Conditions: Anatomic Stage I Breast Cancer AJCC v8 Anatomic Stage IA Breast Cancer AJCC v8 Anatomic Stage IB Breast Cancer AJCC v8 Anatomic Stage II Breast Cancer AJCC v8 Anatomic Stage IIA Breast Cancer AJCC v8 Anatomic Stage IIB Breast Cancer AJCC v8 Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IIIA Breast Cancer AJCC v8 Anatomic Stage IIIB Breast Cancer AJCC v8 Anatomic Stage IIIC Breast Cancer AJCC v8 Early-Stage Breast Carcinoma Invasive Breast Carcinoma Prognostic Stage I Breast Cancer AJCC v8 Prognostic Stage IA Breast Cancer AJCC v8 Prognostic Stage IB Breast Cancer AJCC v8 Prognostic Stage II Breast Cancer AJCC v8 Prognostic Stage IIA Breast Cancer AJCC v8 Prognostic Stage IIB Breast Cancer AJCC v8 Prognostic Stage III Breast Cancer AJCC v8 Prognostic Stage IIIA Breast Cancer AJCC v8 Prognostic Stage IIIB Breast Cancer AJCC v8 Prognostic Stage IIIC Breast Cancer AJCC v8
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 161
Healthy volunteers: no

Brief summary:
This phase II trial studies how well anastrozole and letrozole after surgery work in treating patients with stage I-III breast cancer. Drugs, such as anastrozole and letrozole, may stop the growth of tumor cells by decreasing the amount of estrogen made by the body. Giving anastrozole and letrozole after surgery may prevent breast cancer from coming back (recurrence).

Detailed description:
PRIMARY OBJECTIVE:

I. To estimate the proportion of women who have adequate estrone (E1) and estradiol (E2) suppression after 8-10 weeks of adjuvant anastrozole 10 mg once daily (ANA10) having had inadequate E1 and E2 suppression after 8-10 weeks of standard dose anastrozole 1 mg once daily (ANA1).

SECONDARY OBJECTIVES:

I. To estimate the proportion of women with elevated E1 and E2 levels after 8-10 weeks of adjuvant ANA1.

II. To estimate the proportion of women with elevated E1 and E2 levels after 8-10 weeks of adjuvant ANA1 whose E1 and E2 levels remain elevated after 8-10 weeks of adjuvant ANA10.

III. To examine the toxicity profile of ANA1 over the 8-10 weeks of treatment, ANA10 over the 8-10 weeks of treatment, and letrozole over the 8-10 weeks of treatment.

IV. To examine concentrations of anastrozole at both the ANA1 and ANA10 dose levels.

V. To examine E1 and E2 concentrations, as well as letrozole drug levels, in patients receiving letrozole (following ANA10).

VI. To bank deoxyribonucleic acid (DNA) for examination of single-nucleotide polymorphism (SNP)-set(s) determined in the ongoing Mayo Clinic Breast Cancer Specialized Program of Research Excellence (SPORE) Project 4.

EXPLORATORY OBJECTIVE:

I. To examine association between clinical variables such as age, age at menopause, body mass index (BMI), receipt of chemotherapy, chemotherapy regimen, and dose on E1 and E2 levels after 8-10 weeks of ANA10.

OUTLINE:

Patients receive anastrozole orally (PO) once daily (QD) for 56-70 days (8-10 weeks). Patients with E1 \>= 1.3 pg/ml and E2 \>= 0.5 pg/ml continue to receive anastrozole PO QD for another 56-70 days (8-10 weeks). Patients then receive letrozole PO QD for 8-10 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Arms:
arm 1: Patients receive anastrozole PO QD for 56-70 days (8-10 weeks). Patients with E1 \>= 1.3 pg/ml and E2 \>= 0.5 pg/ml continue to receive anastrozole PO QD for another 56-70 days (8-10 weeks). Patients then receive letrozole PO QD for 8-10 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Anastrozole intervention 2: Letrozole
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO

Protocol document:
Prot_SAP_001.pdf: 
MC1931 
Protocol Version Date: 19Nov2020 
Mayo Clinic Cancer Center 
MC1931-Pharmacodynamic Study of Estrogen Suppression Threshold-Directed Therapy (ESTDT) 
of Anastrozole as Adjuvant Therapy for Early Stage Breast Cancer 
Sponsor/Principal Investigator: 
  
 
 
Co-Investigators: 
 
 
 
 
 
Statistician: 
 
Patient Advocate: 
 
√Study contributor(s) not responsible for patient care 
FDA IND #: 146718 
Trial Supported by:  
Funding: Mayo Clinic Breast Cancer Specialized Program of Research Excellence (SPORE) 
Drug Availability: 
Commercial Agents: anastrozole (1mg), letrozole 
Supplied Agents: anastrozole (10mg) 
Site Investigators & Participating sites:  
 
  
  
 
  
  
 
 
Document History 
(Effective Date) 
Activation 
28Apr2020 
MCCC Amendment 1 
04Nov2020 
MCCC Amendment 2 
pending 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
 
 
Drug administration, infusion pumps,  
nursing guidelines 
 
 
 
Clinical Research Coordinator (lead site) 
 
 
Clinical Data Coordinator (lead site) 
 
 
 
Breast Program Coordinator 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
 
 
  
Laboratory contact 
 
 
 
 
 
Serious Adverse Event Reporting 
 
 
 
*No waivers of eligibility allowed 
 
 


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Table of Contents 
MC1931-Pharmacodynamic Study of Estrogen Suppression Threshold-Directed Therapy (ESTDT) of 
Anastrozole as Adjuvant Therapy for Early Stage Breast Cancer ................................................................ 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ........................................................................................................................................... 12 
3.0 
Registration Patient Eligibility .................................................................................................... 13 
4.0  
Test Schedule .............................................................................................................................. 16 
5.0 
Stratification Factors: None ........................................................................................................ 17 
6.0 
Registration/Randomization Procedures ..................................................................................... 17 
7.0 
Protocol Treatment ...................................................................................................................... 19 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 23 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 24 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 25 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 34 
12.0 
Descriptive Factors: None ........................................................................................................... 34 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 34 
14.0 
Body Fluid Biospecimens ........................................................................................................... 36 
15.0 
Drug Information ........................................................................................................................ 41 
16.0 
Statistical Considerations and Methodology ............................................................................... 44 
17.0 
Pathology Considerations/Tissue Biospecimens: None .............................................................. 47 
18.0 
Records and Data Collection Procedures .................................................................................... 48 
19.0  
Budget ......................................................................................................................................... 48 
20.0 
References ................................................................................................................................... 49 
Appendix I 
ECOG Performance Status ............................................................................................... 50 
Appendix II 
Patient Medication Diary .................................................................................................. 51 
.


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Schema 
 
 
Registration 
 
 
 
 
↓ 
 
 
 
 
Cycle 1: 
Anastrozole (ANA1) 
 
 
 
 
↓ 
 
 
 
 
Check blood levels: 
E1≥1.3 pg/ml 
AND 
E2≥0.5 pg/ml 
 
 
no 
 
yes↓ 
 
 
Off study 
 
Re-registration 
 
Events at any time: 
Disease Progression 
Intolerable adverse effects 
Patient refusal 
 
 
↓ 
 
↓ 
 
 
Cycle 2*: 
Anastrozole (ANA10) 
 
Off study 
 
 
↓** 
 
 
 
 
Cycle 3: 
Letrozole (LET) 
 
 
 
 
↓ 
 
 
 
 
Off study 
 
 
 
*Enrollment will be temporarily suspended after 6 patients have been re-registered and started ANA10 
**Adverse event assessment will be carried out for all patients who begin ANA10, 28-35 days after the 
completion of ANA10 (regardless of whether the patient continued on to letrozole) 
Cycle = 56-70 days (8-10 weeks) 
ANA1 = Anastrozole 1 mg 
ANA10 = Anastrozole 10 mg  
LET = Letrozole 
Generic name: anastrozole 
Brand name(s): Arimidex® 
Availability: Commercial (ANA1) 
Provided by study (ANA10) 
Generic name: letrozole 
Brand name(s): Femara® 
Availability: Commercial 


