecimen Submission Using the Alliance Specimen Tracking System ................................................ 40 
14.5 
Biospecimen Shipment ............................................................................................................................... 40 
14.6 
Correlative Study Methodology and Biospecimen Use/Storage Information ............................................ 41 
14.7 
Return of Genetic Testing Research Results .............................................................................................. 45 
15.0 
DRUG INFORMATION .............................................................................................................. 46 
15.1 
Metformin hydrochloride tablets ................................................................................................................ 46 
15.2 
Placebo ....................................................................................................................................................... 48 
16.0 
STATISTICAL CONSIDERATIONS AND METHODOLOGY ............................................. 48 
16.1 
Study Design .............................................................................................................................................. 48 
16.2 
Statistical Analysis and Power Calculation ................................................................................................ 49 
16.3 
Study Monitoring ....................................................................................................................................... 52 
16.4 
Inclusion of women and minorities ............................................................................................................ 53 
17.0 
PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS .......................................... 53 
18.0 
BUDGET ........................................................................................................................................ 53 
19.0 
REFERENCES .............................................................................................................................. 54 
APPENDIX I: MODEL CONSENT FORM .......................................................................................... 58 
APPENDIX II: STANDARD OPERATING PROCEDURE FOR RPFNA ........................................ 75 
APPENDIX III: PATIENT MEDICATION DIARY ............................................................................ 78 
APPENDIX IV: NURSE/CRA PHONE CONTACT GUIDE ............................................................... 79 
APPENDIX V: FOLLOW-UP RPFNA PHONE CONTACT .............................................................. 80 
APPENDIX VI: IND EXEMPTION LETTER ...................................................................................... 81 
APPENDIX VII: SINGLE QUESTION – PATIENT-REPORTED KNOWLEDGE OF THE ARM 
TO WHICH THEY WERE RANDOMLY ASSIGNED BEFORE UNBLINDING OF THE STUDY 
AGENT ...................................................................................................................................................... 85 
 
 
 

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1.0 
BACKGROUND 
 
1.1 
Background 
There is a need for alternative prevention strategies with acceptable toxicities. Tamoxifen (Tam) 
is currently standard of care for breast cancer prevention in women with atypia. While there are 
clear benefits to Tam, Tam does not prevent estrogen receptor-negative (ER-) breast cancer and 
only prevents half of ER (+) breast cancer1, 2.  Additional interventions are needed to prevent ER 
(-) breast cancer.  
We have performed over 3,000 RPFNA and have not found a RPFNA that was suspicious for 
cancer (unless we already knew that the woman was being evaluated via a surgical work up for 
suspected cancer). We include a detailed description of information that is communicated to 
women undergoing RPFNA regarding their cytology results (see Section 14.6.1.2). Women are 
told that this RPFNA is an investigational protocol. If findings are found that are suspicious for 
cancer the woman will have a clinical breast examination, mammogram, and, if clinically 
appropriate, breast magnetic resonance imaging. 
1.2  
Rationale 
1.2.1 Evidence for Metformin from Population and Clinical Studies 
Metformin (1,1-dimethylbiguanide hydrochloride) is a well-tolerated biguanide currently 
undergoing testing for secondary breast cancer prevention in women with prior breast 
cancer. Metformin belongs to a biguanide class of oral hypoglycemic agents and prescribed 
to over 120 million Type II diabetic patients worldwide, with an excellent safety profile.  
Recently published population studies suggest that metformin decreases the incidence of 
cancer and cancer-related mortality in diabetic patients3-17. Other clinical and epidemiologic 
evidence links hyperinsulinemia and insulin resistance to increased mitogenic effects and 
thus to increased risk of several cancers, in addition to leading to poor breast cancer 
outcomes. In addition, it is also hypothesized that insulin can promote tumorigenesis via a 
direct effect on epithelial tissues, or indirectly by affecting the levels of other modulators, 
such as insulin-like growth factors, sex hormones, and adipokines.   In a limited retrospective 
study of patients who received neoadjuvant chemotherapy for breast cancer showed that 
diabetic cancer patients receiving metformin during neoadjuvant chemotherapy had a higher 
pathological complete response rate than diabetic patients not receiving metformin (24% 
versus 8%, p = 0.007) providing evidence for the potential role of metformin as an 
antineoplastic agent for breast cancer10.  
1.2.2 Evidence for Metformin from in vitro and preclinical studies  
The antineoplastic effects of metformin in breast cancer are supported by its modulation of 
signaling keynodes associated with breast cancer9-17. Several lines of evidence demonstrate 
that metformin inhibits the growth of tumor cells, including breast cancer cells. In the liver, 
Metformin inhibits transcription of key gluconeogenesis genes and increases glucose uptake 
in skeletal muscle. It reduces levels of circulating glucose, increases insulin sensitivity, and 
reduces insulin resistance-associated hyperinsulinemia. There is evidence that metformin 
exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial 
respiratory chain16. At the level of cell signaling, several mechanisms of metformin action 
have been proposed; the most important one relates to the activation of AMPK. Metformin 
regulates the AMPK/mTOR pathway. Work by Zakikhani, et al. demonstrated that 
Metformin inhibits the growth of breast cancer cells in an AMPK-dependent manner17. 
Several tumor suppressors are involved in the AMPK signaling network and activated 
AMPK results in suppression of cell proliferation in normal and tumor cells9-17. The growth 

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inhibition was associated with decreased mTOR activation and a general decrease in mRNA 
translation. Given the potential complexity of metformin, it is important to design 
biomarkers to evaluate the full range of metformin’s downstream signaling targets. 
1.3 
Feasibility and Preliminary Studies 
1.3.1 Random Periareolar Fine Needle Aspiration (RPFNA) 
RPFNA is a research technique developed to test for early cytological changes in women 
who are at high-risk for developing breast cancer18-20. RPFNA has been prospectively 
validated in high-risk women to test for 1) short-term breast cancer risk and 2) response to 
chemoprevention18-20. The presence of atypia in RPFNA predicts a 5-6-fold independent 
increase in breast cancer risk in high-risk women. These observations support the use of 
cellular atypia in RPFNA as an independent surrogate marker of short-term breast cancer 
risk in high-risk women19.   
1.3.2 CALGB RPFNA Study 
There is increasing acceptance of RPFNA. The Cancer and Leukemia Group B (CALGB) 
Prevention Group tested the reproducibility of RPFNA in a multi-institutional cross-
sectional study21. Sixty-three high-risk women from five CALGB institutions (Duke, Ohio 
State, Roswell Park, Dana Farber, and Vermont) underwent RPFNA.  Duplicate bilateral 
RPFNA was performed on each woman by a single investigator on a single day. Masood 
Cytology Index score was assessed by a single blinded cytopathologist.  We observed a high 
degree of statistical agreement in the Masood Cytology Index scores of duplicate RPFNA 
samples from the same breast, with a Spearman correlation coefficient of 0.8312 
(p<0.0001)21. Our multi-institutional study demonstrates that RPFNA is a reproducible 
measure of breast cytology in a cooperative group cross-sectional trial.  RPFNA did not 
demonstrate a high degree of agreement between breasts, suggesting that breast cancer risk 
and progression may occur at different rates in individual breasts from a single woman. 
These studies provide proof-of-principle for future RPFNA-based studies. 
1.3.3 RPFNA and Response to Tam Prevention 
In a single institution Pilot and Feasibility analysis at Duke University we tested for 
persistent atypia in a heterogeneous collection of 40 high-risk women who took Tam 
prevention. Women underwent RPFNA before and after Tam chemoprevention 
administered at 20 mg/day.  The presence or absence of atypia was measured by a single 
blinded cytopathologist using a 1) five point qualitative descriptor (normal, hyperplasia, 
atypia, suspicious, cancer) and 2) a numeric scoring system, the Masood Cytology Score 
Index. After 12 months of Tam, approximately half of the women had persistent cytological 
atypia in their RPFNA aspirate and half had disappearance of cytological atypia. RPFNA 
was performed at 18 and 24 months; no woman who had persistent atypia at 12 months had 
disappearance of atypia at 18 and 24 months. 
1.3.4 High Through-Put Reverse Phase Protein Microarray of RPFNA 
Reverse Phase Protein Microarray (RPPM) profiling of RPFNA cytology is able to detect 
protein phosphorylation patterning in 10,000 micro-dissected epithelial cells22-31.  In our 
published studies31,32, RPPM profiling of RPFNA cytology was tested in 5,000 micro 
dissected epithelial cells in duplicate. Each array was scanned; spot intensity was analyzed; 
data were normalized; and a standardized, single data value was generated for each sample 
on the array (Image Quant v5.2). Spot intensity was integrated over a fixed area. Local area 
background intensity was calculated for each spot with the unprinted adjacent slide 
background.  

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1.3.5 RPPM analysis of RPFNA cytology 
In a single institution study at Duke University, we tested for the reproducibility of RPPM 
measurements for 53 individual proteins in quadruplicate. RPFNA samples from two 
independent test sets of 38 and 39 high-risk women. Importantly, there was a high level of 
community participation in this trial. Of the 77 women enrolled in this trial, 45% (35/77) of 
women in this trial were African American. Five thousand epithelial cells were 
Microdissected, solubilized, and tested by RPPM. Duplicate samples were prepared from 
micro dissection of paired RPFNA aspirates. Fifty of 53 proteins tested by RPPM had an 
interclass correlation coefficient of agreement of >0.80. These 50 proteins included EGFR, 
EGFR-pTyr992, EGFR-pTyr1148, ErbB2, ErbB2-pTyr1248, ErbB3, ErbB3-pTyr1289, 
IGF1R, ER, ER-pSer118, IRS1-pSer612, MEK-pSer217/221, ERK-pThr202/Tyr204, 
HIF1, VEGF, GSK3, AKT-pSer473, mTOR-Ser2448, 4EBP1-pThr37/46, eIF4G-
pSer209, 70S6K-pThr412, FKHR-pSer256, IKB-pSer32-36, NFκB(p65)-pSer536, Bad-
pSer136, Bcl2-pSer70, 14-3-3-ζ, p38MAPK, p90RSK, PTEN-pSer380, p53, p21, Stat3, 
Stat5, Src-pTyr416, Fak-pTyr576, paxillin, catenin-pThr42/Ser41, Snail-1, vimentin, E-
cadherin, pACC-pSer79, and IRS1-pSer61231.  
Three high-intensity ER(-) clusters were identified: 1) Cluster #1 activated 
Akt/mTOR/insulin/Stat3/vimentin: AKTpSer473, mTORpSer2448, 4EBP1pThr37/46, 
eIF4GpSer209, 70S6KpThr412, p38MAPK, p90RSK, 14-3-3, Src-pTyr416, Fak-pTyr576, 
Stat3-pTyr694, Stat3-pSer727, vimentin, ACC-pSer79, and IRS1-pSer612. 2) Cluster #2 
activated 
EGFR/MEK/ERK:EGFR, 
EGFRpTyr1068, 
MEKpSer217/221, 
ERKpThr202/Tyr204, HIF1, VEGF, GSK3-pTyr279/216, catenin-pThr42/Ser41. 3) 
Cluster #3 mitochondrial survival proteins Bad, Bad-pSer137, Bcl2-pSer270, Bax, Bcl-xl, 
PTEN-Ser137.  
These data demonstrate our ability to test for phosphoprotein expression in mammary 
cytology from high-risk women. We also provide evidence for our ability to recruit African 
American women to RPFNA trials.  The ability to associate RPFNA cytology with RPPM 
in a longitudinal study will lead to increased understanding of signaling pathways activated 
during breast cancer initiation. 
1.3.6 Rationale for Metformin Dose 
Our rationale for dose selection was to maximize bioavailability and the opportunity to 
observe efficacy for this new indication, while minimizing toxicity and adverse events in 
this cohort, based on earlier studies where metformin was used in other indications and age 
groups.   
There is evidence that the use of metformin in individuals with “normal” insulin levels 
appears to be safe and it reduces insulin levels. Studies by Goodwin et al. show that in breast 
cancer patients given metformin (1500 mg/day), the mean baseline fasting insulin level was 
in the “normal” range (75.7 pmol/L) and only one woman had an insulin level above 140 
pmol/L (the level was 150 pmol/L)10. Insulin levels were reduced by 22% without the 
occurrence of hypoglycemia10. Similar safety and insulin-lowering effects of metformin 
have been reported in non-diabetic, non-breast cancer subjects with normal insulin levels.  
In a recent study of polycystic ovary syndrome (PCOS)53, metformin (2250 mg/day) 
lowered fasting insulin levels by 18% from a mean baseline insulin of 64.5 pmol/L in women 
in the lowest quartile of baseline insulin (greater reductions were seen in women with insulin 
levels markedly above normal). Similar results in PCOS subjects were reported by 
Roumaldi54 (mean baseline fasting insulin 47.0 pmol/L, 15% reduction after metformin at a 
low dose of 1000 mg/day for 6 months). Based on these observations, we anticipate that 
metformin will safely lower insulin levels but not promote significant hypoglycemia. 

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There is clinical evidence that fasting insulin levels are associated with poor breast cancer 
outcomes4,6. We have chosen a dose of metformin for breast cancer prevention that mirrors 
MA-32, an ongoing adjuvant multicenter trial of metformin vs. placebo in women with 
breast cancer. At the dose we propose Metformin safely lowers insulin levels by about 20% 
in 1) non-diabetic women with breast cancer and 2) women without cancer who have 
baseline fasting insulin levels in the normal range10,53,54. Evidence in observational, non-
interventional trials suggests that metformin use in diabetics may reduce cancer risk and 
mortality in women receiving chemotherapy for breast cancer7,10,11. We hypothesize that the 
dose of metformin we propose will reduce breast cancer risk through its secondary targeting 
of insulin/Complex 1 and primary targeting of AMPK/Akt/mTOR. 
There is growing evidence that metformin exerts an insulin independent effect on breast 
cancer via activation of an insulin independent 1) AMPK-dependent energy stress 
response7,17 and 2) PI3K/Akt/mTOR. The existence of this direct (non-insulin dependent) 
metformin’s effect on AMPK/mTOR14 provides justification for inclusion of women with a 
broad range of insulin levels in rather than limiting enrolment to those with insulin levels 
above an arbitrarily chosen cut-point. Because metformin is a readily available, inexpensive 
oral agent, with known (and easily manageable) toxicities, we believe evaluation of its 
ability to prevent breast cancer will be feasible as well as tolerated. 
1.3.7 Summary of Feasibility Data and Significance 
Ultimately, the most effective way to reduce breast cancer mortality is to prevent breast 
cancer. Here we aim to conduct prevention trials using biomarker-guided efficacy 
evaluation with an agent that targets signaling pathway that is known to be activated in ER- 
breast cancer.  Metformin is a well-tolerated, inexpensive, oral hypoglycemic agent and 
prescribed to over 120 million Type II diabetic patients worldwide, and is safe in pregnancy. 
While metformin is undergoing pilot clinical testing in women with breast cancer, 
metformin’s mechanism of action is poorly understood.  It is known that metformin targets 
Akt/mTor, AMPK, and promotes a secondary reduction in mitochondrial complex 1 and 
insulin signaling9-17. However, there is also evidence that metformin may also target NFB 
and IL6. Given the potential complexity of metformin, we need to be able to precisely track 
signaling pathways targeted by metformin prevention. 
We have developed the scientific framework, biomarkers, and strategies to test the ability 
of targeted agents to eliminate cytologic atypia in high-risk women. Using our combined 
proteomic/tracking tools we can directly test in an individual woman 1) for activated 
signaling pathways, 2) whether the prevention agent eliminates cytologic atypia, and 3) if 
not, we can then identify additional signaling pathways that can be targeted.  The ability to 
test whether a prevention drug is working in an individual woman allows us to rapidly 
deliver targeted prevention tailored to an individual woman.  
1.3.8 Proposed Study Overview  
Premenopausal women at elevated risk for the development of breast cancer by either family 
history, a Gail risk greater than or equal to 1.66%, or a prior biopsy containing atypical 
lobular hyperplasia, atypical ductal hyperplasia, lobular carcinoma in situ, (LCIS) or ductal 
carcinoma in situ (DCIS) will be considered for RPFNA. RPFNA can be performed in the 
operating room at the time of surgical excision. Women are required to have atypia on 
RPFNA of non-radiated breast tissue (Masood Cytology Index Score 14-17). Women who 
are eligible to take tamoxifen must be offered tamoxifen prevention as part of their clinical 
care and have refused tamoxifen chemoprevention. Women will be randomized to receive 
RPFNA and metformin or RPFNA and placebo control.  

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We propose to test RPFNA at 0, 12, and 24 months (RPFNA at 24 months for the placebo-
only group is optional for patients who remain on placebo arm and will not receive 
metformin) on both right and left breasts after metformin 850 mg p.o. b.i.d. versus placebo 
control for the 1) presence or absence of atypia or 2) changes in the Masood Cytology Index 
Score. These determinations will test for the presence or absence of cytological atypia in 
RPFNA before and after metformin administration and be compared with women who take 
placebo (control subjects). These studies will also serve as proof of principle for the 1) use 
of RPFNA to test for the presence or absence of atypia before, during, and after the 
administration of a prevention agent and 2) utility of cytological atypia in RPFNA to serve 
as a surrogate biological endpoint in a multi-institutional cross sectional trial. As a 
secondary objective, we will test the reproducibility of RPPM in duplicate RPPM 
determinations in a single RPFNA specimen. We will test for the presence of atypia after 
metformin or placebo; the presence of atypia means any atypia on RPFNA. 
 
 

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2.0 
OBJECTIVES 
2.1 
Primary objective 
Test for the presence or absence of cytological atypia (as measured by a Masood Cytology Index 
Score of 14-17) in unilateral or bilateral RPFNA aspirates after 12 and 24 months (24 month is 
optional for placebo-only group for patients who remain on placebo arm and will not receive 
metformin) for women receiving metformin versus placebo control.  The presence of cytological 
atypia means any atypia in any RPFNA specimen. 
2.2 
Secondary objectives 
2.2.1 Use the Masood Cytology Index Score to test for the presence of cytological atypia or 
disappearance of cytological atypia in RPFNA aspirates after 12 months for both arms, and 
24 months (24 month is optional for placebo-only group for patients who remain on placebo 
arm and will not receive metformin, and mandatory for crossover patients) for women 
receiving metformin 850 mg p.o. bid (metformin group). 
2.2.2 Compare Masood Cytology Score values at 0 and 12 months in right and left breasts (if both 
breasts were aspirated) from the same individual in the metformin and placebo group. 
2.2.3 Test the reproducibility of RPPM in duplicate RPPM determinations from individual 
RPFNA specimens. 
2.2.4 Correlate baseline RPPM values with presence of atypia (as measured by Masood Cytology 
Index Score) at month 12 and month 24 (month 24 optional for placebo-only group; for 
patients who remain on placebo arm and will not receive metformin) RPFNA. 
2.3 
Correlative Research 
2.3.1 Test whether metformin alters RPFNA or blood biomarkers associated with breast cancer 
risk.  Surrogate biomarkers of breast cancer risk include the following: 
• 
Atypia - surrogate endpoint biomarker and risk biomarker 
• 
Phosphoprotein expression – exploratory biomarker 
• 
Circulating insulin growth factor (IGF) - surrogate biomarker and risk biomarker  
2.3.2 Test whether metformin alters markers associated with obesity and insulin resistance.  
Markers of obesity and insulin resistance include the following: 
• 
Waist to hip ratio 
• 
Fasting serum insulin, fasting serum glucose 
• 
Hemoglobin A1C (HgbA1c) 
2.3.3 Test other exploratory measures in RPFNA and serum including the following: 
• 
Metformin levels 
• 
Estrogen/Progesterone. 
2.3.4 Banking 
As part of ongoing research for Alliance Cancer Control studies, we are banking residual 
blood and RPFNA products for future studies. 

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13 
3.0 
PATIENT ELIGIBILITY 
3.1 
Pre-registration - Inclusion Criteria 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. 
It is not required to complete or submit the following page(s). 
___ 
3.1.1 
Must be at increased risk for breast cancer, defined as at least one of the following 
four criteria: 
a. Having had a prior biopsy demonstrating atypical hyperplasia, lobular carcinoma in 
situ (LCIS), or ductal carcinoma in situ (DCIS). 
b. A Gail Model Risk of >1.66% over 5 years. 
c. A strong family history of breast and/or ovarian cancer which is defined as at least one 
of the following: 
• 
One first-degree relative with breast cancer before the age of 50 years 
• 
One first degree relative with bilateral breast cancer  
• 
Two or more first-degree relatives with breast cancer 
• 
One first degree relative and two or more second or third degree relatives with 
breast cancer 
• 
One first-degree relative with breast cancer and one or more relatives with ovarian 
cancer 
• 
Two second or third degree relatives with either breast cancer and one or more 
with ovarian cancer 
• 
One second or third degree relative with breast cancer and two or more with 
ovarian cancer 
• 
Three or more second or third degree relatives with breast cancer 
d. Known BRCA1 or BRCA2 mutation carrier providing that the woman has 1) met with 
a Genetic Counselor to review genetic testing results, and 2) has been offered the 
opportunity to undergo prophylactic mastectomy and oophorectomy. 
___ 
3.1.2 
Age 25-55 years. 
___ 
3.1.3 
Pre-menopausal women as defined as four menstrual cycles within the last six months 
prior to pre-registration. Women with less than 4 menses within 6 months prior to pre-
registration, or women who have had a hysterectomy with ovaries intact will be considered 
premenopausal if FSH level is < 20.  Women who are using hormonal contraceptives that 
cause amenorrhea (e.g. injectable and extended oral contraceptives, hormone containing 
contraceptive ring, or hormone containing intrauterine device) will be considered eligible 
if they had a minimum of 4 menstrual cycles within the last six months prior to starting on 
the contraceptive. 
___ 
3.1.4 
Digital mammogram within 365 days prior to pre-registration. 
___ 
3.1.5 
Mammograms must be read as not suspicious for breast cancer (ACR Class I-III). 
Subjects with a class IV mammogram may be enrolled once they have been evaluated by 
a breast surgeon and there is no evidence of invasive malignancy. 
___ 
3.1.6 
Must be non-lactating for at least one year prior to pre-registration. 
___ 
3.1.7 
If currently menstruating, subjects must use a reliable method of birth control. 
___ 
3.1.8 
Willing to provide RPFNA and blood samples for correlative research purposes (see 
Section 6.0 and 14.0). 

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3.2 
Pre-registration Exclusion Criteria 
___ 
3.2.1 
Other active malignancy ≤5 years prior to pre-registration.  EXCEPTIONS: Non-
melanotic skin cancer or carcinoma-in-situ of the cervix.  NOTE: If there is a history or 
prior malignancy, they must not be receiving other specific treatment, i.e., other hormonal 
therapy, for their cancer. 
___ 
3.2.2 
BMI < 25. 
___ 
3.2.3 
Receiving warfarin. 
___ 
3.2.4 
Bilateral breast implants or autologous breast flap reconstruction. 
___ 
3.2.5 
Active diagnosis of alcoholism 
___ 
3.2.6 
Contraindication to metformin prevention such as acute hypersensitivity or allergic 
reaction to metformin. 
___ 
3.2.7 
Currently receiving tamoxifen or raloxifene. 
___ 
3.2.8 
Administration of any investigational agent  30 days prior to pre-registration. 
___ 
3.2.9 
Previous radiation to both breasts. 
___ 
3.2.10 Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment 
of the investigator, would make the patient inappropriate for entry into this study or 
interfere significantly with the proper assessment of safety and toxicity of the prescribed 
regimens. 
___ 
3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
___ 
3.2.12 Receiving pyrimethamine, cimetidine, rifampin or cephalexin. 
___ 
3.2.13 Women who have a core biopsy or excisional biopsy containing invasive cancer. 
___ 
3.2.14 Women who have taken metformin within the past 90 days. 
___ 
3.2.15 Patients with hemoglobin a1c > 6.3 or who are being actively treated for diabetes. 
 
 

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3.3 
Registration/Randomization Inclusion Criteria 
___ 
3.3.1 
Qualifying cytological atypia in RPFNA, Masood score of 14-17. 
The qualifying RPFNA (of one or both breasts) must be sent to 
laboratory 
for cytological scoring and proteomic analysis. Score results must be received from 
 
lab prior to patient registration/randomization. Test must be done ≤ 120 
days prior to registration/randomization. 
Note: Only the contralateral breast can be aspirated in women with DCIS and those 
undergoing surgery for an atypical lesion. The decision to aspirate the contralateral breast 
is at the discretion of the woman’s surgeon. 
___ 
3.3.2 
The 
following 
laboratory 
values 
obtained 
 
30 
days 
prior 
to 
registration/randomization: 
• 
Hemoglobin  9 g/dL. 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count  75,000/mm3  
• 
Creatinine  1.4 mg/dL  
• 
Total bilirubin  3.0 mg/dL  
• 
Aspartate transaminase (AST)  3 x upper limit of normal (ULN)  
• 
Alanine transaminase (ALT)  3 x ULN 
___ 
3.3.3 
Negative pregnancy test done ≤ 7 days prior to registration/randomization, for women of 
childbearing potential only. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone 
a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for 
at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 
consecutive months). 
___ 
3.3.4 
Women eligible to take tamoxifen must be offered tamoxifen prevention as part of 
their clinical care and have refused tamoxifen treatment. 
 
 
 

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4.0 
TEST SCHEDULE  
Tests and 
Procedures 
Active-Monitoring Phase 
≤ 60 days 
prior to 
Pre-
registration 
≤ 30 days 
prior to 
registration/ 
randomization 
During 4 
week 
ramp up* 
During 
treatment at 
6, 12, and 24 
months**† 
Observation 
at 36 and 48 
months† 
History and exam, 
performance status 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
Weight/BMI 
X 
 
 
X 
X 
Waist/Hip ratio 
X 
 
 
X 
X 
Pregnancy test 
 
X1 
 
 
 
Breast Exam 
X 
 
 
X 
X 
Mammogram  
X2 
 
 
 
 
RPFNAR 
 
X3, 8, 9 
 
X3, 4, 9 
 
Hematocrit, CBC with Diff 
 
X 
 
 
 
Na, K, BUN, Cr, AST, 
ALT, LDH, Bili 
 
X 
 
X 
X 
Hemoglobin a1c 
X 
 
 
X 
 
Glucose (fasting), insulin 
(fasting), 
 
X 
 
X 
X 
Adverse event assessment 
 
X 
X5 
X 
X 
Concomitant Medication  
X 
 
 
X 
X 
Patient Medication Diary 
(Appendix III) 
 
 
X6 
 
 
Nurse/CRA Phone Contact 
Guide (Appendix IV)  
 
 
X6 
 
 
Mandatory Research Blood 
Draw (see Section 14.0)R  
 
X7 
 
X7 
 
Patient-reported knowledge 
of the arm to which they 
were randomized 
 
 
 
X10 
 
* 
The ramp-up period occurs during the first 4 weeks of blinded treatment and during the first 4 weeks of open-label treatment 
for patients who cross over from placebo to metformin. 
** Prior to the 12-month clinic visit, the CRA must call the Alliance Registration Office (507-284-4130) to unblind the patient’s 
treatment assignment.  Patients who were receiving placebo are eligible to crossover to metformin treatment (see Section 6.8).  
† 
+/- 3 weeks for Month 6 visit; +/- 30 days for Month 12, 24, and 36 visits. 
1. 
For women of childbearing potential only.  Must be done 7 days prior to registration/randomization. 
2. 
Baseline mammogram must have been done within 365 days of pre-registration. Mammographic screening should be 
continued as part of the patient’s regular medical care. 
3. 
See Section 14.0 for information regarding available RPFNA kits and RPFNA sample submission instructions. See Appendix 
II for RPFNA collection instructions. Following RPFNA, submit the RPFNA Procedure Documentation Form, available at 
the Alliance and CTSU A211102 study-specific web pages. 
4. 
RPFNA at 12 months and 24 months ONLY. RPFNA at 24 months is optional for patients who were randomized to placebo 
and opted not to continue protocol treatment after 12 months. 
5. 
At completion of 4 week ramp-up (phone). 
6. 
The Patient Medication Diary will be provided for each patient for the ramp-up period. Telephone contact will be made with 
the patient at the end of the ramp up period to assess compliance and adverse events. 
7. 
Blood collections (EDTA whole blood and serum samples) must be collected Monday-Thursday ONLY. 
8. 
Pre-treatment RPFNA specimens must be submitted immediately following pre-registration (see Sections 6.6 and 14.0).  

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9. 
CRA or provider will make a follow-up phone call the day following the RPFNA to check in with the participant and review 
any side effects of the procedure (see Appendix V). 
10. The single question is to be completed at month 12, i.e. after the 1-year study intervention, but before the patient is unblinded 
to the study agents and before they crossover to metformin.  Patients who are beyond the 12-month intervention or off study 
at the time of this amendment should still be reached by the study coordinator – despite the patient already being unblinded to 
the study agents - via telephone to answer the single question or to coordinate a time for the patient to come in to complete 
the single question. 
R 
Research funded (see the A211102 funding sheet, available on the Alliance and CTSU web sites). 
 
5.0 
DATA SUBMISSION   
5.1 
Data Collection and Submission 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to 
 for registration types and 
documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata. To accept the invitation, site staff must either click on the link in the email or 
log in to iMedidata via the CTSU members’ website under Data Management > Rave Home 
and click to accept the invitation in the Tasks pane located in the upper right corner of the 
iMedidata screen. Site staff will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane 
located in the upper right corner of the iMedidata screen. If an eLearning is required for a study 
and has not yet been taken, the link to the eLearning will appear under the study name in the 
Studies pane located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC link 
will replace the eLearning link under the study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section at 
or 
by contacting the CTSU Help Desk at 
 

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5.1.1 Data Quality Portal  
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, generate 
reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and Total 
Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports 
modules are available to access details and reports of unanswered queries, delinquent forms, 
forms with current status and timeliness reports. Review the DQP modules on a regular basis 
to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link 
on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports 
modules. 
6.0 
PRE-REGISTRATION AND REGISTRATION/RANDOMIZATION PROCEDURES 
6.1 
CTEP Investigator Registration 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
 
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 

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19 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
 
 
GCP training 
✔ 
✔ 
✔ 
 
 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
 For questions, please contact the 
RCR Help Desk by email at 
 
6.2 
Cancer Trials Support Unit Site Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU Regulatory Support System 
(RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was previously open at 
the site under the local IRB. International sites should continue to submit Research Ethics Board 
(REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office 
using the Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 

Alliance A211102 
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• 
Local IRB documentation;  
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• 
Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
• 
Compliance with all protocol-specific requirements (PSRs). 
6.2.1 Downloading Site Registration Documents  
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting 
documents is restricted to institutions and its associated investigators and staff on a 
participating roster. To view/download site registration forms: 
• 
Log in to the CTSU members’ website (
) using your CTEP-
IAM username and password; 

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21 
• 
Click on Protocols in the upper left of the screen: 
o Enter the protocol number in the search field at the top of the protocol tree; 
or 
o Click on the By Lead Organization folder to expand, then select Alliance, 
and protocol number A211102. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration to download and complete the forms provided. 
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU.)  
6.2.2 Requirements for A211102 Site Registration  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
• 
Completed and signed 
 RPFNA Training Form (see Section 6.3.4) 
6.2.3 Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 
 
 in order to receive further instruction and support. 
6.2.4 Checking Site’s Registration Status  
Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go: 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
6.2.5 Site credentialing for RPFNA requirement 
6.2.5.1 Participating institutions must have a RPFNA Training Form (RTF) on file with 
CTSU. If this form has been previously submitted to CTSU it does not need to be 
resubmitted unless personnel updates have occurred at the enrolling site. This training 
form will be available on the Alliance and CTSU websites as a supporting document 
to the protocol. 
The completed RTF is to be sent by email to 
  
After receiving documentation of either previous approval to perform RPFNA (see 

Alliance A211102 
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22 
Section 6.2.5.2) or completion of training, 
will complete the signature 
line of the form and return it to the site.  Site staff will then submit the form to the 
CTSU Regulatory Portal per Section 6.2.3. 
6.2.5.2 Sites that either have been approved for participation in CALGB 70806 or routinely 
perform RPFNA (> 10 RPFNA per year) do not need to undergo RPFNA training and 
can indicate this on the RTF. 
6.2.5.3 RPFNA training 
For sites that wish to undergo RPFNA training, this can consist of either 1) video 
training and phone conferencing with 
 or, 2) on-site training at 
 
Contact information for training is: 
 
 
For sites that desire electronic training, there is a training video that can be sent and 
 can be available either by phone or email to answer questions and 
provide suggestions and feedback 
We have an on-site training program for any institution that is interested in performing 
RPFNA in the operating room and in the clinic. In our prior CALGB study testing of 
the reproducibility of RPFNA, all interested sites sent a team to Duke University for 
RPFNA training. Typically, teams sent for training included either a surgeon or a 
physician assistant/midlevel provider who was well skilled in breast procedures.  
6.3 
Patient Registration Requirements 
Informed consent: The patient must be aware of the neoplastic nature of her disease and 
willingly consent after being informed of the procedure to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Current 
human protection committee approval of this protocol and a consent form is required prior to 
patient consent and registration. 
Protected Health Information: RPFNA and whole blood collected for this study will be sent 
directly to City of Hope Hospital in California. These samples will be labeled with patient 
initials, study ID, and collection date. 
6.4 
Patient pre-registration (Step 0) procedures 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) 
for retrieval of patient registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 

Alliance A211102 
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To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient transfer 
in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB approval on their 
Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or NPIVR must be assigned 
the appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable).  
 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records.  
Access OPEN at 
or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
For any additional questions, contact the CTSU 
Help Desk at 
 
6.5 
Central review of RPFNA samples 
After pre-registration and prior to registration/randomization, RPFNA samples must be 
collected and shipped to 
 laboratory per Section 14.0 for determination of 
eligibility (cytological atypia defined as Masood score of 14-17). 
laboratory will 
report the results within 30 days (20 business days) from receipt of RPFNA specimens. The 
results, along with the cytology report, will be sent to the registering institution and the Alliance 
Pathology Coordinators at Mayo Clinic Rochester. The Alliance Pathology Coordinator will 
then go into the pre-approval application, mark the patient as approved or not approved. See 
Section 14.6.1 for an explanation of the cytology report.  
If approved, the patient may be registered and randomized to the study.  
Email Template (to be completed by 
 
Study Number: A211102 
Patient ID: 
Approved or Not approved: 
Site contact information: 
CRA/Study Coordinator’s name: 
Phone number: 
E-mail address: 
6.6 
Registration/Randomization (step 1) procedures 
6.6.1 All site staff will use OPEN to enroll patients to this study. OPEN can be accessed at 
or from the OPEN tab on the CTSU members’ side of the website at 
 Note: The OPEN system will provide the site with a printable 
confirmation of registration. Please print this confirmation for your records. 
6.6.2 Treatment on this protocol must commence at the accruing institution under the supervision 
of an Alliance member physician. 

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6.6.3 Study treatment cannot begin prior to registration/randomization and must begin 14 days 
after registration/randomization. 
6.6.4 Pre-treatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.6.5 All pre-treatment symptoms/conditions must be evaluated and documented at baseline (see 
Section 10.5.1). 
6.6.6 RPFNA results are available on site. 
Note: Once the above conditions have been met, access the OPEN website and follow the 
instructions for registration/randomization. 
6.6.7 Correlative Research: 
6.6.7.1 A mandatory correlative research component (i.e., RPFNA and blood samples) is part 
of this study for all patients, the patient will be automatically registered onto this 
component (see Sections 3, 4, and 14 of the protocol).  
6.6.7.2 Patient has/has not given permission for coded samples and related coded information 
to be kept for use in future research to learn about, prevent, or treat cancer. This may 
also include research on inherited traits (genes passed on in families). 
6.6.7.3 Patient has/has not given permission for coded samples and related coded information 
to be kept for use in future research to learn about, prevent, find or treat other health 
problems (for example: diabetes, Alzheimer’s disease, or heart disease). This may 
also include research on inherited traits (genes passed on in families). 
6.6.7.4 Patient has/has not given permission for someone from their hospital or the Alliance 
to contact them in the future to ask to take part in more research. 
6.7 
Stratification factors 
The stratification factors defined below will be used at the time of patient registration: 
• 
BRCA mutation (Yes vs. No mutation or unknown). 
• 
Prior abnormal excisional biopsy results (Yes vs. No or unknown). 
• 
Fasting baseline insulin: (Fasting insulin > 2x ULN vs. Fasting Insulin ≤ 2x ULN) 
After the patient has been registered to the study, the values of the stratification factors will be 
recorded.  The patient then will be assigned to one of the following treatment groups using the 
Pocock and Simon60 dynamic allocation procedure which balances the marginal distributions of 
the stratification factors between the treatment groups: 
• 
Metformin  
• 
Placebo 
6.8 
Procedures for Double-Blinding the Treatment Assignment 
After the treatment assignment has been ascertained in the OPEN application, the patient’s study 
medication code number will be displayed on the confirmation of registration screen.  If the code 
number is not displayed, contact the Registration Office at 
 
 
  
The number of the treatment bottle assigned to the patient will be recorded on the Treatment 
Form by institutional staff. 

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6.9 
Open-label and crossover re-registration (step 2) procedures 
At the time of the 12-month RPFNA visit, all patients will be unblinded per Section 7.3.  
All patients who were randomized to receive metformin will be re-registered and begin receiving 
open-label metformin as described below.  
Patients who were randomized to receive placebo and elect to cross over to open-label 
metformin therapy will be re-registered to receive open-label metformin as follows: 
Patient re-registration steps: 
• 
Log into the OPEN registration system and select the appropriate patient. 
• 
Select the next registration step. 
• 
Complete OPEN Enrollment Form for the patient to be registered to the open-label arm. 
• 
Enter Cycle # of the last treatment received during blinded treatment, as well as the 
stratification factors, on the OPEN Enrollment Form. 
• 
Once the open-label registration has been successfully completed confirmation will be 
displayed in OPEN. 
If assistance is needed with this process, contact the Alliance Registration Office. 
Following re-registration, open-label metformin should be ordered per Section 15.1.8. 
 