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1.0 
Background  
1.1 
Rationale for selected approach 
The third-generation aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole, 
all play a major role in the adjuvant therapy of postmenopausal women with early stage 
estrogen receptor α (ERα)-positive breast cancer1,2. The assumption is that for all three 
AIs the mechanism of action in inhibiting tumor growth is only through decreasing 
estrogen production from androgenic precursors, by inhibiting aromatase3, which is 
encoded by the CYP19A1 gene4-6. Whereas all three AIs are potent in terms of inhibition 
of in vivo aromatization7-9, letrozole has been found to be the most potent10. However, 
large phase III adjuvant clinical trials do not indicate any difference in efficacy between 
the three AIs. Specifically, the MA.27 trial showed no significant difference between 
anastrozole and exemestane11 in terms of DFS, and the FACE trial showed no difference 
between anastrozole and letrozole in terms of both DFS and OS12. 
We previously performed a pharmacokinetic and pharmacodynamic study in 649 patients 
receiving anastrozole adjuvant therapy13 that showed 21% and 30%, respectively, had 
estradiol (E2) and estrone (E1) concentrations above the lower limit of quantitation 
(LLQ), with a broad range of detectable concentrations. 
Until recently there were no clinical studies which systematically tested whether the 
degree of estrogen suppression is associated with AI efficacy in early stage ERα-positive 
breast cancer. To address this unmet need, matched case-control studies14 were performed 
utilizing data from the MA.27 and PreFace trials. MA.27 enrolled postmenopausal 
women with resected stage I-III ERα-positive breast cancer who were randomized to 
either anastrozole or exemestane for five years. PreFace evaluated adjuvant letrozole in a 
single-arm phase IV trial. A breast event was considered to be any of the following: 
local-regional breast cancer recurrence [including ipsilateral DCIS], distant breast cancer 
recurrence, contralateral breast cancer [invasive or DCIS], or death with or from breast 
cancer without prior recurrence. 
Due to the lack of an independent validation cohort, a bootstrap re-sampling approach 
was undertaken to determine ‘best’ cut points for the biomarkers, E1 and E2. 
Specifically, 500 bootstrap samples were constructed by sampling with replacement 
using 222 matched case-control sets from the 247 matched case-control sets. The set of 
potential cut-points assessed for each biomarker included values from its lower limit of 
quantification to its 85th percentile value (across all women). The ‘best’ cut point for a 
given biomarker was chosen using the maximum concordance approach of Liu.15 
Specifically, for each potential cut point yi, an indicator variable xi was constructed where 
xi=1 if the patient’s biomarker value was at or above yi; xi=0 otherwise. Then, for each 
bootstrap sample, j,  and each cut point, i, a concordance statistic Cij was generated from 
fitting a stratified Cox model with case-control set as the strata, time set to the constant of 
1, and the indicator variable for the cut point was fit to the data.16 The cut point where the 
maximum value of the concordance statistic, max Cj, occurred was determined for each 
bootstrap sample j. The cut point most often found to be the max Cj cut point across the 
500 samples was chosen for further evaluation. Having established cut points for E1 and 
E2, multivariate conditional logistic regression modeling using all 247 matched pairs was 
used to refine the model of risk. A secondary exploratory analysis was carried out using 
the refined model to obtain an estimate of the odds of EBCE for each treatment cohort 
separately. Statistical analyses were carried out using SAS 9.4 and the survConcordance() 
function in the survival package of R software. 


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The pre-AI E1 and E2 concentrations were similar among the 3 treatment cohorts, and 
were highly correlated within each treatment cohort with Spearman rank coefficients (ρ) 
of 0.84 for anastrozole; 0.89 for exemestane; and 0.90 for letrozole. After six months of 
AI therapy, E1 and E2 concentrations were below the LLQ in 41.3% and 11.9%, 
respectively, for anastrozole; 63.7% and 35.4%, respectively, for exemestane, and 79.3 % 
and 48.7%, respectively, for letrozole. The correlation between E1 and E2 concentrations 
after six months of AI therapy was moderate for anastrozole (ρ= 0.54) and exemestane 
(ρ=0.52) but weak for letrozole (ρ= 0.15). There was a very weak correlation between 
both E1 and E2 with AI concentrations after 6 months of treatment (ρ=-0.20 and -0.12 for 
anastrozole; -0.18 and -0.12 for exemestane, and -0.11 and -0.09 for letrozole, 
respectively). Six-month plasma concentrations of each of the AIs showed substantial 
inter-patient variability. 
1.2 
Estrone and Estradiol Suppression and Risk of an Early Breast Cancer Event 
A potential cut point for E1 after six months of treatment was searched for between its 
lower limit of quantification (1.0 pg/mL) and the 85th percentile value of its distribution 
(1.7 pg/mL). For each cut point, a stratified Cox model was fit to the first of 500 
bootstrap samples, and an estimate of the odds of EBCE and the concordance statistic 
was determined. This process was repeated for the remaining 499 bootstrap samples. 
From the 500 estimates of the odds ratio for a given cut point, the median and 2.5th and 
97.5th percentile value of its distribution was determined and presented in Figure 1 for E1 
and in Figure 2 for E2. The value of E1 most often having the maximum concordance 
value was 1.3 pg/mL and as such is the threshold for E1 (Figure 1). The process was 
repeated for E2 searching between the lower limit of quantification (0.3 pg/mL) and 85th 
percentile value of its pre-treatment distribution (0.7 pg/mL). The value of E2 most often 
having the maximum concordance value among the 500 bootstrap samples was 0.5pg/mL 
(Figure 2).  
Using the cut point values identified for E1 and E2, multivariate conditional logistic 
modeling was used to assess whether or not the risk of EBCE differed with respect to 
whether E1 and E2 remain at or above its threshold after 6 months of treatment. Patients 
with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL were found to have a 2.2 fold (95% CI: 1.42-
3.47) increase in risk of an EBCE relative to patients with E1, E2, or both below these 
thresholds. 
The question as to whether this relationship holds for each treatment group was 
determined. The risk of an EBCE was increased 3.0 fold (sets=91: 95% CI: 1.56-5.76, 
p=0.001) for those with E1 and E2 values at or above their threshold after 6 months 
of anastrozole; but not in those treated with exemestane (sets=95: 95% OR=1.66; CI: 
0.82-3.33, p=0.16) or letrozole (sets=59: 95% OR=1.62; CI: 0.39-6.82, p=0.51). 
In the case of anastrozole, an odds ratio of three means that a patient with an E2 and E1 at 
or above the thresholds had a three-fold risk of recurrence compared with a patient with 
the same matching factors (in this case: age, disease stage, BMI category, and adjuvant 
chemotherapy status) who had an E2 or E1 below the threshold. 


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Figure 1 
 
Figure 1 Legend. Bootstrap Resampling for E1 Odds Ratio 
Distributions from (all 247 Case-Control Sets). E1>1.3 vs. <1.3 
Odds Ratio (95% CI): 1.75 (1.19, 2.55), p=0.004 
 
Figure 2 
 
Figure 2 Legend. Bootstrap Resampling for E2 Odds Ratio Distributions 
from (all 247 Case-Control Sets). E2>0.5 vs. <0.5 Odds Ratio (95% CI): 
1.44 (1.02, 2.03), p=0.04 


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1.3 
Preclinical laboratory studies supporting a difference between anastrozole and 
exemestane and letrozole 
Our preclinical data indicated that anastrozole, but not letrozole or exemestane, behaved 
in a fashion similar to E2. Anastrozole could activate ERα-dependent transcription 
(Figure 3), but the effect decreased with increasing concentrations. Additionally, in the 
presence of 100 nM anastrozole, we also observed time-dependent ERα degradation. 
Given that these data indicated that anastrozole but not exemestane or letrozole, had a 
mechanism of action in addition to inhibition of aromatase, and was a ligand for ERα, we 
performed radioligand binding assays (Figure 4), surface plasmon resonance (Figure 5), 
and nuclear magnetic resonance studies (Figure 6) that confirmed that, indeed anastrozole 
was a ligand for ERα. 
Figure 3. 
 
Figure 3 Legend: Estrogen response element-dependent luciferase 
assay in CYP19A1 CRISPR KO T47D cells treated with indicated 
concentrations of E2, anastrozole (Ana), letrozole (Let) or exemestane 
(Exe). 
 
Figure 4. 
 
Figure 4 Legend: Radioligand binding assays. [H3]-anastrozole binding 
with ERα protein. TB: total binding, NSB: non-specific binding, SB: 
specific binding. 
 
 
 


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Figure 5. 
 
Figure 5 Legend: ERα binding assays of anastrozole at different 
concentrations as indicated using a surface plasmon resonance 
biosensor. Comparisons among all four compounds at 2 μM. 
 
Figure 6. 
 
Figure 6 Legend: Anastrozole binding of ERα detected by nuclear 
magnetic resonance (NMR) spectroscopy. One-dimensional proton 
Carr-Purcel-Meiboom-Gill NMR spectroscopy of 120 μM anastrozole in 
the absence (top, red) and presence (bottom, blue) of 3 μM ERα 
protein. Dashed boxes showed decreased NMR signals. Spectra were 
normalized to each other using β-mercaptoethanol (βMe) signal shown 
in purple. 
We then tested the effect of anastrozole on cell proliferation in the presence of estrogen 
levels below, at, and above the thresholds identified in the clinical studies described 
above. In vitro, E1 and E2 below 1.3 pg/mL and 0.5 pg/mL, respectively, had little effect 
on CYP19A1 KO T47D cell proliferation. Anastrozole, but neither letrozole nor 
exemestane, potentiated estrogen effects on cell proliferation when estrogen levels were 
above the thresholds, compared to estrogen alone, especially when both E1 and E2 were 
above the thresholds (Figure 7 A-C). Anastrozole, but neither letrozole nor exemestane, 
potentiated estrogen-induced ERE luciferase activity when estrogen levels were above 
the thresholds (Figure 7 D-F).These phenomena were also observed in an MCF7 cell line. 


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Figure 7. 
 
Figure 7 Legend: Anastrozole potentiates estrogen’s effects when estrogen 
levels are above the thresholds. A. Cell growth of CYP19A1 KO T47D cells in the 
presence of anastrozole (A) (27 ng/ml) plus indicated concentrations of estrone 
(E1) (0.13, 1.3, 2.6, and 26 pg/mL) and estradiol (E2) (0.1, 0.5, 2.5, and 25 
pg/mL). B. Cell growth of CYP19A1 CRISPR KO T47D cells in the presence of 
letrozole (L) (215 ng/mL) plus estrone (E1) and estradiol (E2). C. Cell 
proliferation of CYP19A1 CRISPR KO T47D cells in the presence of exemestane 
(E) (10 ng/mL) plus estrone (E1) and estradiol (E2). D-F. Estrogen response 
element-dependent luciferase assay in CYP19A1 CRISPR KO T47D cells treated 
with indicated concentrations of E1 (0.13, 1.3, 2.6, and 26 pg/mL), E2 (0.1, 0.5, 
2.5, and 25 pg/mL), or in combination with anastrozole (A) (27 ng/mL), letrozole 
(L) (215 ng/mL), and exemestane (E) (10 ng/mL). Error bars represent the SEM 
of 3 independent experiments. **p<0.01. 
 
1.4 
Trial Design 
To evaluate the clinical impact of these findings, this clinical trial is designed to evaluate 
anastrozole in the adjuvant setting for patients with early stage ERα-positive breast 
cancer. Specifically, E1 and E2 levels will be assessed in patients who receive standard 
dose adjuvant anastrozole (1mg once daily). For patients who have inadequate 
suppression of E1 and E2 after 2 months of treatment, with levels above the thresholds of 
1.3 pg/ml and 0.5 pg/ml respectively, the dose of anastrozole will be escalated to 10 mg 
once daily. E1 and E2 levels will be re-assessed after 2 months of treatment on 10 mg of 
anastrozole. E1 and E2 will be measured by a CLIA-approved liquid chromatography 
with tandem mass spectrometry (LC/MS/MS) in the Immunochemical Core Laboratory at 
Mayo Clinic. Details of the methodology have been published17-19. In addition, 
anastrozole and letrozole concentrations will be measured by Zeruesenay Desta, PhD, at 
Indiana University, a long-time collaborator, who has performed these assays in past 
studies20. The main purpose of performing the AI assays is to ensure that the patients are 
taking the drug, but we are also interested in the steady state concentrations of 
anastrozole in the women who take the 10 mg daily dose. 
The 10 mg dose of anastrozole has been previously compared with standard 1 mg dosing 
in patients with metastatic breast cancer21. There was no difference in clinical efficacy 
and toxicities were comparable. Regarding the cost of anastrozole therapy, the 1 mg dose 


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costs about $2/day and the 10 mg dose costs roughly $20/day, which translates to 
$60/month and $600/month, respectively. For patients who receive anastrozole at 10 mg 
per day for 8-10 weeks, patients will be advised to take letrozole, an FDA-approved 
agent, to complete their course of adjuvant endocrine therapy. After 8-10 weeks of 
letrozole, patients will have blood samples obtained for E1, E2, and letrozole 
concentrations. The rationale for this approach is that further research will be required 
before it is known if continuing anastrozole at 10 mg per day will provide long term 
benefit to patients.  
1.41 
Safety Run-in 
At the request of the FDA, re-registration to the ANA10 treatment portion of the 
trial will be initially limited to a maximum of 6 patients. After 6 patients have re-
registered, enrollment will temporarily halt. If  two or more of these 6 patients 
develop a DLT (as specified in Section 7.0 of the protocol) within 28-35 days of 
starting ANA10, the study will remain closed to enrollment to allow the study 
team to review toxicity data thoroughly and make decisions regarding changes to 
the protocol. If at most one of these 6 patients develops a DLT within 28-35 days 
of starting ANA10, the FDA will be notified and re-registration will be reopened. 
1.42 
Adjustments to Eligibility in Response to the COVID-19 Pandemic 
Due to the COVID-19 pandemic and late 2020 surge in cases, some patients have 
experienced delays in their surgical procedures and have been started on 
endocrine therapy preoperatively to bridge to the operating room. Typically the 
time on treamtment is several weeks or up to 4 months. In response to this, the 
protocol has been amended to adapt to these circumstances, and allow patients 
who have received preoperative endocrine therapy to participate. Specifically, the 
half-life of anastrozole and letrozole is approximately 50 hours and exemestane 
is 24 hours; as such, these agents are cleared from the system after 5 half-lives. 
To this end, patients who received preoperative endocrine therapy with an 
aromatase inhibitor can participate if they have been off treatment for at least 4 
weeks prior to registration. This will allow adequate elimination of the drug and 
baseline steady-state prior to study participation. Tamoxifen is much less 
commonly used in postmenopausal women as preoperative therapy. Due to its 
longer half-life of 5-7 days, patients who received preoperative tamoxifen can 
participate if they have been off treatment for at least 12 weeks prior to 
registration.  
In alignment with these changes, prior receipt of an aromatase inhibitor or SERM 
(tamoxifen or raloxifene) for the prevention of breast cancer is allowed. In this 
setting, given these agents are typically administered for up to 5 years, a longer 
wash out of 6 months is preferred.  
Additionally, there have been delays for post-operative Medical Oncology 
consultation; as such, the requirement to complete all cancer treatment within 60 
days prior to registration has been removed. Specifically, patients must have 
completed treatment, but any time between that and registration is permissible.


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2.0 
Goals  
2.1 
Primary Goal 
To estimate the proportion of women who have adequate estrone (E1) and estradiol (E2) 
suppression after 8-10 weeks of adjuvant anastrozole 10 mg once daily (ANA10) having 
had inadequate E1 and E2 suppression after 8-10 weeks of standard dose anastrozole 1 
mg once daily (ANA1). 
2.2 
Secondary Goals 
2.21 
To estimate the proportion of women with elevated E1 and E2 levels after  
8-10 weeks of adjuvant ANA1. 
2.22 
To estimate the proportion of women with elevated E1 and E2 levels after  
8-10 weeks of adjuvant ANA1 whose E1 and E2 levels remain elevated after  
8-10 weeks of adjuvant ANA10. 
2.23 
To examine the toxicity profile of ANA1 over the 8-10 weeks of treatment, 
ANA10 over the 8-10 weeks of treatment, and letrozole over the 8-10 weeks of 
treatment. 
2.24 
To examine concentrations of anastrozole at both the ANA1 and ANA10 dose 
levels. 
2.25 
To examine E1 and E2 concentrations, as well as letrozole drug levels, in patients 
receiving letrozole (following ANA10). 
2.26 
To bank DNA for examination of SNP-set(s) determined in the ongoing Mayo 
Clinic Breast Cancer SPORE Project 4 
2.3 
Exploratory Objectives 
To examine the association between clinical variables such as age, age at menopause, 
BMI, receipt of chemotherapy, chemotherapy regimen, and dose on E1 and E2 levels 
after 8-10 weeks of ANA10. 
 