 

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7.0 
PROTOCOL TREATMENT 
7.1 
Treatment Schedule 
7.1.1 Months 1-12 
Agent 
Dose and Duration 
 
Metformin 
/Placebo 
 
850 mg (1 tablet) p.o. one a day for 4 weeks (ramp-up period),  
then 
850 mg (1 tablet) p.o. twice a day, (pending gastrointestinal toxicity 
evaluation) for months 2-12. 
7.1.2 Months 13-24 (See Section 7.3) 
For unblinded patients originally randomized to metformin: 
Agent 
Dose and Duration 
 
Metformin 
 
 
850mg (1 tablet) p.o. twice a day for months 13-24 
 
For unblinded patients originally randomized to placebo who choose to 
crossover to metformin: 
Agent 
Dose and Duration 
 
Metformin 
 
850 mg (1 tablet) p.o. one a day for 4 weeks (ramp-up period), then  
 
850 mg (1 tablet) p.o. twice a day, (pending gastrointestinal toxicity 
evaluation) for months 2-12. 
 
For unblinded patients originally randomized to placebo who choose not to 
crossover to metformin: 
Agent 
Dose and Duration 
 
None 
 
 
Months 13-24 
7.2 
Patient Monitoring 
A Patient Medication Diary will be provided for each patient for the ramp-up period and 
telephone contact will be made with the patient one month +/- 3 days after enrollment to assess 
compliance, toxicity, and to ensure the patient has increased medication to twice daily. (The 
diary is intended only as a tool to assist subjects in adjusting to full dose at the correct time after 
starting study treatment.) A record of the telephone contact will be made on the Nurse/CRA 
Phone Contact Guide (see Appendix IV). Any problems identified will be communicated to the 
responsible Investigator.  
Optimal medication compliance is defined as ≥ 80%. Patients found to be non-adherent with 
their medication will receive additional interventions by the treatment team to improve 
adherence (i.e., registered nurse phone calls as a first-line intervention and extra study visits will 
be scheduled if non-adherence is still noted at the next follow-up time point). 
 

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7.3 
Crossover 
During the first 12 months of treatment, patients will not be unblinded except in cases of 
emergencies (see Section 7.5)  
Prior to the patient’s 12 month clinic visit, the CRA must call the Alliance Registration Office 
to find out which study agent the patient is receiving.  
7.3.1 Patients who were receiving metformin will be re-registered to receive open-label 
metformin. 
7.3.2 Patients who were receiving placebo are eligible to cross over to metformin therapy.  
If the patient was receiving placebo, the CRA must contact her and ask her if she wishes to  
1) receive metformin 850 p.o. bid for 12 mos. (including 4-week ramp-up of 850 mg p.o. 
qd) or 
2) discontinue protocol therapy.  
If the patient wishes to crossover to metformin therapy, the CRA will then re-register the 
patient per Section 6.9 and to receive open label metformin, and the patient will be 
administered the drug as outlined in Section 7.1.2. 
Patient Monitoring: The Patient Medication Diary will be provided for each patient who 
crosses over from placebo to open-label metformin to be completed during the ramp-up 
period and telephone contact will be made with the patient one month +/- 3 days after 
crossover to assess compliance, toxicity, and to ensure the patient has increased medication 
to twice daily. (The diary is intended only as a tool to assist patients in adjusting to full dose 
at the correct time after starting study treatment.) A record of the telephone contact will be 
made on the Nurse/CRA Phone Contact Guide (see Appendix IV). Any problems identified 
will be communicated to the responsible Investigator.  
7.4 
Emergency unblinding 
Before the crossover at 12 months, unblinding may be done only in cases of an emergency. 
Follow the directions below to unblind patient treatment. Please note that if a treatment 
assignment is unblinded, the patient must discontinue protocol therapy. 
Emergency Unblinding Procedures: 
Examples of emergencies include 1) a life-threatening unexpected adverse event that is at least 
possibly related to the investigational agent and for which unblinding would influence treatment 
decisions; or 2) medication error, such as accidental overdose. Expected adverse events are listed 
in the “Toxicities” section below.  
Contact the Alliance Executive Officer on call by calling 
 
  
The institution must provide the following information to the Alliance Executive Officer:  
• 
Alliance study ID (“A211102”)  
• 
Alliance patient ID number (e.g., “999999”)  
• 
Patient initials (e.g., “L,FM”)  
• 
Institution name  
• 
Name and telephone number of treating physician  
• 
Name and contact information of person requesting the unblinding procedure  
• 
Name and contact information of person to inform of treatment assignment  
• 
Reason for emergency unblinding  

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Please remember that emergency unblinding request may be authorized only by an Alliance 
Executive Officer, and emergency unblinding applies only if unblinding would influence 
management of the medical situation.  
After the Executive Officer deems unblinding is warranted, the treatment assignment will be 
provided to the contact person at the treating site.   
8.0 
DOSAGE MODIFICATION BASED ON ADVERSE EVENTS 
8.1 
Summary 
The major toxic effects of metformin which limit dose are gastrointestinal (GI) (nausea, 
abdominal bloating, and diarrhea). Dose adjustments, for reasons of GI side effects, will be as 
in the tables below. (Please note that none of the recommended dose adjustments requires 
splitting of study medication pills. Pills are not to be split or crushed, prior to taking, for any 
reason.) Breaks of up to 4 weeks consecutively or 8 weeks overall are allowed to ascertain the 
cause of symptoms. Beyond this, treatment is at the discretion of the treating physician.   
8.2 
Dose modifications  
Strictly follow the modifications in this table, until individual treatment tolerance can be 
ascertained.  Thereafter, these modifications should be regarded as guidelines to define mild-to-
moderate, but not debilitating, side effects.  If multiple adverse events are seen, administer dose 
based on greatest reduction required for any single adverse event observed. Reductions or 
increases apply to treatment given in the preceding cycle and are based on adverse events 
observed since the prior dose. 
8.2.1 If the patient has grade 3 or 4 diarrhea, metformin/placebo should be discontinued. 
 
 

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8.2.2 Dose modification tables 
→ → Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENT 
Gastrointestinal 
disorders 
Grade 1 
 
Abdominal distension 
Bloating 
Diarrhea 
Nausea 
Vomiting 
Gastrointestinal 
disorders – Other, 
specify 
 
Metformin Patient should be encouraged to remain on 
full dose. If patient is unwilling, delay 
study treatment for one week.  
For subjects who were unwilling to remain 
on full dose, after one week without study 
drug, follow the ramp-up procedure. If 
Grade 1 symptoms persist or recur during 
the ramp-up or at full dose and the patient 
is 
unwilling 
to 
continue, 
follow 
instructions for Grade 2 toxicity.  
Gastrointestinal 
disorders  
≥ Grade 2 or higher 
 
Abdominal distension 
Bloating 
Diarrhea 
Nausea 
Vomiting 
Gastrointestinal 
disorders – Other, 
specify 
 
Metformin Reduce to one tablet per day for one week. 
If symptoms resolve or are Grade 1 only, 
after one week, resume full dose (2 tablets 
per day).  
If symptoms persist or recur at Grade 2 or 
higher, delay study treatment for 4 weeks, 
then resume study treatment as follows:  
Re-start study drug according to original 
ramp-up schedule (one tablet per day for 4 
weeks then one tablet twice a day if 
tolerated). If toxicity persists or recurs, the 
study drug should be adjusted to the 
maximum dose that is tolerated with Grade 
1 toxicity or lower. A second attempt to 
increase to full dose should be made 3 
months later and if the full dose is not 
tolerated at that time, the maximum 
tolerated dose should be used for the 
remainder of the 2-year (metformin group) 
or 1-year (Placebo crossover group) 
intervention. 
* 
Located at 
 
9.0 
ANCILLARY TREATMENT/SUPPORTIVE CARE  
This is a prevention trial. If the patient clinically requires hydration and hospitalization, all 
appropriate supportive measures should be used. 
 
 

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10.0 ADVERSE EVENT (AE) REPORTING AND MONITORING  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for expedited AE reporting. However, CTCAE v5.0 must be used for serious AE 
reporting through CTEP-AERS as of April 1, 2018.  All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
web 
site: 
  
10.1.1 Adverse event monitoring and reporting is a routine part of every clinical trial.  First, identify 
and grade the severity of the event using the CTCAE.  Next, determine whether the event is 
expected or unexpected (see Section 10.2) and if the adverse event is related to the medical 
treatment or procedure (see Section 10.3). With this information, determine whether the 
event must be reported as an expedited report (see Section 10.4).  Important: Expedited 
adverse event reporting requires submission of an Adverse Event Reporting System (CTEP-
AERS) report(s). Expedited reports are to be completed within the timeframes and via the 
mechanisms specified in Sections 10.4 and 10.5. The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for expedited AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the 
CTCAE 
version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
website: 
 
All 
AEs 
reported via expedited mechanisms must also be reported via the routine data reporting 
mechanisms defined by the protocol (see Sections 10.5 and the schedule of forms). 
10.1.2 Each CTCAE term in the current version is a unique representation of a specific event used for 
medical documentation and scientific analysis and is a single MedDRA Lowest Level Term 
(LLT).  Grade is an essential element of the guidelines and, in general, relates to severity for the 
purposes of regulatory reporting to NCI. 
• 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as serious 
AE which is defined in the table in Section 10.4. 
10.2  Expected vs. Unexpected Adverse Events (AEs)  
The determination of whether an AE is expected is based on agent-specific information provided 
in Section 15.0 of the protocol. 
Unexpected AEs are those not listed in the agent-specific information provided in Section 15.0 
of the protocol. 
NOTE: “Unexpected adverse events” means any adverse event that is identified in nature, 
severity, or frequency of risk in the information neither provided for IRB review nor mentioned 
in the consent form.  
 
 

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10.3 
Assessment of Attribution 
10.3.1 When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the drug 
and the adverse event.  
10.3.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
anomalies or birth defects, must be reported immediately if they occur at any time following 
treatment with an agent under an IND/IDE since they are considered to be a serious AE and 
must be reported to the sponsor as specified in 21 CFR 312.64(b). 
10.3.3 Death 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
• 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and administration 
site conditions.” Evidence that the death was a manifestation of underlying disease 
(e.g., radiological changes suggesting tumor growth or progression: clinical 
deterioration associated with a disease process) should be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an IND/IDE requires expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of possible, probable, or 
definite to an agent/intervention under an IND/IDE requires expedited reporting within 
24-hours. 
• 
Pregnancy loss: Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy loss” under 
the Pregnancy, puerperium and perinatal conditions SOC. A Pregnancy loss should 
NOT be reported as a Grade 5 event under the Pregnancy, puerperium and perinatal 
conditions SOC, as currently CTEP-AERS recognizes this event as a patient death. 
• 
Death Neonatal: A neonatal death should be reported expeditiously as Grade 4, “Death 
neonatal” under the General disorders and administration SOC. 
 
 
 

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10.4 
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
10.4.1 Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND/IDE 
trial within 30 Days of the Last Administration of a Commercial Agent 1, 2. 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
• 
Grade 1 
Timeframes 
• 
Grade 2 
Timeframes 
• 
Grade 3 
Timeframes 
• 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour; 
5 Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS ≤ 24 hours 
of learning of the AE, followed by a complete expedited report ≤ 5 calendar days of the 
initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted ≤ 10 
calendar days of learning of the AE. 
1 Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report ≤ 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs  
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  

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• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive 
half lives, rounded UP to the nearest whole day, after the agent/intervention was last administered.  
Footnote “1” above applies after this reporting period. 
Refer to Section 10.4.3 for NCI Contact Information or Technical Help regarding CTEP-AERS reporting.  

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10.4.2 Additional Instructions or Exceptions to Adverse Event Reporting System (CTEP-
AERS) Reporting Requirements:  
The Alliance SAE Coordinator will forward a copy of all CTEP-AERS reports to the 
Alliance IND Coordinator who will notify the FDA as warranted by the event and stipulated 
in the U.S. Code of Federal Regulations. 
In the rare event when internet connectivity is disrupted, a 24 hour notification must be made 
to NCI by telephone. An electronic report must be submitted immediately upon 
establishment of internet re-connection. 
10.4.3  Contact Information for NCI Safety Reporting: 
 
Website for submitting Adverse events 
(CTEP-AERS) 
 
 
CTEP-AERS MD Help Phone (for CTEP)* 
Monday through Friday, 7:00 AM to 7:00 PM  
(US Eastern Time) 
CIP Help Phone for SAE reporting* 
Monday through Friday, 7:00 AM to 7:00 PM  
(US Eastern Time) 
Fax for expedited report supporting Medical 
Documentation for CTEP trials 
 
Fax for expedited report supporting Medical 
Documentation for CIP trials 
 
CTEP-AERS MD Help Email: 
 
CIP SAE Reporting Email 
 
Technical (e.g., IT or computer issues ONLY) 
Help Phone* 
 
Practice application 
 
CTEP-AERS Technical Help Email 
  
CTCAE v5.0 Help/Questions Email 
 
CTEP-AERS Computer Based Training link 
 
* 
Office phone and fax are accessible 24 hrs per day 7 days a week (The CTEP-AERS MD phone 
line is staffed from Monday through Friday, 7:00 AM to 7:00 PM ET.  Any phone call after these 
hours will go to voicemail.  Please leave contact information and the phone call will be returned 
the following business day. 
10.5  Other Required Event Reporting 
Event Type 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events and/or Any 
Hospitalizations During Treatment Not 
Otherwise Warranting an Expedited 
Report 
Complete the Grade 4 or 5 Non-AER Reportable 
Events/Hospitalization Form electronically via the Remote Data 
Entry System within 5 working days of the date the Clinical 
Research Associate (CRA) is aware of the event(s) 
necessitating the form. 
If an CTEP-AERS report has been submitted, this form does not 
need to be submitted. 
 

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10.5.1 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to be 
evaluated at baseline per CTCAE v4.0 grading unless otherwise stated in the table below: 
System Organ Class 
(SOC) 
Adverse event 
 
Baseline 
Each 
evaluation 
Gastrointestinal disorders 
Abdominal distension 
X 
X 
 
Bloating 
X 
X 
 
Diarrhea 
X 
X 
 
Nausea 
X 
X 
 
Vomiting 
X 
X 
 
Gastrointestinal disorders – 
Other, specify 
X 
X 
 
Gastrointestinal disorders 
– Other, # of stools / day 
X 
 
10.5.2 Submit via appropriate Alliance Case Report Forms (i.e., paper or electronic, as applicable) 
the following AEs experienced by a patient and not specified in Section 10.5.1. 
10.5.2.1 Grade 2 AEs deemed possibly, probably, or definitely related to the study treatment 
or procedure. 
10.5.2.2 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
10.5.2.3  Grade 5 AEs (Deaths) 
• 
Any death within 30 days of the patient’s last study treatment or procedure   
regardless of attribution to the study treatment or procedure. 
• 
Any death more than 30 days after the patient’s last study treatment or procedure 
that is felt to be at least possibly treatment related must also be submitted as a Grade 
5 AE, with a CTCAE type and attribution assigned. 
10.5.3 Refer to the instructions in the Forms Packet (or electronic data entry screens, as applicable) 
regarding the submission of late occurring AEs following completion of the Active 
Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
11.0 TREATMENT EVALUATION 
Study outcomes are outlined in Section 16.0. 
11.1 
Primary endpoint 
As a primary endpoint we will test for the presence or absence of cytological atypia in RPFNA 
bilateral aspirates after 12 and 24 months (24 month is optional for placebo-only group for 
patients who remain on placebo arm and will not receive metformin) for women receiving 
metformin versus placebo control.  The presence of cytological atypia means any atypia in any 
RPFNA specimen. 
11.2 
Secondary endpoints 
As secondary endpoints we will compare Masood Cytology Score values at 0 and 12 months in 
right and left breasts from the same individual in the Metformin and placebo group, test the 
reproducibility of RPPM in duplicate RPPM determinations from individual RPFNA specimens. 
12.0 DESCRIPTIVE FACTORS 
None 

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13.0 TREATMENT/FOLLOW–UP DECISION AT EVALUATION OF PATIENT   
13.1 
Discontinuation due to side effects 
Patients who discontinue study medication before the completion of metformin due to side 
effects should still be followed per the test schedule for data collection time points. If the patient 
refuses, then the patient should be removed from study. Off Treatment Form must be submitted 
per the schedule of forms. 
13.2 
Diagnosis of breast cancer 
Upon the diagnosis of breast cancer the patient should undergo standard therapy for the 
treatment and removal of the cancer. The Off Treatment Form must be submitted per the 
schedule of forms and the patient will go directly to off treatment. 
13.3 
Pregnancy 
If a patient should become pregnant, the study medication will be discontinued and the patient 
should still be followed per the test schedule for data collection time points.  The Off Treatment 
Form must be submitted per the schedule of forms. 
13.4 
Ineligible patients 
A patient is deemed ineligible if after registration/randomization, it is determined that at the time 
of registration/randomization, the patient did not satisfy each and every eligibility criteria for 
study entry.   
• 
If the patient received treatment, all data up until the point of confirmation of ineligibility 
must be submitted. The Off Treatment Form must be submitted per the schedule of forms 
and the patient will go directly to off treatment. 
• 
If the patient never received treatment, on-study material must be submitted. 
13.5 
Protocol deviations 
A protocol deviation is deemed a major violation, if protocol requirements during the first month 
of therapy are so severely violated that evaluability for the primary end point is questionable.  
All data up until the point of confirmation of a major violation must be submitted. The Off 
Treatment Form must be submitted per the schedule of forms and the patient would be off 
treatment. 
13.6 
Cancellations  
A patient is deemed a cancel if she is removed from the study for any reason before any study 
treatment is given.  On-study material and the Off Treatment Form must be submitted and patient 
would be off treatment. The patient should be followed as required. 
13.7 
Tamoxifen, raloxifene, pyrimethamine, cimetidine, rifampin and cephalexin 
If the patient is found at any time during the study to be taking tamoxifen, raloxifene, 
pyrimethamine, cimetidine, rifampin or cephalexin the patient would go off treatment 
immediately. 
 
 

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14.0 CORRELATIVE STUDIES 
14.1 
Summary 
For all patients registered to Alliance A211102: The submission of the biomarkers and 
biospecimens listed in Table 14.1 is required for all patients registered/randomized to this 
study.  Rationale and methods for the scientific components of these studies are described in 
Section 14.6. 
Table 14.1 
Summary of Mandatory A211102 Biomarker/Biospecimen Collections for Correlative Studies 
Biomarker/ 
Biospecimen 
Mandatory 
Collection 
time point 
 
 
Correlative Studies 
Random 
Periareolar Fine 
Needle Aspiration 
(RPFNA) on both 
breasts1 
Prior to treatment* 
12 months 
24 months2 
• Atypia - surrogate endpoint biomarker and risk biomarker 
• Estrogen/Progesterone – exploratory biomarker 
• Phosphoprotein expression – exploratory biomarker 
(See Section 14.6.1 for additional information.) 
Research Serum 
 
Prior to treatment 
6 months 
12 months 
24 months 
• Insulin growth factor (IGF), estrogen, progesterone – 
Surrogate markers of breast cancer risk 
• Metformin levels (banked serum) – exploratory biomarker 
(See Section 14.6.2 for additional information.) 
Whole blood (for 
DNA/plasma 
White blood cells)  
Prior to treatment 
• White Blood Cell Complex 1 
• DNA imprinting 
• Pharmacogenomic studies 
 (See Section 14.6.3 for additional information.) 
Measures of 
Obesity and 
Insulin Resistance 
Prior to treatment 
6 months 
12 months 
24 months 
36 months 
48 months 
• BMI 
• Waist to hip ratio 
• Serum glucose (fasting) 3, insulin (fasting) 3– markers of 
obesity and insulin resistance 
(See Section 14.6.4 for additional information.) 
* 
Pretreatment RPFNA must be submitted immediately following pre-registration. 
1 
Note: Only the contralateral breast can be aspirated in women with DCIS and those undergoing surgery 
for an atypical lesion. 
2 
RPFNA at 24 months for patients who were randomized to placebo and opted not to continue protocol 
treatment after 12 months is optional. 
3 
These tests will be performed in the participating site’s clinical lab. 
 
 

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14.2 
Biospecimen Kits 
14.2.1 Participating institutions may obtain kits for RPFNA sample collection and submission by 
completing the RPFNA Supply Order Form (found on the A211102 page of the Alliance 
and CTSU Web sites) and emailing it to the email address listed on the form.  Fill out the 
site address to which the kits will be shipped on the form.  Because the Alliance is charged 
for all outgoing kits, a small, but sufficient supply of the specimen collection kits should be 
ordered prior to patient entry. 
14.2.2 Kits will be sent via FedEx® Ground at no additional cost to the participating institutions.  
Allow at least two weeks to receive the kits. Kits will not be sent via rush delivery service 
unless the participating institution provides their own FedEx® account number or alternate 
billing number for express service.  The Alliance will not cover the cost for rush delivery of 
kits.  
14.2.3 For sites that routinely perform RPFNAs and have materials available at their own 
institution, kit contents and instructions are provided in Appendix II. If you have any 
questions please call 
at the number(s) listed on the cover page of the protocol. 
14.2.4 No kits will be provided for the blood collections for this study. 
14.3 
Research Biospecimen Collection and Processing 
RPFNA and all blood collections (serum and EDTA whole blood samples) must be collected 
Monday-Thursday ONLY.  All samples (refrigerated RPFNA, frozen serum, and EDTA 
whole blood) must be shipped the same day they are collected.  
Research biospecimens will be collected and processed at the following time points for these 
studies: 
Table 14.3: Mandatory Research Biospecimens to Be Collected and Submitted for this Protocol 
Specimen to be 
submitted by 
participating 
site 
Processing 
required at site 
after specimen 
collection? 
Collection tube 
and color 
Prior to 
treatment 
Months 
Shipping conditions 
6 
12 
24 
RPFNA (both 
right and left 
breasts)3 
No 
10 mL modified  
Cytolyte in 15 mL 
conical tube (1 
tube per breast) 
X* 
 
X 
X1 
Styrofoam insulated 
box with 2-3 blue ice 
packs to 
 
Research 
Serum2 
Yes 
SST 
1 x 8.5 mL 
X 
X 
X 
X 
Frozen, Styrofoam 
insulated box with dry 
ice to OSU 
Research 
Serum2 
Yes 
Red top (no 
additive) 
2 x 10 mL 
1 x 5 mL 
X 
X 
X 
X 
Frozen, Styrofoam 
insulated box with dry 
ice to OSU 
Whole Blood2 
No 
EDTA 
(purple top) 
2 x 10 mL 
X 
 
 
 
Styrofoam insulated 
box with 2-3 blue ice 
packs to  
 
* 
Pretreatment RPFNA must be submitted immediately following pre-registration. 
1 
This RPFNA collection is optional for patients who were randomized to placebo and opted not to 
continue protocol treatment after 12 months. 
2 
Order of blood draw:  1) SST tube, 2) 3 red top no-additive tubes, and 3) two EDTA tubes last. 
3 
Only contralateral breast is to be aspirated for patients with DCIS or surgery for atypical lesion. 

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14.3.1 RPFNA collection and submission 
Kits are available for this collection (see Section 14.2.1).  The RPFNA kit contains all 
necessary supplies and instructions for collecting, processing, and shipping RPFNA 
specimens.  For sites that routinely perform RPFNAs and have materials available at their 
own institution, kit contents and instructions are provided in Appendix II.  Please include 
the study ID (A211102), patient initials, collection date, and Alliance patient ID 
number on all specimen containers and paperwork submitted with the specimens. 
Please note on the shipping form whether the RPFNA specimen was obtained in the 
operating room or in the clinic. 
RPFNA has been performed at Duke University for 9 years with over 400 women 
participating. Bruising at the site is expected. Otherwise the number of complications is very 
low. The only reported complication was a single skin infection in a woman who had a prior 
history of skin infection. This infection resolved rapidly with oral antibiotics. Average pain 
score is 0-1 out of 10 with 0 being no discomfort and 10 being labor pain.  Ativan is offered 
to all participants. The aspiration takes 15 minutes. 
Briefly, RPFNA is performed as follows: Approximately 105 cells and 0.5-cc breast fluid 
will be withdrawn twice from each anaesthetized breast. Two areas in each breast (10:00 
and 2:00 position) will be infiltrated with lidocaine and epinephrine.  Two 15 mL tubes 
containing 10 mL modified Cytolyte (Cytolyte 9 mL + 1 mL 10% formalin freshly prepared 
on the morning of aspiration).  The tubes will be provided by 
 lab and labeled 
Right and Left. For each breast, eight (8) 10 cc syringes with 21 gauge 1.5 inch needles will 
be pre-wetted with about 0.2 mL sterile tissue culture media or saline. Multiple passes will 
be made through the breast tissue with each needle, with the goal of covering as much of 
the breast tissue as possible.  A total of 8 needles will be used per breast.  Half of the 
aspirations will be made through the 2:00 skin site (4 needles) and half through the 10:00 
skin site (4 needles). 
14.3.2 Blood collection and serum and whole blood processing 
Draw blood sequentially into 1 x 8.5 mL SST tube, 2 x 10 mL and 1 x 5 mL red top (no 
additive) tubes, and 2 x 10 mL EDTA tubes.  Gently invert each tube 4-5 times. 
Serum Processing: Allow the blood to clot in the red top and SST tubes for 15-30 minutes 
at room temperature. Centrifuge at 3000 rpm for 10 minutes. After centrifugation, aspirate 
the top clear serum layer (being careful to avoid the transfer of cells) and place 1 mL aliquots 
into 2.0 ml cryogenic vials*.  Do NOT mix the serum collected from the SST tube with the 
serum collected from the red top no-additive tubes.   
* 
Cryovial Choices: Some examples of acceptable 2.0 mL cryovials are: Nalgene (Cat 
#5012-0020), Fisher (Cat #05-669-57), Corning (Cat #430488), VWR (Cat#16001-
102). 
Label all serum cryovials with the following information: 
1) Alliance study number (i.e., A211102) 
2) Alliance patient number 
3) Patient’s initials (last, first, middle) 
4) Procurement date and time 
5) Red top-serum or SST-serum (as applicable). 
Freeze serum samples at –70°C and keep frozen until ready to ship on dry ice to the Alliance 
Biorepository at the Ohio State University.  Frozen samples should be shipped on dry ice on 

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the day of collection. Dry ice should be replenished as needed to ensure samples stay frozen 
and there is enough to last throughout shipment. 
Whole blood processing: Label and refrigerate the EDTA tubes until ready to ship with the 
RPFNA specimen (see Section 14.5.1).  There is no further processing required for the 
EDTA tubes. 
Label EDTA tubes with the following information: 
1) Alliance study number (i.e., A211102) 
2) Alliance patient number 
3) Patient’s initials (last, first, middle) 
4) Procurement date and time 
5) Whole blood. 
14.4 
Biospecimen Submission Using the Alliance Specimen Tracking System 
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA THIS 
SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on Alliance 
trials. 
Authorized 
individuals 
may 
access 
BioMS 
at 
the 
following 
URL: 
 using most standard web browsers (Safari, 
Firefox, Internet Explorer). For information on using the BioMS system, please refer to the 
‘Help’ links on the BioMS web page to access the on-line user manual, FAQs, and training 
videos. To report technical problems, such as login issues or application errors, please contact: 
 For assistance in using the application or questions or problems related to 
specific 
specimen 
logging, 
please 
contact: 
 
 
 
 
After logging collected specimens in BioMS, the system will create a shipping manifest. This 
shipping manifest must be printed and placed in the shipment container with the specimens. 
Instructions for the collection of samples are provided above in Section 14.3. Please be 
sure to use a method of shipping that is secure and traceable. Extreme heat precautions 
should be taken when necessary. 
14.5 
Biospecimen Shipment 
All shipments should follow appropriate International Air Transport Association (IATA) 
guidelines 
including 
shipment 
in 
a 
biohazard 
bag 
(
).  At 
a minimum, all samples must be packaged within two containers to control any spill or leakage. 
The outer container must be puncture resistant (e.g. cardboard mail tube, corrugated cardboard 
box). A biohazard sticker must be affixed to both the inner and outer containers.  
Collection of multiple specimen types will require shipment in independent packaging (e.g. dry 
ice shipment for frozen serum, cold packs for RPFNA and whole blood). ALL SPECIMENS 
should be sent by a reliable courier service with a tracking number (such as FedEx or UPS).  
Shipment of specimens must comply with appropriate regulations as specified by the carrier. All 
specimens must be shipped the same day they are collected, Monday through Thursday, by 
overnight service for next day delivery to assure receipt to the appropriate Alliance bio 
repository or designated non-Alliance laboratory (see below).  Do not send specimens Thursday-
Saturday or the day before a federal holiday.   

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14.5.1 Refrigerated RPFNA and refrigerated EDTA whole blood specimen shipment on 
Monday through Thursday by overnight service for next day delivery to assure receipt is 
encouraged.  Do not ship specimens Friday-Saturday or just prior to federal holidays.  
RPFNA and one EDTA specimens should be placed in a Styrofoam box with a minimum of 
two cold packs (preferred three cold packs if between the months of May to September). 
Please call 
if you have questions regarding the shipment.  RPFNA and 
EDTA whole blood samples should be sent to the following address: 
 
 
 
 
 
 
14.5.2 Frozen serum specimens shipment on Monday through Thursday by overnight service for 
next day delivery to assure receipt is encouraged.  Do not ship specimens Friday-Saturday 
or just prior to federal holidays. Frozen serum samples should be shipped in a Styrofoam 
box with sufficient dry ice for 48 hours. Please call 
if you have questions 
regarding the shipment.  Frozen serum samples should be sent to the following address: 
 
 
 
 
 
 
 
14.6 
Correlative Study Methodology and Biospecimen Use/Storage Information 
14.6.1 RPFNA Analyses 
laboratory (City of Hope, Duarte California) will process the specimens and 
perform ER/PR analyses. 
(Miami, FL) will perform cytology analysis. 
 
laboratory (George Mason, Manassas, VA) will perform proteomic 
analysis.   
14.6.1.1  Masood Cytology Index:  Cytology slides will be scored by 
 
(Miami, FL) utilizing the Masood Cytology Index scoring system. 
 was part 
of the original team that developed RPFNA and has served as the cytopathologist for 
our prior studies and our published CALGB study.  
 will be joined by an 
additional cytologist, 
 at University of Pittsburg. The Masood 
Cytology Index allows for reproducible identification of early cytological changes in 
mammary epithelial cells and has been used to evaluate RPFNA cytology in risk 
assessment trials at Duke University, University of Kansas, and in our prior CALGB 
trial.  For reliability of RPFNA, see Section 1.3 above for discussion of our published 
CALGB studies testing for reproducibility of RPFNA in our CALGB cross sectional 
cohort22. 
 
Cellular 
morphology 
Cellular 
pleomorphism 
Myoepithelial 
cells 
Aniso-
nucleosis 
Nucleoi 
Chromatin 
clumping 
Score* 
Monolayer 
Absent 
Many 
Absent 
Absent 
Absent 
1 

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Cellular 
morphology 
Cellular 
pleomorphism 
Myoepithelial 
cells 
Aniso-
nucleosis 
Nucleoi 
Chromatin 
clumping 
Score* 
Nucl. overlap 
Mild 
Moderate 
Mild 
Micro-
nucleoli 
Rare 
2 
Clustering 
Moderate 
Few 
Moderate 
Micro-
nucleoli 
Occasional 
3 
Loss 
cohesion 
Conspicuous 
Absent 
Frequent 
Macro-
nucleoli 
Frequent 
4 
*Sum of Masood scores: 6-10 Normal; 11-13 Hyperplasia; 14-17 Hyperplasia with Atypia; >17 Suspicious 
for cancer.  Women with scores of >17 will be referred to a breast surgeon for evaluation.  
14.6.1.2 All women will be informed of the RPFNA results.  Following are the details of the 
RPFNA information that will be provided to the patient: 
• 
Participants are told that RPFNA is a research technique. 
• 
Participants are told that RPFNA is not a diagnostic (cancer finding) technique.  
Examples of diagnostic techniques are provided to subjects and include 
mammography and breast MRI. 
• 
Participants are told that the presence of atypia in high-risk women increases a 
woman’s chance of subsequently developing breast cancer.  It does not matter what 
technique is used to find atypia (excisional biopsy, core needle biopsy, FNA, or 
RPFNA), but that the presence of atypia increases the subsequent risk of breast cancer 
in high-risk women.  The article Fabian et al. JNCI, 2000 may be provided to women 
to provide evidence that the presence of atypia in RPFNA increases breast cancer risk.  
This article is available on request. 
• 
Participants are told that atypia is not cancer and that not all women with atypia will 
develop breast cancer.  Sometimes atypia will go away of its own accord, sometimes 
atypia will stay atypia, and in some situations atypia will progress to become cancer.  
Currently, we do not have the ability to determine which specific woman with atypia 
will go on to develop breast cancer.  This is the long-term goal of our research as well 
as the research of many other investigators. 
• 
Participants are told that we may find atypia in RPFNA (about 30% of samples, 
common), and we may find cells that are suspicious for cancer (<1%, rare).  All 
participants are given a copy of their RPFNA cytology report that includes cell count 
and cytology score.  The report is presented to the participant, and all questions 
answered. 
It is standard of care that if cells are found in the breast of high-risk women that are 
suspicious for cancer, that these women undergo a standard diagnostic work up for 
cancer with a breast surgeon.  In accordance with standard-of-care practices, if cells 
are found in RPFNA that are suspicious for cancer, the participant is referred to a 
breast surgeon for a standard diagnostic work-up.  Further clinical decision-making is 
determined based on the findings of this standard diagnostic work up and not based 
on the RPFNA results. This course of action is stated in our NCI grants funding this 
trial and is standard-of-care. Participants are also told that if we fail to find atypia, 
suspicious, or cancerous cells in their RPFNA, this does not mean that these cells are 
not present in their breast.  Again, participants are told that RPFNA is not diagnostic. 
• 
Women with a known BRCA1 or BRCA2 mutation will be re-offered the opportunity 
to undergo prophylactic oophorectomy and mastectomy. 

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14.6.1.3  RPPM Analysis:  RPPM will be performed (as described in Section 1.3) through 
funding provided by a Susan G. Komen Promise grant.  The Promise grant provides 
funding for RPPM analysis only.  RPPM will be performed at Theranostics under the 
guidance of 
(George Mason) as was done in the study described 
in the Background Section. Theranostics provides CLIA-CAP certified RPPM 
analysis. 
The sample will be immediately placed into fixative. The sample is sealed and sent 
by overnight priority Fed-EX to 
lab per Section 14.5, micro-dissected 
within 24 hours of receipt, and “micro-dissection caps” placed at -80oC until analysis. 
Using our published methods30,31, 5,000 micro-dissected epithelial cells will be spun 
onto a glass slide and isolated. Serial dilution of protein lysate will be arrayed onto 
nitrocellulose-coated slides. Samples will be spotted at 150 uM. In parallel with 
antibody staining, total protein concentrations will be determined by Spyro Ruby 
fluorescent staining (Mol. Probes) as a final normalization step. Each array will be 
scanned, spot intensity will be normalized, data will be normalized, and standard 
single value will be generated for each sample on the array (Image Quant v5.2). Local 
background intensity will be calculated for each spot with the unprinted adjacent slide 
background (JMP v5.0, SAS).  
We will test 50 endpoints.  These include: 1) AKT/mTor [pAKT-S473, mTor, 
p4EBP1-S65, p4EBP1-T37-46, peIF4E-S209, p70S6Kinase, pp70S6Kinase-T412, 
pIKB-S32-36, pNFKappaB-S536], 2) Receptor Tyrosine Kinase/Ras/RAF [EGFR, 
pEGFR-Y992, ErbB2, ErbB2-Y1248, ErbB3-Y1289, pERK1-2-T202-Y204, pMEK-
S217, Ras, Raf, Ras-GRF1-S916], 3) IGF/Insulin [IGF1R-IR-Y1131-46, IRS1-
pS612, 
pACC-S79, 
AMPKbeta-S108, 
ATPCL-S454, 
CREB-S133], 
4) 
Apoptosis/mitochondrial signaling: [caspase-9/7/3, pBad-S136, Bad, Bax, Bcl-xL, 
pBcl2-S70, pBad-S136], 5) IL6/Stat: [IL6, pStat3-T705, Stat1, Stat6, Stat-5, Jak2-
Y1007, vimentin], 6) Proliferation: [Ki67], and 7) Miscellaneous: [VEGFR2-Y951, 
pGSK3alpha/beta-Y279-Y216, E-Cadherin, HIF1alpha, p38MAPKinase-T180-
Y182]. 
14.6.1.4  Reliability of RPPM Measurements (signal to noise, dynamic range, and 
linearity of RPPM measurements): 
• 
Signal to Noise Ratio: For a given protein target (e.g. AKT-pSer473, mTOR, 
etc.), we scanned the array and the spot intensity normalized relative to total 
protein calculated using Spyro Ruby fluorescent staining. A standard single 
value was generated for each sample on the array using Image Quant v5.2 
software. Spot intensity was integrated over a fixed area (signal). Local 
background intensity was calculated for each spot with the unprinted adjacent 
slide background using JMP v5.0 software (noise). The limit of detection was 
defined as 2 standard deviations above the background while the functional 
sensitivity was defined as the lowest signal giving a CV% of less than or equal 
to 20% within an array; 10 replicates of three defined cell lines were used to 
estimate the coefficient of variation in the average intensity of each protein.  
Individual RPPM protein targets that did not fall above 2 standard deviations 
above background in at least one cell condition were not carried forward in our 
analysis of RPFNA cytology. 
• 
Defining the Dynamic Range and Linearity in RPPM:  We tested for the 
dynamic range and linearity of RPPM for key nodal signaling proteins, through 
(a) internal serial dilution and (b) a mixture experiment. The range of and 