 


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3.0 
Registration Patient Eligibility 
3.1 
Registration - Inclusion Criteria 
3.11 
Women of age ≥18 years. 
3.12 
Disease characteristics: 
3.121 
Histological confirmation of invasive breast carcinoma. 
3.122 
Stage I-III breast cancer 
3.123 
Estrogen receptor (ER) positive disease according to ASCO/CAP 
guidelines as ER≥1% positive nuclear staining. 
3.13 
Completion of all planned cancer treatments prior to registration: 
1) surgical resection of breast and nodal surgery; 
(NOTE: Reconstructive surgery does not have to be completed) 
2) adjuvant radiation therapy, if needed;  
3) and neoadjuvant and/or adjuvant chemotherapy, if needed. 
3.14 
Post-menopausal defined as 
• 
Age ≥60 and amenorrhea >12 consecutive months 
OR  
• 
Previous bilateral oophorectomy  
OR 
• 
Age <60 and amenorrhea >12 consecutive months and documented follicle 
stimulating hormone (FSH) level within post-menopausal range according to 
institutional standard 
NOTE: Patients who did not meet these criteria at time of diagnosis and received 
pre-operative (neoadjuvant) or post-operative (adjuvant) chemotherapy 
will not be allowed to participate. 
3.15 
ECOG Performance Status (PS) 0, 1, or 2 (Appendix I). 
3.16 
The following laboratory values obtained ≤14 days prior to registration:  
• 
Hemoglobin ≥8.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥70,000/mm3 
• 
Total bilirubin ≤1.5 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x 
ULN  
3.17 
Ability to swallow oral medication 
3.18 
Provide written informed consent. 
3.19a 
Willingness to provide mandatory blood specimens for correlative research (see 
Section 14.0). 
3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study).  
 
 


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3.2 
Registration - Exclusion Criteria 
3.21 
Pre-menopausal women receiving ovarian function suppression (goserelin, 
leuprolide, etc.) 
3.22 
Stage IV (metastatic) breast cancer. 
3.23 
HER2 positive breast cancer as defined by 
• 
HER2 IHC ≥3+ 
• 
HER2/CEP17 ≥2.0  
• 
HER2/CEP17 <2.0 and average HER2 copy number of ≥6.0 signals/cell 
3.24 
Prior endocrine therapy for this breast cancer. 
Exceptions: 
1) Pre-operative aromatase therapy (anastrozole, letrozole, or exemestane)  and 
last treatment was ≥4 weeks prior to registration 
OR 
2) Pre-operative tamoxifen therapy and last treatment was ≥12 weeks prior to 
registration 
3.25 
Currently receiving any of the following cancer-directed therapies: 
• 
Radiation therapy 
• 
Systemic therapy such as chemotherapy (standard or investigational) 
3.26 
Bisphosphonate therapy started <4 weeks prior to registration. 
NOTE: If patient is currently on bisphosphonate therapy she must be on stable 
dose for ≥4weeks prior to registration. 
Patients not currently taking bisphosphonates will be allowed to start 
bisphosphonate therapy after completion of anastrozole (1mg and 10 mg 
daily (if given)). Information regarding bisphosphonate therapy will be 
collected. 
3.27 
Current use of systemic or topical exogenous estrogen or progesterone 
(menopausal hormone replacement therapy [HRT]). 
3.28 
Prior ovarian function suppression (leuprolide, goserelin, etc). 
3.29a 
Inability to provide informed consent. 
3.29b History of contralateral DCIS or invasive breast cancer. 
NOTE: Exception allowed if 
1. Patient did not receive adjuvant endocrine therapy 
OR 
2. Patient received adjuvant endocrine therapy but has been off treatment for at 
least 6 months prior to registration 
3.29c 
Concurrent active malignancy or history of malignancy ≤3 years prior to 
registration. 
NOTE: Exceptions allowed for successfully treated cervical carcinoma in situ, 
lobular carcinoma in situ of the breast, papillary thyroid cancer, or non-
melanoma skin cancer. 
 
 


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3.29d Prior prevention therapy with an aromatase inhibitor or a SERM. 
Exception: Therapy with a SERM (tamoxifen or raloxifene) is allowed if patient 
has been off treatment for ≥6 months prior to registration. 
3.3 
Re-Registration – Inclusion Criteria 
3.31 
Confirmation that baseline blood sample was drawn and submitted. 
3.32 
Blood estrogen levels after Cycle 1anastrozole (ANA1) must meet the following 
criteria: 
E1≥1.3 pg/ml, AND 
E2≥0.5 pg/ml 
 


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4.0  
Test Schedule 
4.1 
Test schedule for breast cancer 
 
Active Monitoring Phase 
Tests and procedures 
≤14 days 
prior to 
registration 
At end of 
Cycle 11 
Re-registration 
After 
ReReg and 
prior to Tx 
on C2D12 
Nurse call 
2-4 weeks 
after starting 
ANA10 
First 6 pts: 
once during 
Cycle 2 
Days 28-353 
At end of 
Cycle 24 
30 days 
after last 
dose of 
ANA10 
At end 
of 
Cycle 3 
Window 
 
±7 days 
 
±7 days 
 
±7 days 
±3 days +14 days 
History and exam5 
X 
X 
X6 
 
 
 
 
X 
Height and weight7 
X 
X 
 
 
 
XR 
 
X 
Adverse event assessment, vital 
signs (BP, pulse), ECOG PS 
X 
X 
X 
X8 
XR 
XR 
XR 
X 
Hematology: CBC/differential 
X 
XR 
 
 
XR 
XR 
XR 
 
Chemistries: 
alanine transaminase (ALT), 
aspartate transaminase (AST), 
total bilirubin 
X 
XR 
 
 
XR 
XR 
XR 
 
Research blood specimens  
(see Section 14.0),R 
XR 
XR9 
 
 
 
XR 
 
XR 
Medication Diary 
 
X 
 
 
 
X 
 
X 
Cycle = 56-70 days (8-10 weeks), R= Research funded 
 
1 Approximately 9 weeks after start of ANA1 ±7 days; or at discontinuation of ANA1 if that event occurs earlier than 8-10 weeks. 
2 Visit to obtain prescription after blood results are received. 
3 One-time safety assessment for first six patients who re-register to ANA10 
4 Approximately 9 weeks after start of ANA10 ±7 days; or at discontinuation of ANA10 if that event occurs earlier than 8-10 weeks. Must be prior to starting 
letrozole. 
5 Physical exam is required at baseline. After baseline, physical exam may be performed at any time as clinically indicated, but is not required for protocol. 
6 Nurse visit for ANA10 education (prior to starting ANA10) 
7 Only weight needed after baseline 
8 Call to assess/collect adverse events and verify patient is taking ANA10 and wants to continue (no vital signs or PS); Refill ANA10 by mail if needed 
9 E1 and E2 results required prior to re-registration. 


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4.2 
Survival Follow-up 
This study does not follow patient survival. Once patients complete protocol treatment 
and procedures they are off study. 
5.0 
Stratification Factors: None 
6.0 
Registration/Randomization Procedures 
6.1 
Registration (Step 1) 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the registration/randomization application. The registration/ randomization application is 
available 24 hours a day, 7 days a week. Back up and/or system support contact 
information is available on the website. If unable to access the website, call the MCCC 
Registration Office at 
between the hours of 8 a.m. and 4:30 p.m. Central 
Time (Monday through Friday). 
The instructions for the registration/randomization application are available on the 
MCCC web page 
and detail the process for 
completing and confirming patient registration. Prior to initiation of protocol treatment, 
this process must be completed in its entirety and an MCCC subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual registering 
the patient to confirm the process has been successfully completed prior to release of the 
study agent. Patient registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
 If the patient was fully 
registered, the MCCC Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.2 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.3 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 
If the necessary documentation is not submitted in advance of attempting 
patient registration, the registration will not be accepted and the patient may not be 
enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 


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6.4 
Correlative Research 
6.41 
Mandatory 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19a and 14.0). 
6.42 
Banking  
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use her/his data and 
sample(s) for future research on cancer at Mayo. 
• 
Patient has/has not given permission to store and use her/his data and 
sample(s) for future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give her/his data and 
sample(s) to researchers at other institutions. 
6.5 
Treatment on protocol 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
medical oncologist. 
6.6 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤21 days after registration. 
6.7 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.8 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded. 
6.9a 
Study drug 
Study drug is available on site. 
6.9b 
Blood draw kits 
Blood draw kit is available on site for sites outside of Rochester, Minnesota. 
6.9c 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 


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6.9d 
Re-registration (Step 2) 
6.9d1 To re-register a patient, access the Mayo Clinic Cancer Center (MCCC) web 
page and enter the registration/randomization application. The registration/ 
randomization application is available 24 hours a day, 7 days a week. Back up 
and/or system support contact information is available on the website. If unable 
to access the website, call the MCCC Registration Office at 
 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday through 
Friday). 
NOTE: Re-registration to Cycle 2 will be temporarily halted once 6 patients have 
been re-registered for a safety run-in. 
6.9d2 Treatment cannot begin prior to re-registering to the second phase and will begin 
≤14 days after registration to the second phase. 
7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Treatment medication table 
Cycle Agent 
Dose Level 
Route 
Day 
Duration 
1 
Anastrozole 
1 mg 
oral 
daily 
8-10 weeks 
2 
Anastrozole 
10 mg 
oral 
daily 
8-10 weeks 
3 
Letrozole 
2.5 mg 
oral 
daily 
8-10 weeks 
7.2 
Agents 
Anastrozole and letrozole are oral agents commonly used as adjuvant treatment for ER-
positive breast cancer to reduce the risk of recurrence. 
Protocol treatment should be taken at the same time every day (morning preferred) and 
may be taken without regard for food. EXCEPTION: On the day of the end of cycle 
blood draw, the treatment  should be taken  after the blood draw is completed. 
7.3 
Cycle 1 Anastrozole (ANA1) 
7.31 
Basics 
A research blood sample must be drawn at baseline prior to treatment or patient 
is unevaluable and must be replaced. 
All patients will be prescribed the FDA-approved dose of anastrozole at 1mg 
daily (standard adjuvant dose) for the first 8-10 weeks.  
At the end of the first cycle, blood will be drawn for drug levels and E1 and E2 
levels.  
Patients should be encouraged to take their anastrozole in the morning each day 
EXCEPT the day of the blood draw when they should take their anastrozole after 
this sample has been drawn. 
7.32 
Blood draw at end of cycle 
Patients will have blood drawn for estrone and estradiol concentrations and all 
samples for the week will be batched for processing in the Immunochemical Core 
Laboratory the following Monday. 


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Results will be reported the following day (usually Tuesday).  
Patients who do not meet the following criteria will be given a recommendation 
for 5 years of anastrozole and go off study. 
E1≥1.3 pg/ml 
AND  
E2≥0.5 pg/ml 
Patients whose estrogen levels meet these criteria and are willing to continue will 
proceed to Cycle 2.  
NOTE: Patients unwilling to continue will go off study and be replaced. 
7.33 
Logistics 
Study team will contact patients by telephone and tell the patients to either: 
1) Continue anastrozole 1mg and go off study. 
OR 
2) Come to the clinic for an appointment in the next couple weeks (prior to 
running out of ANA1) to re-register and obtain the new prescription. 
Re-registration is required for these patients prior to Cycle 2. 
7.4 
Cycle 2 Anastrozole (ANA10) 
7.41 
Safety run-in period (first six patients re-registered to ANA10) 
Re-registration will temporarily halt after maximum of 6 patients have been re-
registered to the study. 
Re-registered patients will be given a 4-5 week supply of anastrozole 10 mg 
(ANA10) daily. 
A study nurse will call patients after 2-3 weeks to review AEs and determine 
whether patients are willing to continue ANA10. 
Also, after 28-35 days of ANA10 treatment, first six patients will return to 
registering instituion for adverse event monitoring. A patient is considered to 
have developed a DLT if any of the following serious adverse event definitely, 
probably, or possibly attributed to anastrozole 10 mg occurs within 28-35 days of 
starting ANA10. 
CTCAE SOC 
DLT Definition 
Cytopenias 
(including Blood and 
lymphatic system disorders 
and Investigations) 
Grade 4 Neutrophil count decreased lasting >7 days 
≥Grade 3 Platelet count decreased with clinically significant 
bleeding 
Febrile neutropenia 
Hepatobiliary disorders 
≥Grade 3 Hepatic failure: Any drug-induced liver injury 
(DILI) (AKA Hy’s Law cases)  


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CTCAE SOC 
DLT Definition 
Unspecified 
Any ≥Grade 3 adverse event per NCI Common Terminology 
Criteria for Adverse Events v5.0, excluding the following:  
Any ≥Grade 3 electrolyte alteration* lasting 
≤72 hours, is not clinically complicated, and 
resolves spontaneously or responds to conventional 
medical interventions 
Any ≥Grade 3 serum amylase increased or lipase 
increased not associated with symptoms or clinical 
manifestations of pancreatitis 
Grade 3 nausea, vomiting, or diarrhea (lasting 
≤72 hours) which responds to maximal supportive 
treatment(s) 
Grade 3 fatigue (even if it lasts >1 week) 
Death 
Any death occurring in these patients during treatment or 
during 30 days after last dose 
 
*Electrolyte alterations may include the following events in SOC “Metabolism 
and nutrition disorders” 
Hypercalcemia or Hypocalcemia 
Hyperglycemia or Hypoglycemia 
Hyperkalemia  or Hypokalemia 
Hypermagnesemia or Hypomagnesemia 
Hypernatremia or Hyponatremia 
Hyperphosphatemia or Hypophosphatemia 
If 1 of the first 6 patients enrolled in the safety run-in experience any dose 
limiting toxicities (DLTs) (as defined in Section7.4.1 above), attributed 
(definitely, probably, or possibly) to anastrozole 10mg the FDA must be notified 
immediately. 
If two or more of thse 6 patients develops a DLT (as specified in Section 7.0 of 
the protocol) within 28-35 days of starting ANA10, the study will remain closed 
to enrollment to allow the study team to review toxicity data thoroughly and 
make decisions regarding changes to the protocol. If at most one of these 6 
patients develops a within 28-35 days of starting ANA10, re-registered will 
reopen. 
Patients who develop a DLT will have a research blood draw and go to the 
extended follow-up phase where an adverse event assessment will be undertaken 
28-35 days after treatment discontinuation. 
Patients who do not develop a DLT and are willing to continue, will have the 
remaining ANA10 supply (5-6 weeks) shipped to the patient by FedEx. 
At the end of the second cycle, or at discontinuation of ANA10, blood will be 
drawn for drug levels and E1 and E2 levels. 
Patients should be encouraged to take their anastrozole in the morning each day 
EXCEPT the day of the blood draw when they should take their anastrozole after 
this sample has been drawn. 
Patients who complete Cycle 2 will proceed to Cycle 3. 