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linearity of RPPM protein expression was compared to western analysis. Twenty 
replicates of a defined standard titration curve [1:0, 1:1; 1:2; 1:5; 1:9; 0:1] were 
arrayed on each slide. Analysis was performed by taking the mean intensity of 
20 individual applications for a given concentration within a slide and comparing 
it to the mean intensity of the remaining six slides. Analysis of inter- and intra-
spot reproducibility and linearity showed good correlation (correlation 
coefficient r2=0.989). There was agreement for the 5 proteins tested AKT-
pSer473 (r2=0.999), EGRF (r2=0.982), ERK-pThr204 (r2=0.991), MEK-
pSer217 (r2=0.977), and mTor (r2=0.992). These data show strong correlation 
between RPPM and western analysis.  
14.6.1.5 Exploratory Biomarker: RPFNA samples will be banked for future determination 
of metformin tissue levels. This endpoint will help support a direct insulin-
independent mechanism. Tissue will be analyzed from the fluid associated with 
RPFNA using a protocol adapted from Wang et al.58. Therefore, there will be no 
additional risk or discomfort to the patient. This analysis will be performed in the 
laboratory of 
as an exploratory study. 
14.6.2 Research Serum 
14.6.2.1 The risk of these serum studies is the loss of about 33.5 mL of blood.  The blood 
collected will yield approximately 10-12 mL red top serum and 4 mL SST serum.   
14.6.2.2 Measures of Obesity: Serum IGF and other cytokines such as IL6, IL8, MCP-1, 
TGFbeta, and leptin will be analyzed by ELISA.  It is unclear whether the benefit 
from metformin is due to a direct effect on Akt/mTor or an indirect reduction on serum 
insulin. There is also evidence for the ability of metformin to affect IGF levels. Serum 
IGF as well as the other cytokines listed above will be measured by a commercially-
available ELISA (ENZO kit number ADI-900150) according to manufacturer’s 
instructions in the laboratory of 
Approximately 2.0 ml serum 
will be required for these assays. 
14.6.2.3 Measures of Breast Cancer Risk: Serum samples will be tested for estrogen and 
progesterone by commercially available ELISA assays according to manufacturer’s 
instructions (Cayman Chemical Item Numbers 582251 and 582601) in the laboratory 
of 
Approximately 500 microliters of serum will be required 
for this assay. 
14.6.2.4 Exploratory Biomarker: Serum samples will be banked for future determination of 
metformin levels.  This endpoint will help support a direct insulin-independent 
mechanism. 
14.6.3 EDTA Whole Blood 
14.6.3.1 The risk of these EDTA whole blood studies is the loss of about 20 mL of blood.  
DNA will be extracted from 10 mL and stored by the Alliance PCO.  From the second 
10 mL tube of whole blood, DNA will be extracted and white blood cells will be 
isolated from the collected blood in the laboratory of 
 
14.6.3.2  White Blood Cell Complex 1: Samples will be measured from isolated white blood 
cell mitochondria using the protocol outlined by in Methods in Enzymology59.  This 
assay will be performed in the laboratory of 
 

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14.6.3.3  DNA Imprinting: 
laboratory will extract DNA from the EDTA 
whole blood and initially analyze a portion of the DNA for the presence of imprinting 
using standard laboratory protocols. 
14.6.3.4  Pharmacogenomic studies:  DNA extracted by 
laboratory will be 
used for future risk/response assays (e.g., for genetic polymorphisms such as DNA 
repair proteins that may correlate with efficacy and tolerability). 
14.6.4 Measures of Obesity and Insulin Resistance 
BMI, waist to hip ratio, fasting serum glucose, fasting serum insulin, serum HOMA, serum 
IGF, hemoglobin A1C, and other inflammatory cytokines (as described in 14.6.2.2) will be 
analyzed.  It is unclear whether the benefit from metformin is due to a direct effect on 
Akt/mTor, indirect reduction on serum insulin, or due to an indirect reduction in weight. 
These measures will help to support a direct insulin-independent versus an indirect insulin-
dependent mechanism. BMI and waist to hip ratio will be measured by standard clinical 
criteria. We plan to examine whether baseline glucose predicts metformin benefit 
independent of insulin or whether glucose modifies effects of insulin as a predictor of 
metformin benefit. We will also investigate HOMA, an empirically derived estimate of 
insulin sensitivity calculated from a single measure of fasting insulin and glucose that 
correlates well with the gold standard frequently sampled intravenous glucose tolerance 
test57, as a predictor of metformin benefit, focusing on whether it provides additional 
prediction beyond insulin alone. The blood collection for fasting glucose and insulin is a 
mandatory part of the baseline, 6-month, and yearly evaluations. Serum fasting glucose and 
fasting insulin will be determined by standard clinical criteria at the participating sites. 
14.6.5 Residual Biospecimens 
All residual specimens remaining after correlative studies are completed will be shipped to 
the Alliance Biorepository at Ohio State University, where they will be permanently stored 
at -80ºC according to patient consent information, until specific analyses are identified.  As 
protocols are developed, they will be presented for Alliance and IRB review and approval.  
(This collection is part of a general strategy of investigation for the majority of Alliance 
studies.) 
14.7 
Return of Genetic Testing Research Results 
14.7.1 This study will only test for low penetrance alleles that confer minimal risk. Because the 
results generated by the genetic testing described above are not currently anticipated to have 
clinical relevance to the patient or their family members and will be conducted in a research 
facility, the genetic results will not be disclosed to the patients or their physicians.   
14.7.2 If, at any time, genetic results are obtained that may have clinical relevance, IRB review and 
approval will be sought regarding the most appropriate manner of disclosure and whether 
or not validation in a CLIA-certified setting will be required prior to reporting any finding.  
Sharing of research data with individual patients should only occur when data have been 
validated by multiple studies and testing has been done in CLIA-approved laboratories or in 
a setting where a clinical trial is available based on a CLIA laboratory validated sequencing 
result and the patient has consented to re-contact for additional studies. 

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15.0 DRUG INFORMATION 
15.1 
Metformin hydrochloride tablets 
15.1.1 Background:  Metformin hydrochloride is an oral antihyperglycemic agent used in the 
management of type 2 diabetes.  It lowers both basal and postprandial glucose levels in type 
2 diabetes patients through several mechanisms: decreases hepatic glucose production, 
decreases intestinal absorption and increases peripheral glucose uptake and improves insulin 
sensitivity.  Metformin hydrochloride is not chemically or pharmacologically related to any 
other classes of oral antihyperglycemic agents.  
The Alliance considers this study to be IND exempt. Consistent with the FDA Guidance 
"IND Exemptions for Studies of Lawfully Marketed Drugs or Biological Products for the 
Treatment of Cancer", the Alliance is not planning to use the results of A211102 to get a 
new indication for metformin. Metformin has been and is currently being investigated for 
treatment and prevention of cancer. It is not anticipated that the toxicity profile of metformin 
in A211102 is different from that already known. The FDA has confirmed this study to be 
IND exempt (IND 122334). 
15.1.2 Formulation: Metformin hydrochloride tablets, containing 500 mg, 850 mg, or 1000 mg 
metformin hydrochloride per tablet, are manufactured and distributed by various 
pharmaceutical companies.  The metformin hydrochloride 850 mg tablets used in this trial 
are available commercially from Heritage Pharmaceuticals.  McKesson Clinical Research 
Services will use study-provided funds to purchase the metformin tablets.  Each tablet also 
contains the inactive ingredients malto dextrin, hypromellose, magnesium stearate, 
polyethylene glycol, povidone, corn starch, and blackberry.  The tablets will be bottled and 
labeled by Pharm Ops, Inc.  Each bottle packaged by Pharm Ops, Inc. will contain 175 
tablets.   
15.1.3 Preparation and storage: The tablets should be stored at a controlled room temperature, 
with excursions to 15-30°C (59-86°F) permitted.  All tablets should be kept in a secured 
storage area. 
15.1.4 Administration:  Metformin hydrochloride tablets should be taken with meals. 
15.1.5 Pharmacokinetic information:  The time to peak serum level for the immediate release 
product is 2 to 3 hours.  The onset of action is within days, with maximum effects up to two 
weeks.  Metformin is negligibly bound to plasma proteins.  Metformin is excreted in the 
urine, with 90% as unchanged drug.  It does not undergo hepatic metabolism.  Renal 
clearance is approximately 3.5 times greater than creatinine clearance, which indicates that 
tubular secretion is the major route of elimination.  Bioavailability while fasting is 50% to 
60%.  Half-life elimination in plasma is 4 to 9 hours. 
15.1.6 Potential Drug Interactions:  Concomitant use of the following agents may cause 
hyperglycemia: thiazides, other diuretics, corticosteroids, phenothiazines, thyroid products, 
estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium 
channel blockers, and isoniazid.  Metformin may interact with highly protein bound drugs 
(salicylates, sulfonamides, chloramphenicol, probenecid).  Concurrent use of other glucose-
lowering agents may cause hypoglycemia.  Fluoroquinolones and antidiabetic agents have 
been reported to cause blood glucose changes.  Beta blocking agents present a minimal risk 
of altering glucose control in nondiabetic individuals, although severe hypoglycemia has 
been reported with at least one beta blocking agent.  Concurrent use of metformin is 
contraindicated in participants receiving intravascular iodinated contrast media due to an 
association with lactic acidosis and acute renal failure.  

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15.1.7 Known potential toxicities:  Metformin is considered to have a favorable safety profile in 
diabetes mellitus patients.  In a US double-blind clinical trial for patient with type 2 diabetes, 
gastrointestinal symptoms such as diarrhea, nausea and vomiting, abdominal discomfort, 
flatulence, indigestion, and asthenia were the most common reactions to the drug.  These 
symptoms were dose-dependent, transient, and resolved spontaneously with continued use.  
The drug may cause GI upset so should be taken with food.  Additional adverse reactions 
reported in 1 to 5% of subjects were abnormal stools, hypoglycemia, myalgia, 
lightheadedness, dyspnea, nail disorder, rash, increased sweating, taste disorder, chest 
discomfort, chills, flu syndrome, flushing and palpitation.  A recently published trial of 
patients with type 2 diabetes mellitus reported a vitamin B12 deficiency with long term 
treatment.  Lactic acidosis is a rare, but serious, metabolic complication that can occur due 
to metformin accumulation during treatment.  Reported incidence of lactic acidosis in 
patients receiving metformin is very low.  Reported cases have occurred primarily in 
diabetic patients with significant renal insufficiency.   
15.1.8 Drug procurement:  Metformin Hydrochloride 850 mg tablets will be purchased for use in 
the trial.  Placebo tablets that are similar in size and color will also be purchased.  The 
metformin and placebo tablets will be bottled and labeled by Pharm Ops, Inc.  The bottles 
will be labeled so that study participants, caregivers, and investigators are blinded to the 
contents. 
Blinded metformin/placebo: Patient-specific supplies of metformin/placebo will be ordered 
by the registering institution after each patient is enrolled to the study. 
Fax or email the Alliance A211102 Drug Order Form to: 
  
 
  
 
  
 
Patients will need to return to the clinic to receive additional supplies of blinded drug at 3, 
6, and 9 months after registration. Sites may dispense a 6 month supply. However, sites that 
dispense a 6 month supply will be responsible for reconciliation of all medication returns. 
Institutional staff will contact the Registration Office for a study medication code number. 
Drug orders for these additional supplies should be submitted at least one week prior to each 
of these visits using the Alliance A211102 Drug Order Form.  
Open-label metformin: All patients will be unblinded at 12 months (see Section 6.9). All 
patients, except those who were randomized to placebo and who opt not to cross over to 
open-label metformin will receive open-label metformin. After re-registering the patient per 
Section 6.9, site staff will order patient-specific supplies of open-label metformin using the 
A211102 Drug Order Form. Orders should be placed at least 1 week prior to the patients’ 
12-, 15-, 18-, and 21-month visits.  

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Open-label metformin will be provided as 100 count bottles. Sites are responsible to label 
the bottles according to their respective state pharmacy laws. A sample label is below: 
 
The Alliance A211102 Drug Order Form is available at the Alliance and CTSU Web sites. 
Outdated or remaining drug/product should be destroyed on-site per procedures in place at 
each institution.   
15.1.9 Nursing Guidelines:  
• 
Metformin can have numerous drug to drug interactions that can cause either hyper or 
hypoglycemia. Assess patient’s concomitant medications (including OTC) and instruct 
patients not to start any new medications while on the study without checking with the 
study team. 
• 
Warn patients of gastrointestinal side effects when initially starting agent, including 
diarrhea, nausea, abdominal discomfort, flatulence, indigestion and vomiting. Agent 
should be taken with food to minimize these side effects.  
• 
There is a rare but serious risk of lactic acidosis. Instruct patients to report nausea or 
weakness. Patient with these symptoms should have their electrolytes checked and/or 
corrected under the direction of the physician.  
• 
Drug may cause hypoglycemia. Instruct patients in the signs and symptoms of 
hypoglycemia and to seek medical attention if they experience these. 
• 
Instruct patients that if they need to have any procedure (i.e. CT scan with contrast) with 
iodinated contrast they must discontinue metformin per institutional practice prior to the 
procedure and must not resume it until their creatinine level is satisfactory (per 
institutional practices).  
15.2 
Placebo 
A placebo tablet will be provided which will be similar in appearance to the metformin HCl 
850mg tablet.   
Formulation:  Pharm Ops, Inc., Inc. will formulate and produce the placebo tablets.  The tablets 
will contain microcrystalline cellulose and other inactive ingredients: croscarmellose sodium, 
colloidal silicon dioxide and magnesium stearate.  
16.0 STATISTICAL CONSIDERATIONS AND METHODOLOGY  
16.1 
Study Design  
16.1.1 Study Populations  
A total of 177 premenopausal women will be pre-registered, among which 96 patients with 
atypia (Masood Score 14-17) on RPFNA at baseline are expected to be randomized between 

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Metformin arm and placebo control arm.  It is expected that the accrual rate will be 1 patient 
per month and that accrual will be completed about 8 years after study activation. The 
randomization will be stratified for known BRCA mutation (BRCA1 or BRCA2 mutation 
vs. no mutation), prior excisional biopsy (atypical epithelial hyperplasia, atypical lobular 
hyperplasia, flat epithelial hyperplasia vs. DCIS vs. LCIS), and baseline fasting insulin > 2x 
ULN vs. ≤ 2x ULN. 
At 12 months the women in the placebo arm will be allowed to take metformin.  Based on 
experience from 300 women undergoing serial RPFNA at Duke, it is anticipated that 
approximately 40% of women who are randomized to the metformin arm will have 
disappearance of atypia at 12 months and 60% will have persistent atypia.  The estimated 
drop-out rate is 5% at 6 months and 10% at 12 months.  Over 98% of women with atypia 
will have atypia on repeat RPFNA on the non-metformin arm.  
We propose to test RPFNA on both right and left breasts at, 12 and 24 months after 
registration/randomization for the presence or absence (Masood score ≤13) of atypia by 
Masood Cytology Index Score. The RPFNA at 24 months is optional for women who 
continue on the placebo control arm and will not receive metformin. The outcomes collected 
at 24 months will be exploratory. In analysis, we will consider taking a transformation, such 
as logarithm, of positive variables in order to improve the normality and variance 
stabilization. Among the 96 randomized patients, we expect that about 10% of patients will 
drop out at month 12. So, the power analyses are based on N= 88 patients (44 per arm). 
16.2 
Statistical Analysis and Power Calculation 
16.2.1 Primary Objective: 
Test for the presence or absence of atypia in RPFNA after 12 months (24 month optional 
for placebo group for patients who remain on placebo arm and will not receive metformin); 
Metformin versus placebo control:  
16.2.1.1 Primary Analysis 
Multiple Masood scores from each breast will be averaged for each time point. The 
primary endpoint of the study is the binary outcome of atypia (Masood score ≥ 14). 
In this analysis, the sampling units will be women, so that, if a woman has atypia in 
one breast and no atypia in the other breast, this woman will be called atypia. Presence 
of atypia at month 12 will be compared between two arms using the chi-square test in 
univariate analysis, and regressed on group indicator, age, race, stratification factors, 
and baseline Masood score using logistic regression in multivariate analysis. As an 
exploratory analysis, we will also conduct a regression analysis including the timing 
of baseline RPFNA (intraoperative vs. in clinic) and the number of breasts with atypia 
at baseline in addition to these covariates. With 44 women per arm, the primary 
analysis has 90% of power to detect a difference of 90% vs. 60% of atypia between 
placebo and metformin arms at month 12 by a chi-square test with alpha=5%. 
In order to address the worst score rule, we will repeat above analyses using the 
maximum, instead of average, Masood score from each breast.  
16.2.1.2 Exploratory Analysis 
An exploratory analysis will be conducted using the breasts as sampling units, not 
women, so that all eligible breasts of eligible patients will be included in data analysis. 
The variance of the test statistic for comparing the presence of atypia at month 12 will 
be estimated using the generalized estimating equation (GEE) approach53 to account 
for the possible dependency among the binary atypia observations from each patient. 