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Patients unable to complete Cycle 2 will have research blood draw and then go to 
extended follow-up where an adverse event assessment will be undertaken 28-
35 days after treatment discontinuation. 
7.42 
After safety run-in period 
Re-registered patients will be given a 4 week supply of anastrozole 10 mg 
(ANA10) daily. 
Study nurse will call patients after 2-3 weeks to review AEs and determine 
whether patients are willing to continue ANA10.  
If patients are willing to continue, then the remaining ANA10 supply (6 weeks) 
will be shipped to the patient by FedEx. 
At the end of the second cycle, or at discontinuation of ANA10, blood will be 
drawn for drug levels and E1 and E2 levels. 
Patients should be encouraged to take their anastrozole in the morning each day 
EXCEPT the day of the blood draw when they should take their anastrozole after 
this sample has been drawn. 
Patients who complete Cycle 2 will proceed to Cycle 3. 
Patients unable to complete Cycle 2 will have research blood draw and then go to 
extended follow-up, where an adverse event assessment will be undertaken 28-
35 days after treatment discontinuation. 
7.5 
Cycle 3 Letrozole 
Patients will be prescribed the FDA-approved dose of letrozole at 2.5 mg daily for 8-
10 weeks. 
At the end of the third cycle, blood will be drawn for drug levels and E1 and E2 levels. 
Patients should be encouraged to take their letrozole in the morning each day EXCEPT 
the day of the blood draw when they should take their letrozole after this sample has been 
drawn. 
Patients will be given a recommendation for 5 years of letrozole and go off study. 
7.6 
Return to consenting institution  
For this protocol, the patient must return to the consenting institution as indicated in the 
Test Schedule Section 4.0 (Active Monitoring Phase). 
7.7 
Treatment by local medical doctor (LMD) 
Treatment by a local medical doctor (LMD) for routine clinical and emergent care is 
allowed. 
 
 


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8.0 
Dosage Modification Based on Adverse Events  
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
Dose 
Level 
Anastrozole (ANA1) 
Anastrozole (ANA10) 
Letrozole (LET) 
1* 
1 mg daily 
10 mg daily 
2.5 mg daily 
*Dose level 1 refers to the starting dose. 
NOTE: There are no dose modifications for anastrozole or letrozole. 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) current version (v5.0)* 
unless otherwise specified   
* 
Located at 
 
8.2 
Anastrozole 
There will be no anastrozole dose reductions.  
If any Grade 3 or 4 adverse event is encountered that is considered at least possibly 
related to anastrozole, anastrozole therapy will be discontinued. For unrelated or unlikely 
related events, hold anastrozole until the AE has resolved. Once resolved, resume 
anastrozole at the previous dose. If anastrozole is held for >3 weeks, permanently 
discontinue anastrozole therapy. 
Single missed doses of anastrozole are not made up.  
Any treatment interruption of 3-7 days should be made up at the end of the cycle. 
Any treatment interruption greater than 7 days and patient will go off study and will be 
replaced. 
 
 


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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Contraindicated agents 
9.51 
Any agent with estrogenic or putatively estrogenic properties. NOTE: This 
includes menopausal hormone therapy of any type, including systemic and 
topical therapies. This also includes agents such as megestrol acetate or SERMS 
(raloxifene or tamoxifen) 
9.52 
Over-the-counter products and supplements considered to have an estrogenic 
effect such as: ginseng, gingko biloba, black cohosh, dong quai or fortified soy 
supplements/phytoestrogen preparations. 
9.53 
Any other cancer directed treatment approach, such as chemotherapy or 
radiation, must not be administered while the patient is taking study drug. 
9.54 
Bisphosphonates are not allowed to be initiated during anastrozole therapy. 
Initiation of bisphosphonate therapy will be allowed after completion of 
anastrozole therapy (ANA10 or ANA1 if patient is not going on to ANA 10). 
NOTE: Patients on stable dose of bisphosphonates for ≥4 weeks at the time of 
registration are allowed to continue. 
 
 


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10.0 
Adverse Event (AE) Monitoring and Reporting  
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor-investigator is responsible for notifying FDA and all participating investigators in a 
written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
 
 
 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting Form:  
 
 
 
Will automatically be sent to 
 
 
 
 


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Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 
Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware 
of the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but 
that for a specific protocol are being reported via expedited means in order to facilitate the 
review of safety data (may be requested by the FDA or the sponsor).  
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 
5.0 will be utilized for AE reporting. 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: 
 
a. Identify the grade and severity of the event using the CTCAE version 5.0. 
b. Determine whether the event is expected or unexpected (see Section 10.2). 
c. Determine if the adverse event is related to the study intervention (agent, treatment or 
procedure) (see Section 10.3). 
d. Determine whether the event must be reported as an expedited report. If yes, 
determine the timeframe/mechanism (see Section 10.4).  
e. Determine if other reporting is required (see Section 10.5). 
f. Note: All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
NOTE: A severe AE is NOT the same as a serious AE, which is defined in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 


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Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Attribution to agent(s) or procedure 
When assessing whether an adverse event (AE) is related to a medical agent(s) medical or 
procedure, the following attribution categories are utilized: 
Definite - The AE is clearly related to the agent(s)/procedure. 
Probable - The AE is likely related to the agent(s)/procedure. 
Possible - The AE may be related to the agent(s)/procedure. 
Unlikely - The AE is doubtfully related to the agent(s)/procedure. 
Unrelated - The AE is clearly NOT related to the agent(s)/procedure. 
10.31 AEs Experienced Utilizing Investigational Agent(s) and Commercial Agent(s) on 
SEPARATE Arms 
• An AE that occurs on an arm using an investigational agent /intervention under an 
IND must be assessed in accordance with the guidelines for investigational agents.  
• An AE that occurs on an arm using a commercial agent on a separate treatment arm 
must be assessed as specified in the protocol. (Refer to the Commercial Reporting 
Table in Section 10.4).  
Commercial agent expedited reports must be submitted to the FDA via 
MedWatch 3500A  
10.32 EXPECTED Serious Adverse Events: Protocol Specific Exceptions to Expedited 
Reporting 
For this protocol only, the following Adverse Events/Grades are expected to occur 
within this population and do not require Expedited Reporting. These events must still 
be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 


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CTCAE 
System Organ Class (SOC) Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an 
expedited manner1 
General disorders and 
administrations site 
conditions 
Fatigue  
≤Grade 3 
Investigations 
Alanine aminotransferase 
increased 
≤Grade 3 
Aspartate aminotransferase 
increased 
≤Grade 3 
Blood bilirubin increased 
≤Grade 3 
Musculoskeletal and 
connective tissue disorders 
Arthralgia 
≤Grade 3 
1 These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
The following hospitalizations are not considered to be SAEs because there is no “adverse event” 
(i.e., there is no untoward medical occurrence) associated with the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition requiring the hospitalization 
has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for administration of study 
drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) that was in place 
before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of progression of the cancer. 
 
10.4 
Expedited Reporting Requirements for Commercial or Commercial Imaging Agents 
(Non-IND) Agent(s) ONLY:  
10.41 Expedited Reporting Requirements for Adverse Events that Occur in a Non-IND 
trial within 30 Days of the Last Administration of a Commercial Agent1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor 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). 


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ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor 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 
7 Calendar Days 
24-Hour  
3 Calendar 
Days 
Not resulting in 
Hospitalization  
≥24 hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious 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 within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 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. 
Effective Date: May 5, 2011 
NOTE: Refer to Section 10.32 for exceptions to Expedited Reporting 
10.42 General reporting instructions 
The Mayo IND and/or MCCC Compliance will assist the sponsor-investigator in 
the processing of expedited adverse events and forwarding of suspected 
unexpected serious adverse reactions (SUSARs) to the FDA and IRB. 
Use Mayo Expedited Event Report form 
or investigational agents or 
commercial/investigational agents on the same arm.  
For commercial agents (for commercial agent(s) on its own arm):  
Attach the MedWatch 3500A form to the Mayo Expedited Event Report form 
 
10.43 Reporting of re-occurring SAEs 
ALL SERIOUS adverse events that meet the criteria outlined in table10.41 
MUST be immediately reported to the sponsor within the timeframes detailed in 
the corresponding table. This reporting includes, but is not limited to SAEs that 
re-occur again after resolution. 


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10.5 
Other Required Reporting 
10.51 Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRTSOS) in 
general, include any incident, experience, or outcome that meets all of the 
following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
2. Related or possibly related to participation in the research (in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research); and 
3. Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
Some unanticipated problems involve social or economic harm instead of the 
physical or psychological harm associated with adverse events. In other cases, 
unanticipated problems place subjects or others at increased risk of harm, but no 
harm occurs. 
Note: If there is no language in the protocol indicating that pregnancy is not 
considered an adverse experience for this trial, and if the consent form does not 
indicate that subjects should not get pregnant/impregnate others, then any 
pregnancy in a subject/patient or a male patient’s partner (spontaneously 
reported) which occurs during the study or within 120 days of completing the 
study should be reported as a UPIRTSO. 
Mayo Clinic Cancer Center (MCCC) Institutions: 
If the event meets the criteria for IRB submission as a Reportable 
Event/UPIRTSO, provide the appropriate documentation and use the Mayo 
Clinic Cancer Center Expedited Event Report form 
 
he Mayo Clinic Compliance Unit will 
review and process the submission to the Mayo Clinic IRB and work with the 
IND Coordinator for submission to FDA. 
10.52 Death 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Any death occurring within 30 days of the last dose, regardless of attribution to 
an agent/intervention under an IND 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 requires expedited 
reporting within 24-hours. 


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Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
• 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
• 
Death due to progressive disease that cannot be attributed to a CTCAE 
term associated with Grade 5 should be reported as Grade 5 “Disease 
progression” under the system organ class (SOC) of 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. 
10.53 Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation 
or chemotherapy). A secondary malignancy is not considered a metastasis of 
the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an agent under 
an IND will be reported. Three options are available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
10.54 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
10.55 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 


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form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 
In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
10.551 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.552 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Fetal loss at any gestational age should be reported expeditiously, as 
Grade 4 “Pregnancy loss” under the SOC of “Pregnancy, 
puerperium and perinatal conditions”” under the Pregnancy, 
puerperium and perinatal conditions SOC. 
10.553 
Death Neonatal 
Neonatal death, defined in CTCAE as “Newborn death occurring 
during the first 28 days after birth” that is felt by the investigator to be 
at least possibly due to the investigational agent/intervention.  
A neonatal death should be reported expeditiously as Grade 4 “Death 
neonatal” under the SOC of General disorders and administration 
site conditions.  
 
 


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10.6 
Required Routine Reporting  
10.61 Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse events to 
be graded at each evaluation.  
Grading is per CTCAE v5.0 unless alternate grading is indicated in the table 
below: 
CTCAE  
System/Organ/Class (SOC) 
Adverse event/Symptoms 
Baseline 
End of 
C1/C2 
only 
Each 
evaluation 
Blood and lymphatic 
disorders 
Anemia 
X 
X 
 
General disorders and 
administration site 
conditions 
Fatigue 
X 
 
X 
Investigations 
Alanine aminotransferase 
increased 
X 
X 
 
 
Aspartate aminotransferase 
increased 
X 
X 
 
 
Blood bilirubin increased 
X 
X 
 
 
White blood cell decreased 
X 
X 
 
Musculoskeletal and 
connective tissue disorders 
Arthralgia 
X 
 
X 
Vascular disorders 
Hot flashes 
X 
 
X 
10.62 All other AEs 
Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
10.621 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
10.622 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.623 Grade 5 AEs (Deaths) 
10.6231 
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.6232 
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. 
10.7 
Late Occurring Adverse Events 
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). 


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11.0 
Treatment Evaluation/Measurement of Effect  
Plasma concentration levels of E1 and E2 will be obtained prior to start of protocol therapy, after 
8-10 weeks of anastrozole 1 mg daily (Cycle 1), after 8-10 weeks of anastrozole 10 mg daily 
(Cycle 2), and after 8-10 weeks of letrozole 2.5 mg daily (Cycle 3). 
12.0 
Descriptive Factors: None 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Blood specimens 
13.11 Patients for whom the baseline blood sample (prior to treatment on this study) is 
NOT obtained and submitted, will go off study and be replaced. 
13.12 Patients for whom the blood sample prior to ANA10 is NOT obtained will go off 
study and be replaced. 
13.2 
Anastrozole 1 mg daily for 8-10 weeks (ANA1): 
13.21 Patients who are able to tolerate anastrozole treatment have no signs of disease 
recurrence may continue treatment with anastrozole for a maximum of 10 weeks.  
13.22 Patients who are not able to tolerate anastrozole treatment or develop disease 
recurrence will discontinue protocol treatment and will go off study where 
further treatment is at the discretion of her medical team. 
13.23 Patients who register but then refuse to begin anastrozole treatment will go off 
study where further treatment is at the discretion of her medical team. Baseline 
and on study case report forms are to be submitted. On-study material and the 
End of Active Treatment/Cancel Notification Form must be submitted. No 
further data submission is necessary. 
13.3 
At completion of 8-10 weeks of anastrozole 1 mg daily for 8-10 weeks 
13.31 Patients who have completed a minimum of 8 weeks and maximum of 10 weeks 
of anastrozole 1 mg daily  and whose plasma concentrations of E1 and E2 meet 
one of the following criteria: 
(a) E1>1.3 pg/ml and E2≤ 0.5 pg/ml 
(b) E1≤ 1.3 pg/ml and E2> 0.5 pg/ml 
(c) E1≤ 1.3 pg/ml and E2≤ 0.5 pg/ml 
will go off study where further treatment is at the discretion of her medical team. 
13.32 Patients who have completed a minimum of 8 weeks and maximum of 10 weeks 
of anastrozole 1 mg daily and whose plasma concentrations of E1 and E2 are 
such that: 
E1 ≥1.3 pg/ml and E2≥0.5 pg/ml 
may re-register and begin treatment with anastrozole 10 mg daily for 8-10 weeks. 
Patients who choose not to re-register will go off study where further treatment is 
at the discretion of her medical team.  


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13.4 
Anastrozole 10 mg daily for 8-10 weeks (ANA10): 
13.41 Patients who are able to tolerate anastrozole treatment and have no signs of 
disease recurrence may continue treatment with anastrozole at 10 mg daily dose 
for a maximum of 10 weeks. 
13.42 Patients who are not able to tolerate anastrozole treatment or develop disease 
recurrence will discontinue protocol treatment. A blood specimen is to be 
collected for E1 and E2 determination and then the patient will go off study 
where further treatment is at the discretion of her medical team. 
13.43 Patients who re-register but then refuse to begin anastrozole treatment will go off 
study where further treatment is at the discretion of her medical team.  
13.5 
At completion of 8-10 weeks of anastrozole 10 mg daily for 8-10 weeks 
Patients who have completed a minimum of 8 weeks and maximum of 10 weeks of 
anastrozole 10 mg daily and have a blood draw for E1 and E2 determinations may begin 
treatment with letrozole 2.5 mg daily for 8-10 weeks.  
If the patient chooses not to begin treatment with letrozole, a blood specimen is to be 
collected for E1 and E2 determination. The patient will then go off study where further 
treatment is at the discretion of her medical team. 
13.6 
Letrozole 2.5 mg daily for 8-10 weeks 
13.61 Patients who are able to tolerate letrozole treatment and have no signs of disease 
recurrence may continue treatment with letrozole 2.5 mg daily dose for a 
maximum of 10 weeks. After the completion of a minimum of 8 weeks and 
maximum of 10 weeks of letrozole, a blood specimen is to be collected for E1 
and E2 determination. The patient will then go off study where further treatment 
is at the discretion of her medical team. 
13.62 Patients who are not able to tolerate letrozole treatment or develop disease 
recurrence will discontinue protocol treatment. A blood specimen is to be 
collected for E1 and E2 determination and then the patient will go off study 
where further treatment is at the discretion of her medical team. 
13.7 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient will go off study where futher treatment is at the discretion of her medical 
team. On study and end of treatment case reports are to be submitted. 
13.8 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
 


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14.0 
Body Fluid Biospecimens 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
Research (Section 
for more 
information) 
Specimen 
Purpose  
(check all that 
apply) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube  
(# of tubes to 
be collected) 
Baseline 
Prior to 
C1D1  
End of 
Cycle 1 
End of 
Cycle 2 
End of 
Cycle 3 
Process 
at site? 
(Yes or 
No) 
Temperature 
Conditions 
for Storage 
/Shipping 
DNA 
☒ Correlative 
☒ Eligibility 
Confirmation 
☒ Banking 
☐ Other 
(specify) 
_____________ 
Mandatory 
Whole 
Blood 
EDTA 
(purple) 
10 mL 
(2) 
X 
 
 
 