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In another exploratory analysis, we will compare the continuous Masood score 
between two arms. The sampling unit in this analysis will be breast. The change rate 
(ratio) in Masood score at month 12 from baseline will be compared between 
metformin group and placebo control group using two-sample t-test for univariate 
analysis with 2-sided alpha=5%. We will also conduct multivariate analysis to regress 
the month 12 Masood score on group indicator, age, race, prior excisional biopsy, and 
baseline Masood score.  
Since the sampling unit in this analysis is breast, the Masood score observations from 
two breasts may be potentially correlated. In order to account for possible dependency 
between the data points from two breasts of each woman, the variances of t-test (in 
univariate analysis) and regression estimates (in multivariate analysis) will be 
estimated using the GEE.   
It is expected that about 25% of women (n = 11) will contribute one breast and the 
remaining 75% of women (n = 33) will contribute samples from both breasts, so that 
there will be about77 (= 11x1 + 33x2) data points (breasts) per arm in this analysis. 
Assuming that the intracluster correlation coefficient between two breasts is 0.3, this 
analysis will have 84% power to detect a difference of 0.4 times the standard deviation 
(SD). 
Similar analyses will be conducted for 24 months data.  
The women or breasts with unsatisfactory repeat RPFNAs will be considered missing 
at random in the analysis. 
16.2.2 Secondary Objectives: 
16.2.2.1  Test for Masood score and the presence of atypia or disappearance of atypia in 
RPFNA after 12 (for both arms) and 24 months for Metformin arm: 
We will investigate the trend of Masood score and presence of atypia measured at 
month 0 and 12 for metformin arm and placebo arm. Breasts will be the sampling 
units in the analysis of Masood score, while either women (in the primary analysis) 
or breasts (in the secondary analysis) will be regarded as sampling units in the analysis 
of atypia. At first, we will perform descriptive analyses for summary statistics of 
Masood score and atypia at each measurement time. We will also generate a line plot 
connecting the Masood scores of each breast over time to investigate the time trend.  
We will compare the mean Masood scores between 0 vs. month 12 using paired t-
tests.  In this analysis, we will use the breasts as sampling units. The possible 
dependency between data points from two breasts of each woman will be adjusted 
using the GEE method using the working independent correlation model55. Assuming 
that about 25% of women (n=11) will contribute one breast and the remaining 75% 
of women (n=33) will contribute samples from both breasts for each arm, we will 
have 90% of statistical power to detect a difference of 0.3 times SD if the intracluster 
correlation coefficients between breasts and two time points are 0.3 for each woman. 
We will conduct McNemar test to compare the proportion of atypia between month 0 
and month 12. These analyses will be conducted for each arm, and the results will be 
descriptively compared between two arms.  We will summarize the 24-month data for 
the metformin arm. 
16.2.2.2 Compare Masood Cytology Score value at 0, 12, and 24 months in right and left 
breast from the same individual in the metformin and non-metformin group:   

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Women with DCIS will not have two breasts for comparison.  We anticipate that this 
will constitute approximately 25% of the women who participate in this study.  Based 
on our published CALGB study21 we expect that we will not observe concordance 
between right and left breast Masood Cytology Score.  Our analysis here will further 
investigate these preliminary observations. A scatter plot (for right vs. left) will be 
generated to demonstrate dependency between right and left breast Masood cytology 
scores at each measurement time. Also from each scatter plot, the correlation 
coefficient and its p-value will be estimated. Only 75% of women (N = 33 per arm) 
contributing two breasts will be included in this analysis. In order to investigate the 
time trend in dependency between right and left breast Masood cytology scores, we 
will compare the correlation coefficients over different time points. We will also make 
a plot of differences (right-left) or ratios (right/left) over different time-points, and 
test if there exists any time trend in difference or ratio. The p-value will be calculated 
accounting for the dependency of the longitudinal data using GEE method55.   
16.2.2.3 Test the reproducibility of RPPM in duplicate RPPM determination from single 
bilateral RPFNA specimen: 
At each time of month 0 and 12, we will generate duplicated RPPM data on the 50 
endpoints. The reproducibility of RPPM at each time point will be tested using (i) 
unsupervised hierarchical clustering analysis to check if the duplicated data points are 
clustered together, and (ii) scatter plots between paired RPPM and estimated 
correlation coefficients. We will use an ANOVA method to test if the intracluster 
correlation coefficient is 0 or not.  
16.2.2.4 Correlate baseline RPPM values with presence of atypia at month 12 and month 
24: 
We will combine data set of metformin and no-metformin groups (N = 88) and use 
the breasts as the sampling units in this analysis. The possible dependency in 
observations between the left and right breasts for each woman will be adjusted using 
the GEE approach55.   
The baseline RPPM value of each protein will be correlated with Masood cytology 
score at month 12 using a simple linear regression method. In a multivariate analysis, 
Masood score at month 12 will be regressed on the baseline RPPM value of each 
protein, group indicator, age, race, prior excisional biopsy, and baseline Masood 
scores. Similar analysis will be conducted using the change rate of Masood score 
between baseline and month 12 in place of Masood score at month 12. 
The baseline RPPM value of each protein will be correlated with presence and 
absence of atypia at month 12. A total of 50 proteins will be tested, so that the 
significance of each protein will be adjusted for multiple testing by controlling the 
family-wise error rate (FWER) using the permutation method. We expect that about 
60% of the women will have persistent atypia at 12 months. The 50 proteins were 
selected from a previous study so that they are expected to have reasonable effect 
sizes. Assuming that each woman contributes samples from only one breast and the 
proteins have correlation coefficient of 0.1, the multiple testing procedure controlling 
the FWER at 10% level by two-sided tests will have about 90% probability to detect 
15 or more proteins if 25 of the 50 proteins have an effect size of 0.8 times SD [Jung 
and Young, 2011]56. Since about 75% of women are expected to contribute samples 
from both breasts to the study, the real power for this analysis will be higher.   

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In a multivariate analysis, presence of atypia at month 12 will be regressed on the 
baseline RPPM value of each protein, group indicator, age, race, prior excisional 
biopsy, and baseline Masood scores.  
A similar analysis will be conducted to correlate baseline RPPM value of each protein 
with Masood score and presence/absence of atypia at month 24.   
16.2.2.5 Record and analyze patient-reported knowledge of the arm to which they were 
randomized: 
In March, 2019 the study team was notified of an unexpected unblinding incident.  An 
enrolled patient informed her physician that she was able to google the code (serial 
number) on the pills to uncover whether she was taking metformin or placebo.  
Notably, all metformin tablets have a serial number printed on them while the placebo 
pills do not have any such information; in other words, the placebo tablets were not 
designed to look exactly like the metformin tablets and the risk of potential unblinding 
due to the lack of similarity was known prior to study activation, and this risk was 
deemed acceptable.  The Division of Cancer Prevention at NCI and the Alliance Data 
and Safety Monitoring Board were notified of this single unblinding incident.    
 
Because the primary outcome is an objective measurement, the trial results are not at 
significant risk of bias due to the single known incident of unblinding.  Furthermore, 
the remaining secondary, tertiary, and correlative endpoints are not subjective in 
nature.  Coupled with the fact that this study is intended to serve as proof of principle 
for the use of RPFNA to test for the presence or absence of atypia before, during, and 
after the administration of a prevention agent, this unblinding incident is unlikely to 
affect the validity of the study. 
 
At the time of this amendment, ≤ 10% of the patients had withdrawn from the study 
and the study discontinuation rate was balanced across the randomized arms; 
therefore, any premature unblinding of the study agents was likely to be limited in 
scope.   However, it is important to understand the true extent and impact of the 
unblinding issue.   Therefore, at the end of study intervention (i.e. at 12 months) but 
before the patient is unblinded and before the patient crosses over to metformin, 
patients will be asked the following question: “Did you know with certainty which 
agent you were randomized to receive during the first 12 months of the study?”  This 
single data field will be captured in Rave, our database of record, and will allow us to 
report on the magnitude of the premature unblinding as a patient-reported outcome.  
This information will also allow us to conduct sensitivity analyses on the primary and 
secondary endpoints by excluding patients who were unblinded to assess the impact 
(if any) of the premature unblinding on the study results.  For patients who have 
completed the study, discontinued early, or who are on study but beyond the 1-year 
intervention at the time of this amendment, the site coordinators will still contact the 
patient either by phone or during a protocol scheduled visit to ask them this question.  
Although it is conceivable that some patients may decline to provide a response, we 
anticipate that the success rate for obtaining a response to this single question will be 
high and, therefore, this information will be useful to contextualize the study findings. 
16.3 
Study Monitoring 
16.3.1 This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, and 
administrative information will be provided to the DSMB as per NCI guidelines. 

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16.3.2 Results Reporting on 
: At study activation, this study will have been 
registered within the 
web site. The Primary and Secondary Endpoints 
(i.e., “Outcome Measures”) along with other required information for this study will be 
reported on 
 
 
16.4 
Inclusion of women and minorities 
Breast cancer occurs primarily in women. Men and children are generally not subject to breast 
cancer and they will be excluded from this study. Efforts will be made to enroll individuals of 
all races and ethnic backgrounds. 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska Native 
1 
0 
0 
0 
1 
Asian 
3 
0 
0 
0 
3 
Native Hawaiian or Other Pacific 
Islander 
1 
0 
0 
0 
1 
Black or African American 
15 
0 
1 
0 
16 
White  
60 
0 
15 
0 
75 
More Than One Race 
0 
0 
0 
0 
0 
Total 
80 
0 
16 
0 
96 
 
17.0 PATHOLOGY CONSIDERATIONS/TISSUE BIOSPECIMENS 
None 
18.0 BUDGET 
See the A211102 Study Funding Sheet, available on the A211102 page of the Alliance and CTSU 
web sites. 
 
 

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19.0 REFERENCES 
1) 
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: Report 
of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-
88, 1998. 
2) 
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of Tamoxifen vs Raloxifene on the Risk 
of Developing Invasive Breast Cancer and Other Disease Outcomes: The NSABP Study of 
Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA 295:2727-2741, 2006. 
3)  
Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin use is associated 
with decreased risk of breast cancer. Diabetes Care;33(6):1304-8. 
4) 
Marshall S. Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel 
metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci 
STKE 2006;2006(346):re7. 
5) 
Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes 
mellitus patients. Gastroenterology 2004;127(4):1044-50. 
6) 
Lipscombe LL, Goodwin PJ, Zinman B, McLaughlin JR, Hux JE. Increased prevalence of prior 
breast cancer in women with newly diagnosed diabetes. Breast Cancer Res Treat 2006;98(3):303-
9. 
7)  
Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin 
and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast 
cancer. J Clin Oncol 2009;27(20):3297-302. 
8) 
Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, et al. Variation of breast 
cancer risk among BRCA1/2 carriers. JAMA 2008;299(2):194-201. 
9) 
Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M. Metformin is an AMP kinase-
dependent growth inhibitor for breast cancer cells. Cancer Res 2006;66(21):10269-73. 
10) 
Goodwin PJ, Pritchard KI, Ennis M, Clemons M, Graham M, Fantus IG. Insulin-lowering effect of 
metformin in women with early breast cancer. Clin Breast Cancer, 2008; 8: 501-505. 
11) 
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, 
and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 
2009;69(19):7507 
12) 
Phoenix KN, Vumbaca F, Claffey KP. Therapeutic metformin/AMPK activation promotes the 
angiogenic phenotype in the ERalpha negative MDA-MB-435 breast cancer model. Breast Cancer 
Res Treat 2009;113(1):101-11. 
13) 
Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, et al. 
Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-
2/neu transgenic mice. Exp Gerontol 2005;40(8-9):685-93. 
14) 
Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin 
suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector 
p70S6K1 in human breast carcinoma cells. Cell Cycle 2009;8(1):88-96. 
15) 
Buzzai M, Jones RG, Amaravadi RK, Lum JJ, DeBerardinis RJ, Zhao F, et al. Systemic treatment 
with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer 
Res 2007;67(14):6745-52. 

Alliance A211102 
Version Date 06/14/22 
Update #07 
55 
16) 
El-Mir M-Y, Nogueira V,  Fontaine E, Ave N,  Rigoulet R, and Leverve X.  Dimethylbiguanide 
Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I. J. 
Biol. Chem. 2009;275: 223–228, 2000. 
17) 
Motoshima H, Goldstein BJ, Igata M, Araki E. AMPK and cell proliferation--AMPK as a 
therapeutic target for atherosclerosis and cancer. J Physiol 2006;574(Pt 1):63-71. 
18) 
Fabian CJ, Kimler BF, Zalles CM, Klemp JR, Kamel S, Zeiger S, and Mayo MS. Short-term breast 
cancer prediction by random preiareolar fine-needle aspiration cytology and the Gail risk model. J. 
Natl. Cancer Inst. 92:1217-1227, 2000. 
19) 
Fabian CJ, Kimler BF, Brady DA, Mayo MS, Chang CHJ, Ferraro JA, Zalles CM, Stanton, AL, 
Masoos S, Gizzle WE, Boyd NF, Arneson DW, and Johnson KA. A phase II breast cancer 
chemoprevention trial of oral alpha-difluoromethylornithine: breast tissue, imaging, and serum and 
urine biomarkers. Clin. Cancer Res. 8:3105-3117, 2002. 
20) 
Bean GR, Scott V, Yee L, Ratliff-Daniel B, Troch MM, Seo P, Bowie ML, Marcom PK, Slade J, 
Kimler BF, Fabian CJ, Zalles CM, Broadwater G, Baker JC, Wilke LG, and Seewaldt VL. Retinoic 
acid receptor-beta2 promoter methylation in random periareolar fine needle aspiration. Cancer 
Epidemiol. Biomarkers Prevention, 14:790-798, 2005. 
21) 
Ibarra-Drendall C, Zalles, C, Scott V, Archer LE, Lem S, Yee LD, Lester J, Kulkarni S, 
Murekeyisoni C, Wood M, Wilson K, Garber J, Gentry C, Wilke LG, Stouder A, Broadwater G, 
Owens E, Rabiner S, Barron AC, and Seewaldt VL. Reproducibility of Random Periareolar Fine 
Needle Aspiration in a Multi-Institutional Cancer and Leukemia Group B (CALGB) Cohort Cancer 
Epi Biomarkers Prev, 18:1379-1384, 2009. 
22) 
Ibarra C, Petricoin EF, Seewaldt VL. Feasibility of performing Reverse Proteomic Microarray 
Analysis in Random Periareolar Fine Needle Aspiration Cytology. Cancer Epi Biomarkers Prev., 
2011 submitted. 
23)  
Wulfkule JD, Aquino JA, Calvert VS, Fishman DA, Cukos G, Liottta LA, and Petricoin EF. (2003) 
Signaling pathway profiling of ovarian cancer from human tissue array specimens using reverse 
phase protein microarrays. Proteomics. 3:2085-2090. 
24)  
Petricoin EF, Bichel VE, Calvert VS, Espina V, Winters M, and Liotta LA. (2005) Mapping 
molecular networks using proteomics: a vision for patient-tailored combination therapy. J. Clin. 
Oncol. 15:3614-3621. 
25)  
Petricoin EF, Belluco D, Araujo RP, and Liotta LA. (2006) The blood peptidome: a higher 
dimension of information content for cancer biomarker discover. Nature Reviews. 6: 961-967. 
26)  
Gulmann C, Sheehan KM, Kay EW, Liotta LA, and Petriocoin EF. (2006) Array-based proteomics: 
mapping of protein circuitries for diagnostic, prognostic, and therapeutic guidance in cancer. J. 
Pathol. 208:595-606. 
27)  
Sheehan KM, Calvert VS, Kay EW, Lu Y, Fishmann D, Espina V, Aquino J, Speer R, Araujo R, 
Mills GB, Liotta LA, Petricoin, EF, and Wulfkule JD. (2005) Use of reverse phase protein 
microarrays and reference standard development for molecular network analysis of metastatic 
ovarian cancer. Molecular and Cellular Proteomics. 4:346-355. 
28) 
Petricoin EF, Espina V, Araujo RP, and Liotta LA. (2007) Phosphoprotein pathway mapping: 
AKT/mammalian target of rapamycin activation is negatively associated with childhood 
rhabdomyosarcoma survival. Cancer Res. 67:3431-3340. 
29) 
Begg CB, Haile RW, Borg A, Malone KE, Concannon P, Thomas DC, et al. Variation of breast 
cancer risk among BRCA1/2 carriers. JAMA 2008;299(2):194-201. 
30)  
Pilie P, Ibarra-Drendall C, Broadwater G, Barry W, Petricoin E, Wulfkuhle J, Liotta LA, Zalles C, 
Geradts J, Yu D, and Seewaldt VL. Protein Microarray Analysis of Mammary Epithelial Cells from 

Alliance A211102 
Version Date 06/14/22 
Update #07 
56 
Obese and Non-Obese Women at High-Risk for Breast Cancer: Feasibility Data. Cancer Epidemiol 
Biomarkers Prevention. 20:476-482, 2011 (cover article). 
31) 
Ibarra-Drendall C, Barry W, Petricoin E, Yu D, Zalles C, and Seewaldt VL. Activation of protein 
network signaling during initiation of breast cancer in high-risk women. Breast Cancer Res Treat, 
in press, 2011. 
32)  
Kritikou, E. (2008) Cancer biology: Warburg effect revisited. Nature Reviews Molecular Cell 
Biology 9:264-6 
33) 
Gill J, Maskarinec G, Pagano I, Kolonel LN. Risk of in situ breast cancer and mammographic 
density: The Multiethnic Cohort. 2006;163(11):S97-S. 
34) 
Boyd NF, Rommens JM, Vogt K. Mammographic density as an intermediate phenotype for breast 
cancer (vol 6, pg 798, 2005). Lancet Oncol 2005;6(11):826-. 
35) 
Ma H, Luo J, Press MF, Wang Y, Bernstein L, Ursin G. Is there a difference in the association 
between percent mammographic density and subtypes of breast cancer? Luminal A and triple-
negative breast cancer. Cancer Epidemiol Biomarkers Prev 2009;18(2):479-85. 
36) 
Ziv E, Tice J, Smith-Bindman R, Shepherd J, Cummings S, Kerlikowske K. Mammographic 
density and estrogen receptor status of breast cancer. Cancer Epidemiology Biomarkers & 
Prevention 2004;13(12):2090-5. 
37) 
Chlebowski RT, Anderson GL, Lane DS, et al. Predicting risk of breast cancer in postmenopausal 
women by hormone receptor status. Journal of the National Cancer Institute 2007;99(22):1695-
705. 
38) 
Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE. Plasma insulin-like 
growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res 
2000;60(14):3744-8. 
39) 
Walker K, Fletcher O, Johnson N, et al. Premenopausal Mammographic Density in Relation to 
Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-like Growth Factors. 
Cancer Research 2009;69(16):6490-9. 
40) 
Diorio C, Brisson J, Berube S, Pollak M. Intact and total insulin-like growth factor-binding protein-
3 (IGFBP-3) levels in relation to breast cancer risk factors: a cross-sectional study. Breast Cancer 
Research 2008;10(3). 
41) 
Boyd NF, Lockwood GA, Byng JW, Little LE, Yaffe MJ, Tritchler DL. The relationship of 
anthropometric measures to radiological features of the breast in premenopausal women. Br J 
Cancer 1998;78(9):1233-8. 
42) 
Boyd NF, Stone J, Martin LJ, et al. The association of breast mitogens with mammographic 
densities. Br J Cancer 2002;87(8):876-82. 
43) 
Buist DS, Aiello EJ, Miglioretti DL, White E. Mammographic breast density, dense area, and breast 
area differences by phase in the menstrual cycle. Cancer Epidemiol Biomarkers Prev 
2006;15(11):2303-6. 
44) 
White E, Velentgas P, Mandelson MT, et al. Variation in mammographic breast density by time in 
menstrual cycle among women aged 40-49 years [see comments]. J Natl Cancer Inst 
1998;90(12):906-10. 
45) 
Sala E, Warren R, Duffy S, Welch A, Luben R, Day N. High risk mammographic parenchymal 
patterns and diet: a case-control study. Br J Cancer 2000;83(1):121-6. 

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46) 
Kerlikowske K, Ichikawa L, Miglioretti DL, et al. Longitudinal measurement of clinical 
mammographic  
47) 
Brisson J, Brisson B, Cote G, Maunsell E, Berube S, Robert J. Tamoxifen and mammographic 
breast densities. Cancer Epidemiol Biomarkers Prev 2000;9(9):911-5. 
48) 
Boyd NF, Byng JW, Jong RA, et al. Quantitative classification of mammographic densities and 
breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst 
1995;87(9):670-5. 
49) 
Byrne C, Schairer C, Wolfe J, et al. Mammographic features and breast cancer risk: effects with 
time, age, and menopause status. J Natl Cancer Inst 1995;87(21):1622-9. 
50) 
Saftlas AF, Hoover RN, Brinton LA, et al. Mammographic densities and risk of breast cancer. 
Cancer 1991;67(11):2833-8. 
51) 
Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ. Mammographic densities and breast 
cancer risk. Cancer Epidemiol Biomarkers Prev 1998;7(12):1133-44. 
52) 
Byng JW, Yaffe MJ, Jong RA, et al. Analysis of mammographic density and breast cancer risk 
from digitized mammograms. Radiographics 1998;18(6):1587-98. 
53) 
Goldenberg N, Glueck CJ, Loftspring M, Sherman A, Wang P. Metformin-diet benefits in women 
with polycystic ovary syndrome in the bottom and top quintiles for insulin resistance. Metabolism 
2005; 54:113-121. 
54) 
Romualdi D, Costantini B, Selvaggi L, Giuliani M, Cristello F, Macri F, Bompiani A, Lanzone A, 
Guido M. Metformin improves endothelial function in normoinsulinemic PCOS patients: a new 
prospective. Hum Reprod 2008; 23:2127-2133.  
55) 
Liang K-Y, Zeger SL Longitudinal data analysis using generalized linear models. Biometrika. 
1986;73:13-22.  
56)  
Jung SH and Young SS. Power and Sample Size Calculation for Microarray Studies. J Biopharm 
Stat 2012; 22: 1-13. 
57) 
Vaccaro O, Masulli M, Cuomo V, Rivellese AA, Uusitupa M, Vessby B, Hermansen K, Tapsell L, 
Riccardi G. Comparative evaluation of simple indices of insulin resistance. Metabolism 2004; 53: 
1522-1526. 
58)  
Wang Y, Tang Y, Gu J, Fawcett JP, Bai X. Rapid and sensitive liquid chromatography-tandem 
mass spectrometric method for the quantitation of metformin in human plasma. J Chromatogr B 
Analyt Technol Biomed Life Sci. 2004;808:215-9. 
59) 
de Whitt LEA and Sluiter W., Reliable assay for measuring Complex I activity in human blood 
lymphocytes and skin fibroblasts. Methods in Enzymology. 2009:456:169-181. 
60)   
Pocock SJ, Simon R.  Sequential Treatment Assignment with Balancing for Prognostic Factors in 
the Controlled Clinical Trial. Biometrics 31(1):103-115, 1975 Mar. 
61) 
Stone J, Gunasekara A, Martin LJ, Yaffe M, Minkin S, Boyd NF. The detection of change in 
mammographic density. Cancer Epidemiol Biomarkers Prev 2003;12(7):625-30. 
 
 

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APPENDIX I: MODEL CONSENT FORM 
NCI Informed Consent Template for Cancer Treatment Trials 
(English Language) 
 
 
*NOTES FOR LOCAL INVESTIGATORS: 
 The goal of the informed consent process is to provide people with sufficient information for making 
informed choices.  The informed consent form provides a summary of the clinical study and the 
individual's rights as a research participant.  It serves as a starting point for the necessary exchange 
of information between the investigator and potential research participant.  This template for the 
informed consent form is only one part of the larger process of informed consent. For more 
information about informed consent, review the "Recommendations for the Development of 
Informed Consent Documents for Cancer Clinical Trials" prepared by the Comprehensive Working 
Group on Informed Consent in Cancer Clinical Trials for the National Cancer Institute.  The Web 
site address for this document is 
 
• 
A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant. 
• 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is available for your 
patients.  The pamphlet is entitled: "Taking Part in Cancer Treatment Research Studies".  This 
pamphlet may be ordered on the NCI Web site at 
 to request a free copy. 
• 
Optional feature for Local Investigators:  Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks.  Check with your local IRB regarding review 
of additional materials. 
*These notes for {authors and} investigators are instructional and should not be included in the informed 
consent form given to the prospective research participant. 
 
 
 
 
 
 

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A211102, Testing for Atypia in Random Periareolar Fine Needle Aspiration 
(RPFNA) Cytology After 12 Months Metformin (1,1-Dimethylbiguanide 
Hydrochloride) Chemoprevention Versus Placebo Control in Premenopausal 
Women 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about this 
research study.  If you agree to take part in this study, you need to sign this form.  Your signature 
means that you have been told about the study and what the risks are.  Your signature on this 
form also means that you want to take part in this study. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial 
to you.  Clinical trials include only people who choose to take part.  Please take your time to 
make your decision about taking part.  You may discuss your decision with your friends and 
family.  You can also discuss it with your health care team.  If you have any questions, you can 
ask your study doctor for more explanation. 
 
This study is conducted by the Alliance for Clinical Trials in Oncology, a national clinical research group 
supported by the National Cancer Institute. The Alliance is made up of cancer doctors, health 
professionals, and laboratory researchers, whose goal is to develop better treatments for cancer, to prevent 
cancer, to reduce side effects from cancer, and to improve the quality of life of cancer patients. 
 
You are being asked to take part in this research study because you are considered to be high risk 
for the development of breast cancer in the future. 
 
Why is this research study being done? 
The purpose of this research study is to test whether metformin, a drug commonly used to treat 
diabetes, is able to get rid of atypia (early cell changes that are thought to be a marker of breast 
cancer risk) in women at increased risk for breast cancer.  We will test for the presence of atypia 
in the breast after metformin is given to see if it can get rid of atypia. We would like to compare 
the effects, good and/or bad, of metformin or placebo on atypia to find out which is better.  
 
Note: The standard drug used for the “breast cancer prevention” is tamoxifen. If you are eligible 
to take tamoxifen, you must be offered tamoxifen prevention as part of your clinical care and you 
must have refused tamoxifen treatment to be on this study.  Metformin and tamoxifen are not 
similar and function differently.  This study is not investigating the use of tamoxifen. Metformin 
is not approved for preventing breast cancer, but is currently being tested to determine if it can 
prevent breast cancer. 
 
How many people will take part in the research study? 
About 177 women will take part in this study. 
 
 
 

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What will happen if I take part in this research study? 
In order to find out whether you are eligible to participate in this study, you will have a 
procedure called “Random Periareolar Fine Needle Aspiration” (RPFNA) of your breasts to test 
for atypia (marker of breast cancer risk).  This procedure, which will be repeated if you are 
eligible to participate in the study, is described below.  If the pathologist does not identify 
atypia in the samples you will not be able to participate.  
 
 
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  If you have had some of them recently, they may not need to be repeated.  This will be up 
to your study doctor. 
 
• 
Medical history (questions about your health and any medications you are taking) 
• 
General physical examination including your weight, height, and BMI 
• 
Waist/hip ratio 
• 
A breast exam 
• 
A standard digital mammogram 
• 
Routine blood tests (Blood counts, fasting blood sugar, insulin levels, kidney function) 
• 
Before start of treatment, you will have an evaluation to see if any of the possible side 
effects are already present before treatment. 
 
• 
Random Periareolar Fine Needle Aspiration (RPFNA). RPFNA is a method for 
collecting cells from the breasts. Your doctor will use a small needle to remove and 
collect cells from both of your breasts. Your doctor will do this by inserting 4 needles 
into two locations on each of your breasts (8 needles per breast) and removing cells. 
Usually, this procedure will be done on both breasts. However, if you have been 
diagnosed with DCIS in one breast, you will have this procedure done only on the other 
breast. Or, if you are having surgery to remove atypia from one breast, your surgeon may 
decide to perform the RPFNA procedure on the other breast only during the surgery. 
 
Analysis of RPFNA samples will be done at laboratories associated with the Alliance.  
The RPFNA will be reviewed by a pathologist looking at any changes in the cells under 
the microscope.  In the event that the pathologist identifies cells in your RPFNA sample 
that are suspicious for cancer, your doctor will discuss these results with you and your 
doctor will determine what to do next. 
 
 
 

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During the study… 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
you will be registered and "randomized" into one of the study groups described below.  
Randomization means that you are put into a group by chance (as in the flip of a coin).  A 
computer program will place you in one of the study groups.  Neither you nor your doctor can 
choose the group you will be in.  You will have an equal chance of being placed in either group. 
 
Group 1 
Patients randomized to Group 1 will receive metformin tablets. 
 
Group 2 
Patients randomized to Group 2 will receive placebo tablets, which are not active (like a sugar 
pill). 
 
The placebo is given in Group 2 so that participants in both groups receive similar-looking pills. 
This way, neither you nor your doctor can tell which group you are in, and that makes the study 
more objective. After 12 months of treatment, you will be told by your clinic staff whether you 
were receiving metformin or the placebo.  If you were randomized to receive placebo, you will 
be asked if you wish to switch to metformin pills or stop taking study drug (see below). There is 
no plan to tell you whether you are receiving metformin or placebo during the first 12 months of 
the study except in the case of an emergency. 
 
When you start the study treatment, you will take 1 metformin/placebo pill every day for the 
first 4 weeks (called the “ramp-up period”). After this, you will take one pill by mouth two times 
a day – one pill in the morning and one in the evening. The pills should be taken with food. If 
you miss a dose, you should skip that dose and not try to make it up. The drug dosage may be 
reduced, or may be stopped temporarily or permanently if you suffer side effects that are 
unacceptable. You are encouraged to maintain a healthy weight and moderate degree of exercise.  
You are also encouraged to consult your doctor or study nurse if you decide to stop study drug 
permanently.   
 
Month 
Number of metformin/placebo pills 
1 
1 pill each day by mouth 
(4 week ramp up period) 
2-12 
2 pills each day by mouth  
 
 
 
 

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After 12 months of treatment, you will be told by your clinic staff whether you were receiving 
metformin or the placebo.  
 
If you were receiving metformin, you will continue taking the drug for 12 more months. 
 
Month 
Number of metformin pills 
13-24 
2 pills each day by mouth 
 
If you were receiving the placebo, you will have the option to either: 
 
1) Begin taking metformin for one year (also called “crossover,”) OR 
2) Stop taking study drug 
 
If you choose to cross over to treatment with metformin, you will start with one pill for 4 
weeks and then increase to two pills per day. 
 
Month(s) 
Number of metformin pills 
13 
1 pill each day by mouth 
(4 week ramp up period) 
14-24 
2 pills each day by mouth  
 
If you choose to stop taking the study drug, you will be asked to continue with the tests and 
procedures as scheduled below.  You will have the option to skip the RPFNA procedure that 
is scheduled at 24 months. 
 
 
Tests and procedures 
During the study you will have the following tests and procedures, which will be done around 6, 
12, and 24 months after you start the study. 
 
• 
Medical history (questions about your health and any medications you are taking) 
• 
General physical examination including your weight and BMI 
• 
Waist/hip ratio 
• 
A breast exam 
• 
Routine blood tests (Blood counts, fasting blood sugar, insulin levels, kidney function) 
• 
Evaluation of any side-effects you are having. 
• 
You will be given a Patient Medication Diary to complete during the ramp-up period. 
Before the end of the ramp-up period, you will receive a phone contact to remind you to 
increase your treatment to twice daily after 28 days and to ask about any side-effects you 
may be having.  
 
 
 

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RPFNA: In addition to the RPFNA procedure that you will have before you start the study, 
you will be asked to undergo this procedure after you have received metformin or placebo for 
12 months. After you have received treatment for 24 months, you will asked to undergo the 
RPFNA a third time, unless you were randomized to group 2 and have chosen not to continue 
treatment after 12 months.  
 
Blood samples: You will be asked to provide blood samples for research that are being 
done to see how the study is affecting your body.  About 4 tablespoons of blood will be 
collected at each time point.  These samples will be collected before you start study 
treatment, and at around 6, 12, and 24 months after you start the study.  These samples will 
be used to learn about proteins and genes (also called biomarkers) that might be related to 
atypia.  These samples will be tested at laboratories associated with the Alliance as part of 
this study. It is hoped that this will help investigators better prevent and understand breast 
cancer.  The results of these tests are not currently part of standard clinical care and are only 
for research testing.  Therefore, neither you nor your doctor will receive any specific results 
and the results will not be used in planning your care.  These tests are for research purposes 
only and you will not have to pay for them. 
 
Please see the “Additional Studies” sections at the end of this consent form for additional 
information regarding your RPFNA tissue and blood samples. 
 
 
When I am finished taking the study drug… 
You will be asked to return to the clinic 36 and 48 months after you started the study, with the 
following tests being done at each time point: 
 
• 
Medical history (questions about your health and any medications you are taking) 
• 
General physical examination including your weight and BMI 
• 
Waist/hip ratio 
• 
A breast exam 
• 
Routine blood tests (Blood counts, fasting blood sugar, insulin levels, kidney function) 
• 
Evaluation of any side-effects you are having. 
 
 
 
 

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Study Plan:  
Another way to find out what will happen to you during the study is to read the chart below.  
Start reading at the top and read down the list, following the lines and arrows. 
 
 
 
Start Here 
 
 
 
 
 
 
 
 
 
RPFNA 
To determine if you are eligible for the study 
 
 
 
 
 
 
 
 
 
 
Randomize 
 
 
 
 
 
 
 
 
Start Day 
 
Start taking metformin/placebo 
1 pill each day for one month, then 
2 pills each day for 11 months 
 
 
 
 
 
 
 
6 months 
 
Blood tests, physical exam, and research blood tests 
 
 
 
 
 
 
 
12 months 
 
RPFNA 
Blood tests, physical exam, and research blood tests 
You will learn whether you were receiving metformin or placebo 
 
 
 
 
 
 
If you were taking metformin 
 
If you were taking placebo 
 
 
 
 
 
OR 
 
 
Continue Metformin 
2 pills each day 
for 12 months 
 
Start taking metformin 
1 pill each day for one month, then 
2 pills each day for 11 months 
 
Stop taking 
study drug 
 
 
 
 
 
 
24 Months 
 
RPFNA required 
RPFNA is OPTIONAL 
 
 
Blood tests, physical exam, and research blood tests (all patients) 
 
 
 
 
36 and 48 
months 
 
Blood tests and physical exam (all patients) 
 
 
 

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How long will I be in the research study? 
The duration of the study is 48 months. 
 
 
Can I stop being in the research study? 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about 
stopping or decide to stop.  He or she will tell you how to stop safely. 
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
treatment can be evaluated by your doctor.  Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow up care and testing could be most helpful for 
you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped. 
 
 
What side effects or risks can I expect from being in the research study? 
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  
Side effects may be mild or very serious.  Your health care team may give you medicines to help 
lessen side effects.  Many side effects go away soon after you stop taking metformin. In some 
cases, side effects can be serious, long lasting, or may never go away. There also is a risk of 
death. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study. 
 
RPFNA risks: You may experience some risks and side effects associated with RPFNA, 
however, there are no known lasting health risks from undergoing a RPFNA. There is some 
minimal discomfort after the RPFNA procedure. The main potential risk is bruising at the site of 
the procedure, which is common. There is a less than 1% risk of infection after the RPFNA 
technique. Other potential risks associated with the procedure occur infrequently but include: 
bleeding, slight pain, and hematoma (large bruise), which are standard risks of any invasive 
procedure, including procedures like blood sampling.  
 
Most likely risks of metformin (greater than 20%) These symptoms are generally temporary, 
during the start of treatment, and disappear without stopping the drug. 
• 
Loose stools (Diarrhea)  
• 
Feeling sick to your stomach (Nausea) 
• 
Throwing up (Vomiting) 
• 
Abdominal bloating/discomfort 
• 
Indigestion 
• 
Gas (Flatulence) 
• 
Loss of appetite (Anorexia) 

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Less likely [Occasional] risks of metformin (5 – 20%)  
• 
Loss of taste or metallic taste (during start of therapy)  
• 
Minor weight loss  
 
Rare risks of metformin (1 to 4%) 
• 
Hypoglycemia (low blood sugar) 
• 
Rash, redness or itchiness   
• 
Decrease in your red blood cell count  
• 
Liver function test abnormalities as seen by blood tests or hepatitis (inflammation of your 
liver). These effects will disappear when Metformin is stopped.  
 
Rare but Serious risks of metformin (less than 1%) 
• 
Lactic acidosis (a high acid level in the blood) occurs rarely (3 cases per 100,000 years of 
use) and can cause death. Individuals at risk of this complication include persons with 
diabetes who have kidney abnormalities, heart muscle abnormality or who are over 80 
years of age. Symptoms of lactic acidosis may include tiredness, muscle aches, difficulty 
breathing, vomiting, or severe abdominal pain. If you develop these symptoms or any 
serious medical condition while taking Metformin, you should stop the medication and 
seek medical treatment - your regular physician or your local Emergency Department – 
the physician you see should be informed that you are taking Metformin.  
 
As with any medication, allergic reactions are a possibility. 
 
Risks for blood draws: The risks of drawing blood include pain, bruising or rarely infection at 
the needle site. 
 
CT or MRI Scans: There are risks associated with metformin when receiving scans with 
contrast. If you need to have a CT or MRI scan while taking metformin/placebo, you should 
inform the radiology staff. 
 
Reproductive risks:  You should not become pregnant while on this study because the drugs in 
this study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  
It is important you understand that you need to use birth control while on this study.  Check with 
your health care provider about what kind of birth control methods to use and how long to use 
them.  Some methods might not be approved for use in this study. 
 
For more information about risks and side effects, ask your study doctor. 
 
 
 
 

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Are there benefits to taking part in the research study? 
Taking part in this study may or may not make your health better.  While doctors hope 
metformin will be useful in preventing breast cancer, there is no proof of this yet.  We do know 
that the information from this study will help doctors learn more about metformin as a treatment 
to help prevent breast cancer.  This information could help future patients who have a higher risk 
of getting breast cancer. 
 
 
What other choices do I have if I do not take part in this research study? 
You do not have to be in this study to receive treatment. 
Your other choices may include: 
• 
Getting treatment or care to help prevent your cancer without being in a study 
• 
Taking part in another study 
• 
Receiving standard treatment, i.e., tamoxifen 
• 
Getting no treatment 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  The study doctors have a privacy permit to help protect your records if there is a 
court case. However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
Alliance for Clinical Trials in Oncology (Alliance) 
• 
Institutional Review Boards  
• 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
• 
The Cancer Trials Support Unit (CTSU), a service sponsored by the NCI to provide 
greater access to cancer trials 
 
 
A description of this clinical trial will be made available on 
This 
Web site will not include information that can identify you. At most, the Web site will include a 
summary of study results. You can search this Web site at any time. 
 
[Note to Informed Consent Authors: the above paragraph complies with the new FDA regulation found at 
21 CFR 50.25(c) and must be included verbatim in all informed consent documents. The text in this 
paragraph cannot be revised.] 
 

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[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by local 
institutions.  The regulations may or may not be included in the informed consent form depending on local 
institutional policy.] 
 
 
What are the costs of taking part in this research study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
procedures being done in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular treatment. 
 
The study agents, metformin and placebo, will be provided free of charge while you are taking 
part in this study.  The cost of getting the metformin and placebo ready and giving it to you is not 
paid by the study, so you or your insurance company may have to pay for this.  You will not be 
paid for taking part in this study. 
 
You will not need to pay for tests and procedures that are done just for this research study.  
These tests are: 
• 
Research blood test(s) 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at 
. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
Another way to get the information is to call 
 and ask them 
to send you a free copy. 
 
 
What happens if I am injured because I took part in this research study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)]; if 
you feel that you have been injured because of taking part in this study.  You can tell the doctor 
in person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment. 
 
 
What are my rights if I take part in this research study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution. 
 

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We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
 
Who can answer my questions about the research study? 
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ [telephone number].  
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.]  
 
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
 
 
You may also visit the NCI Web site at 
 
• For NCI’s clinical trials information, go to:  
 
• For NCI’s general information about cancer, go to 
 
• For 
NCI’s 
general 
information 
about 
cancer 
in 
Spanish, 
go 
to 
 
 
You will get a copy of this form.  If you want more information about this study, ask your 
study doctor. 
 
 
ADDITIONAL STUDIES SECTION (REQUIRED): 
Please note:  This section of the informed consent form is about additional research studies 
that are being done with people who are taking part in the main study.  
 

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Research on Tissue  
Please read this section of the informed consent on related research studies and ask about 
anything that is not clear to you. This is to inform you of the possible risks, benefits and 
limits of giving your samples for research.  
As described above, you will be required to have RPFNA tissue and blood samples taken to 
use for protein and gene research studies as part of the main study.  
What are samples and where are they stored? 
A sample is any material taken from your body such as tissue, blood, urine and other fluids. 
If you agree, your samples will be stored for research in a Cooperative Group bank supported 
by the National Cancer Institute. A Cooperative Group bank contains samples and 
information. Your samples are kept along with those from other people in this bank. 
Researchers then ask for samples from the bank to study them. 
What information will be collected? 
Your tissue and some of your blood will be sent along with your initials and the date of 
collection to a laboratory at City of Hope Hospital in California. Some of your blood samples 
will be sent to the Alliance Bank. Any personal information sent with the samples to the 
Alliance bank is not given to researchers. Your privacy will be protected to the fullest extent 
possible. This will be discussed later in the section “How will information related to my 
samples be protected?” 
Other information that might be stored for future research by the Alliance includes: 
• 
Dates of medical procedures  
• 
Any diagnosis and stage of your disease (if you have cancer) 
• 
Your age and race  
• 
Medical and family history  
• 
Treatments you had  
• 
How you responded to treatments  
What will happen to my samples? 
Your samples will be stored in the Alliance Bank. The samples will be kept until they are 
used up or destroyed. The samples are given a code to protect your privacy before they are 
used. Any related information given to researchers will also be coded. Researchers will 
receive the code instead of any information that might directly identify you. 
You or your doctor will not be given reports or other information about the research that uses 
your samples. This information will not be put into your health record. Results may be used 
for future research. 
You will not be named or identified by other personal information if any results are 
published. Most publications contain results from many patients. 
Your samples and related information will be used only for research and will not be sold. It is 
possible that research may help to create new products or treatments. If this should happen, 
you will not be paid.  

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Because the information gained from the research studies performed on your samples can be 
very useful to the research community, several groups including the National Institute of 
Health (NIH) have requested that some of these data be placed in a central database. 
Therefore, some of the coded research information may be sent to a central database. The 
goal is to speed up the process of discovery of new treatments, prevention and diagnosis of 
disease. The information will continue to be made available for approved research. Your 
name or contact information will not be put in the database. 
What kind of research will be done with my samples? 
Many types of research use normal or atypical (marker of cancer risk) or cancerous samples. 
Researchers can study proteins, RNA and DNA (genes). The study of genes (DNA) is often 
called genetic research. 
Your samples may be looked at: 
• 
To see if a trait is passed down in families from one generation to the next 
(inherited). This type of research may help to explain why some cancers run in 
families or why some people have side effects of treatment while others do not. This 
is often studied through blood cells and DNA (genes). 
• 
To learn about changes in the body that happen after you were born (non-inherited). 
For example, being in the sun too much can cause changes in cells that lead to skin 
cancer.  
Will it help me to give my sample for research? 
Using your samples for research will probably not help you. We do hope the research results 
will help people in the future. The best way to prevent, find or treat cancer and other diseases 
is by studying human samples and data. 
What are the risks of giving my samples for research? 
• 
There can be mild pain, or some bleeding or bruising when blood is drawn. Rarely, an 
infection can happen where the needle was placed. Feeling dizzy or fainting can also 
happen, but may only last a few minutes after blood is drawn.  
• 
There is a risk that your information could be misused. The chance of this happening is 
very small. We have many protections in place to lower this risk. See the next section, 
“How will the information related to your samples be protected?” Your privacy will be 
protected to the fullest extent possible. 
• 
There can be a risk in knowing genetic information. New health information about inherited traits 
that might affect you or your blood relatives could be found during a research study. Even though 
your genes are unique, you share some of the same genes with your blood relatives. Very rarely 
health or genetic information could be misused by employers, insurance companies, and others. 
For example, life insurance companies may charge a higher rate based on this information.  
Some states have laws to protect against genetic discrimination. A new federal law called the 
Genetic Information Non-Discrimination Act, or GINA is in effect. This law helps to lower 
the risk of health insurance or employment discrimination. The law does not include other 
types of misuse by life insurance or long term care insurance. To learn more about the GINA 
Law, please check the Internet or ask the study staff. 

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Although we are not able to know all of the risks from taking part in research on inherited 
traits, we believe that the risks to you and your family are very low, because research results 
will not be returned to you or your doctor.  
How will information related to my samples be protected? 
We have many ways to protect the information related to your samples: 
• 
The samples and information sent to the Alliance Bank will receive a unique code. 
Researchers only receive coded samples and information, and will not be able to link 
the code to you. Only approved people in the Alliance can match you to the code on 
your samples and related information.  
• 
Strict security safeguards are in place to reduce the chance of misuse or unplanned 
release of information. Steps we take include, but are not limited to, restricted access 
to buildings, rooms and freezers housing patient samples, numeric coding of both 
patient data and samples, and password protected access to databases housing patient 
data. 
• 
Before samples are given to researchers, studies are reviewed for the quality of the 
science and for patient protection. Records from research studies can be reviewed by 
the Cooperative Group, by the sponsor, and by government agencies. This is to make 
sure the research follows the rules of the Cooperative Group and state or federal 
laws. 
• 
In most cases, research results will not be returned to you or your doctor. If research 
results are required to make a decision regarding your treatment on this study then 
research results may be shared with you or your doctor. If research results are 
published, your name and other personal information will not be given. 
 
 

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ADDITIONAL FUTURE STUDIES SECTION (OPTIONAL): 
Storage of Your Specimens: 
We would like to keep any leftover tissue and blood samples for future research. The choice 
to allow your left over samples to be stored and used for future research is up to you. This 
may help researchers learn more about how to prevent, find and treat cancer and other 
diseases. No matter what you decide, it will not affect your medical care and it will not affect 
whether you take part in other studies. 
The research that may be done with your specimens is not designed specifically to help you. 
It might help people who have cancer and other diseases in the future. Reports about research 
done with your specimens will not be given to you or your doctor. These reports will not be 
put in your health record. The research will not have an effect on your care. The choice to let 
us keep left over specimens for future research is up to you. 
Making your choice 
The choice to take part is up to you. You may choose not to let us use and store your leftover 
samples. If you decide not to let us store and use your samples, you will still receive the same 
medical care. You may also take part in other research studies. 
If you decide that your samples can be kept, you may change your mind at any time. Contact 
the study staff at your hospital and let them know that you do not want your samples used for 
research. Then, any sample that remains in the bank will no longer be used. Samples or 
related information that have already been given to or used by researchers cannot be returned 
or destroyed. 
Thank you for considering whether to allow your samples to be used for the research 
described above and/or banked for future research. 
1. 
My coded samples and related coded information may be kept for use in future 
research to learn about, prevent, find or treat cancer. This may also include research 
on inherited traits (genes passed on in families).   
Yes____   No____ 
2. 
My coded samples and related coded information may be kept for use in future 
research to learn about, prevent, find or treat other health problems (for example: 
diabetes, Alzheimer's disease, or heart disease). This may also include research on 
inherited traits (genes passed on in families).  
Yes____   No____ 
3. 
Someone from my hospital or the Alliance may contact me in the future to ask to take 
part in more research.  
Yes____   No____ 
 
This is the end of the section about additional studies. 
 
 

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Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have read it 
or it has been read to me.  I understand the information and have had my questions answered.  I agree to 
take part in this study. 
 
 
Printed Participant Name: __________________________________________ 
 
 
Participant Signature: ______________________________________________ 
 
 
Date: _____________________________________ 
 
 
Printed name of person obtaining informed consent:  
 
__________________________________________ 
 
 
Signature of person obtaining informed consent: 
 
___________________________________________ 
 
 
Date _____________________________________ 
 
 
 
 

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APPENDIX II: STANDARD OPERATING PROCEDURE FOR RPFNA 
 
Collection and Analysis of Breast Cells by Random Periareolar Fine Needle Aspirate 
(RPFNA) in Women at High Risk for Breast Cancer on Study 
 
Procedure: Participants will undergo RPFNA of both breasts (at the 2 and 10 o’clock position) prior to 
treatment with metformin or placebo and after treatment with metformin or placebo. RPFNA will be used 
to collect breast tissue samples. The entire procedure is expected take 30 minutes. Personnel required will 
include the provider performing the procedure and an assistant. 
Note: Only the contralateral breast can be aspirated in women with DCIS and in those undergoing surgery 
for an atypical lesion. 
 
Prior to Procedure: 
•  RPFNA kits will be assembled in quart-size Ziploc bags. Each kit should be labeled with the study 
name and CRA contact information. Each kit must include: 
 
Item 
Quantity 
12 cc Syringe 
17 
20 gauge needles (1.0-1.5”) 
17 
25 gauge needles (1.0-1.5”) 
5 
6 cc Syringe 
5 
1 mL Syringe (with 25 gauge 5/8 inch needle) 
5 
Cytolyte 
2 vials 
10% formalin 
2 
8.4% Injectable Sodium Bicarbonate 
approx. 5 mL 
Lidocaine 1% (with Epi) 
1 (20 mL) 
RPFNA Procedure Documentation Form 
1 
 
•  Provider/CRA will remind the participant not to use aspirin or other NSAIDs for the 7 days prior to the 
procedure and for 24 hours after the procedure. 
•  At least one day prior to the procedure, the participant will be given Emla crème. (Participating sites 
will need to provide this through their clinic or by writing a pharmacy prescription for the participant). 
 
Day of Procedure: 
•  On the day of the procedure the CRA will be available to help the clinician performing RPFNA collect 
the sample and bring/ship the Cytolyte containing the cellular material to the laboratory of Victoria 
Seewaldt. 
• 
On the day of the procedure the clinician will prepare the modified Cytolyte: two 15 mL tubes 
containing 10 mL modified Cytolyte (Cytolyte 9 mL + 1 mL 10% formalin freshly prepared on the 
morning of aspiration). 
•  On the day of the procedure the participant will apply the Emla crème in a "inch area ~1 inch from the 
areola at 2 and 10 o’clock on each breast 45 minutes to 1 hour before the procedure. 
•  Prior to the procedure the CRA will label the Cytolyte tube with the study name and number, study 
participant ID #, and the date of collection. 
•  The CRA will set up the procedure room prior to the participant’s arrival. 
•  Four 1 mL syringes with 25 gauge 5/8 inch needles should be set up to contain 4 parts lidocaine and 1 
part sodium bicarbonate (0.8 mL lidocaine with epinephrine followed by 0.2 mL of sodium 
bicarbonate). 
•  Four 6 cc syringes with 25 gauge 1.0-1.5 inch (depending on participant breast size) needle setups 
should be put together. These syringe/needle setups will include 5 mL total of lidocaine/sodium 

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bicarbonate with 4 parts lidocaine and 1 part sodium bicarbonate (4 mL lidocaine with epinephrine 
followed by 1 mL sodium bicarbonate). 
•  16 syringe/needle setups (20 gauge 1.0-1.5 inch needles depending on participant breast size) should 
be put together (therefore one extra syringe/needle setup will be available during the procedure if 
needed). These should be pre-wetted with RPMI or saline to the hub of the needle. RPMI/saline should 
be removed just prior to the procedure for each syringe. 
 
Procedure: 
•  The Emla crème will be removed with a soft cloth before the procedure. The affected areas will be 
cleaned with an alcohol swab prior to anesthetizing the area. 
•  1% lidocaine with epinephrine will be used for anesthesia. A small wheel of lidocaine will be made on 
the skin at each site of the Emla crème with the 1 mL syringe with a 25 gauge needle. This will be 
followed by the deeper injection of 1% lidocaine at each site (2 and 10 o’clock on each breast) using a 
1.0-1.5 inch 25 gauge needle. 
•  3 to 5 minutes should be taken to let the lidocaine spread and numb the underlying tissue, as well as to 
be absorbed. It is recommended that all sites be anesthetized prior to beginning the procedure. 
•  Sixteen, 1.0-1.5 inch 20 gauge needles attached to 13 cc syringes will be used for RPFNA at each 
anesthetized site (total 16 needle setups). The breast should be held up in the opposite hand that is 
performing the cell collection. Just before using the needle, squirt out the RPMI/saline from the syringe. 
Then, with the needle under the skin, suction will be applied in a steady manner and multiple needle 
passes per needle/syringe setup will be performed. When the hub of the needle has a visible amount of 
material present, that needle can be withdrawn and a new needle set used. It is important that when 
withdrawing the needle some air enter the needle, but not so much that all the cellular material sprays 
throughout the plastic syringe. 
•  A used needle setup will be handed to the CRA. The CRA will forcefully plunge the contents of the 
syringe/needle into the modified Cytolyte container (Cytolyte 9 mL + 1 mL 10 % formalin freshly 
prepared on the morning of aspiration). The syringe setup should subsequently be washed with 
modified Cytolyte from this same tube to remove any remaining cellular material (wash/plunge an 
additional 3-4 times). 
•  The entire sample from the right breast is pooled into one tube of modified Cytolyte labeled RIGHT - 
and the entire sample from the left breast is pooled into the second tube of modified Cytolyte labeled 
LEFT. 
 
After the Procedure: 
•  Following the procedure each breast should be treated with ice packs over the sites of the procedure for 
10 minutes. 
•  The participant should maintain compression of the breasts for the next 24 hours, even while sleeping. 
This can be done using by wearing a tight fitting sports bra or the Kling wrap/Breast Binder. The 
compression will prevent further bleeding and swelling. 
•  Recommend that the participant take acetaminophen within the hour to alleviate any discomfort as the 
lidocaine wears off. 
•  Provider will complete the RPFNA Procedure Documentation Form, to document the procedure. 
•  CRA or provider will make a follow-up phone call the following day to check in with the participant 
and review any side effects of the procedure. 
 

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For participants at UVM/FAHC: Samples will be taken directly to the cytopathology laboratory where 
the sample will be spun down and processed into cytology slides using the thin preparation method. 
 
For participants at other sites: The 2 tubes of modified Cytolyte will be appropriately packaged (see 
Section 14.0) and sent to the laboratory of Victoria Seewaldt (see shipping address), where it will be 
processed as described in the protocol. 
 
Shipping address: 
 
 
 
 
 
 
 
 
 

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APPENDIX III: PATIENT MEDICATION DIARY 
 
Start Date: _____________________  
Alliance Patient Number: ________________ Patient Initials (LFM) __________________ 
INSTRUCTIONS TO PATIENT: 
• Complete this form during the four week ramp-up period. 
• Please record the date you start taking pills for this study. 
• You should take one pill by mouth once a day. 
• After 4 weeks, you will receive a telephone call to discuss this medication diary. 
 
 
COMMENTS: 
 
 
 
 
 
 
SIGNATURE: ____________________________________________ 
 
DATE: ___________________ (dd/mm/yyyy) 
 
 
 
Day of the 
Week 
Day of the 
Week 
Day of the 
Week 
Day of the 
Week 
Day of the 
Week 
Day of the 
Week 
Day of the 
Week 
 
 
 
 
 
 
 
Day 1 
 
Day 2 
 
Day 3 
 
Day 4 
 
Day 5 
 
Day 6 
 
Day 7  
 
 
 
 
 
 
 
 
Day 8 
 
Day 9 
 
Day 10 
 
Day 11 
 
Day 12 
 
Day 13 
 
Day 14 
 
 
 
 
 
 
 
 
Day 15 
 
Day 16 
 
Day 17 
 
Day 18 
 
Day 19 
 
Day 20 
 
Day 21 
 
 
 
 
 
 
 
 
Day 22 
 
Day 23 
 
Day 24  
 
Day 25 
 
Day 26 
 
Day 27 
 
Day 28 
 
 
 
 
 
 
 
 
 

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APPENDIX IV: NURSE/CRA PHONE CONTACT GUIDE 
 
Patient Phone No. _________________________  
Best Dates/Times to call_______________________ 
 
FOLLOW UP: 
 
1. Phone call schedule:   
• 
Call patient at home after one month to document compliance and address problems.  If the patient 
is seen in clinic, this phone call can be omitted.  
 
• 
Call patient at home for those women on placebo arm and crossing over after 12 months.  
 
2. Physician’s office will record the following information in the patient record. 
▪ 
Date of phone call 
▪ 
Date patient finished ramp-up period ____________________ 
▪ 
Total number of pills taken during ramp-up period: ____________________ 
▪ 
Date patient started protocol treatment: ____________________ 
▪ 
Questions/Comments 
 
If the patient reports any side effects, please document:  
o Side effects: 
▪ 
Abdominal distension - Severity and attribution, if applicable 
▪ 
Bloating - Severity and attribution, if applicable 
▪ 
Diarrhea - Severity and attribution, if applicable 
▪ 
Nausea - Severity and attribution, if applicable 
▪ 
Vomiting - Severity and attribution, if applicable 
▪ 
Any others - Severity and attribution, if applicable. 
 
3. Remind the patient to increase medication to twice daily after 28 days.   
 
Physician/Nurse/Data Manager’s signature _______________________________________________ 
 
Date ______________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX V: FOLLOW-UP RPFNA PHONE CONTACT 
Introduction: 
 
Good morning/afternoon. This is _________speaking and I’m calling from _______________.  Thank you for 
participating in our chemoprevention study comparing Metformin to placebo. I would like to ask a few 
questions about how you are doing following the Random Periareolar Fine Needle Aspiration procedure. 
Please also understand that your answers to these questions will be kept confidential and when the data from 
this research study is reported your data will be included in a summary without your name or any other 
identifying information.  Is now a good time?  
___Yes (continue) 
 ___No: When may I call you back? ___________________________ 
1. 
Did you experience any pain after the RPFNA procedure?  
 Yes    
 No 
If no, skip to question #3. 
If yes, how long did it last? ______________________________________________________________________ 
2. 
If yes, did you take any medication for the pain? 
 Yes    
 No 
If no, skip to question #3. 
If yes, which medication and how many doses? ______________________________________________________ 
_____________________________________________________________________________________________ 
3. 
Do you have any bruising after the RPFNA procedure?  
 Yes    
 No 
4. 
Did you experience any of the following after the RPFNA procedure? 
Fever                        
 Yes    
 No 
If yes, when did it start, how bad was it, did you take any medication for it, did it resolve? 
Comments: ___________________________________________________________________________________ 
Bleeding                    
 Yes    
 No 
If yes, when did it start, how bad was it, did you take any medication for it, did it resolve? 
Comments: ___________________________________________________________________________________ 
Indication of infection, such as redness, warmth, odor, or discharge at the site of the needle insertions?   
 
Yes    
 No 
Comments: ___________________________________________________________________________________ 
_____________________________________________________________________________________________ 
 
Physician/Nurse/Data Manager’s signature _________________________________ Date ____________