No 
Ambient 
E1 and E2 assays 
☒ Correlative 
☒ Banking 
Mandatory 
Serum 
Serum  
(red) 
10 mL 
(1) 
X 
X 
X 
X 
Yes 
Frozen 
Plasma for 
anastrozole 
☒ Correlative 
☒ Banking 
Mandatory 
Plasma 
NaHep 
(green) 
10 mL 
(1) 
 
X 
X 
 
Yes 
Frozen 
Plasma for 
letrozole 
☒ Correlative 
☒ Banking 
Mandatory 
Plasma 
NaHep 
(green) 
10 mL 
(1) 
 
 
 
X 
Yes 
Frozen 
 
 


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14.2 
Collection and Processing  
14.21 Blood for DNA 
Draw two 10 ml EDTA tubes (for DNA extraction). No processing necessary. 
Deliver unrefrigerated to:  
Biospecimen Accessioning and Processing Lab (BAP) at each site. 
BAP will perform DNA extraction from one tube. Extract buffy coat and plasma 
from 2nd tube and store at <-65ºC. 
AZ and FL will batch ship to BAP in Rochester, MN monthly. 
14.22 Blood for E1/E2 Assays 
14.221 
Baseline 
One 10 mL serum (red top) tube (for E1 and E2 assays). Serum will be 
divided into two aliquots with one aliquot to be sent directly to Mayo 
Clinic Immunochemical Core Laboratory. 
Second aliquot will be stored for future use. 
14.222 
End of Cycles 1-3 
NOTE: Blood needs to be drawn immediately before the next dose of 
anastrozole/letrozole to reflect steady state. Patients should be 
encouraged to take their anastrozole/letrozole in the morning each day 
EXCEPT the day of the blood draw when they should take their 
anastrozole after this sample has been drawn. 
One 10 mL serum (red top) tube (for E1 and E2 assays). Serum will be 
divided into two aliquots with one aliquot to be sent directly to Mayo 
Clinic Immunochemical Core Laboratory.  
Second aliquot will be stored for future use. 
14.23 Blood for anastrozole and/or letrozole levels 
One 10 mL sodium heparin tube for aromatase inhibitor level measurement by 
 
Centrifuge within 1 hour of draw at 3000 rpm for 10 minutes.  
Harvest plasma and store in 3 aliquots of approximately 1.5 mL in cryo-freezer 
tubes and frozen immediately at <-65ºC (-80ºC freezer).  
Biospecimens Accessioning and Processing (BAP) will store frozen, and ship 
one 1.5mL aliquot from each sample drawn as a batch at the completion of the 
study. 
The other two aliquots from each draw will be stored frozen for future use. 
14.3 
Shipping and Handling 
14.31 Florida and Arizona only: Kits will be used for this study. 
14.311 
Kits will be supplied by the Biospecimen Accessioning and Processing 
Shared Resource (BAP). 
14.312 
The kit contains supplies and instructions for collecting, processing 
and shipping specimens. 


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14.313 
Participating institutions may obtain kits by faxing the Supply Order 
Form to the number listed on the form. Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry. Supply Order Forms 
must be filled in completely and legibly for quick processing. 
14.314 
Kits will be sent via Fed Ex Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
14.315 
Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex account number or alternate 
billing number for express mail. Cost for rush delivery of kits will 
not be covered by the study. 
14.316 
All specimens must be collected and shipped Monday – Thursday 
ONLY 
For Mayo Clinic in Rochester, MN samples may be collected MON-
FRI (as there is no shipping required) 
14.32 Shipping Specimens 
14.321 
Shipping from Arizona and Florida 
Samples should be spun down, aliquoted, and frozen prior to shipping 
to BAP at Mayo Clinic in Rochester, MN 
Ship one aliquot frozen  directly to Immunochemical Core Lab in 
Rochester, MN on day of collection. 
Remaining samples should be shipped to BAP at Mayo Clinic in 
Rochester, MN on day of collection. 
14.322 
END OF STUDY ONLY: Shipping for anastrozole/letrozole levels 
Indiana University will process the samples for drug level 
measurements. 
Ship one 1.5 mL frozen samples per patient at end of study by 
overnight express service on dry ice to: 
Indiana University School of Medicine 
Division of Clinical Pharmacology 
 
 
 
 
 
 
 
14.4 
Background and Methodology 
14.41 Estrone and estradiol assays 
Pre- and post-AI treatment E1 and E2 levels will be measured by CLIA-approved 
liquid chromatography with tandem mass spectrometry (LC/MS/MS) assays in 
the Immunochemical Core Laboratory at Mayo Clinic. Details of the 
methodology have been published.13,22 The assay involves liquid extraction of 0.5 
ML sample (plasma or serum depending on study) with methylene chloride 


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followed by derivatization with dansyl chloride, separation using a two –
dimensional ultra-performance liquid chromatography system and analysis on an 
Agilent 6490 mass spectrometer using electrospray ionization on a positive 
mode. The combination of derivatization and two-dimensional chromatography 
(separation on two columns [Loading: Agilent Zorbax XDB-C18: 2.1 × 30 mm 
3.5 micron; Analytical: Agilent Poroshell 120 EC-C18: 2.1 × 50 mm 2.7 
micron]) afforded improved sensitivity and precision. Intra-assay CVs for E1 are 
17.8%, 7.5%, and 6.1% at 0.30, 0.50, and 0.84 pg/mL, respectively. Intra-assay 
coefficients of variation (CV) for E2 are 11.8%, 7.3%, and 6.0% at 0.25, 0.51, 
and 0.85 pg/mL, respectively. Inter-assay CVs for E2 are 10.8%, 8.5%, and 6.9% 
at 0.29, 0.50, and 0.77 pg/mL, respectively. 
14.42 Aromatase Inhibitor Assays 
14.421 
Quantification of drugs and metabolites 
Anastrozole and letrozole and relevant metabolites will be measured in 
the laboratory of Zeruesenay Desta, Ph.D., at Indiana University 
School of Medicine, using liquid chromatography-tandem mass 
spectrometry (LC/MS/MS) assays. All chemicals (anastrozole and 
letrozole) and internal standards (anastrozole and letrozole) will be 
purchased from Toronto Research Chemicals (North York, Ontario, 
Canada). LC-MS/MS grade water, methanol, acetonitrile, and 
formic acid were obtained from Fisher Scientific (Waltham, MA). 
Although relevant metabolites of anastrozole may be measured, 
these metabolites are pharmacologically inactive and their 
concentrations are much lower than the parent compounds.  
14.422 
Sample preparation 
Plasma or serum sample aliquots (50 µL) will be spiked with 30 µL of 
an internal standard solution in methanol containing anastrozole 
(50 nM) for assay of letrozole samples and letrozole (50 nM) for assay 
of anastrozole samples. LC-MS/MS grade methanol (220 µL) was 
added to precipitate proteins followed by vortex mixing (90 seconds, 
2,000 rpm), and centrifugation (20 minutes, 3,000 rpm, 4°C). The 
resulting supernatant (150 µL) will be transferred to clean plates for 
analysis via LC-MS/MS. 
14.423 
LC-MS/MS Method 
Chromatographic separation for anastrozole, letrozole, and respective 
metabolites will be achieved using an Acquity BEH C18 column 
(1.7 µM, 2.1 x 100 mm) with a Critical Clean precolumn filter (2.1 x 
0.2 µM) (Waters) heated to 35°C and a binary gradient at a flow rate of 
0.4 ml/min. The gradient elution will be held at 65:35 mobile phase A 
(5 mM ammonium formate with 0.1% formic acid in water): mobile 
phase B (acetonitrile with 0.1% formic acid) for 1 minute. Then this 
will be increased linearly to 52% mobile phase B over 30 seconds, held 
at 52% for 2.5 minutes followed by increase to 100% mobile phase B 
over 30 seconds, and then held at 100% for 30 seconds before 
returning to initial conditions over 0.5 minutes. The total run time is 
expected to be six minutes. Samples will be analyzed (2 µL injection 
volume) using the QTRAP 6500+ UHPLC-MS/MS system (AB Sciex) 
with the turbo electrospray source operated in positive ion mode. 


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Anastrozole (294-225), hydroxy-anastrozole (31o-241), anastrozole-N-
glucuronide (470-294), anastrozole-O-glucuronide 1 (486- 310), 
anastrozole-O-glucuronide 2 (486+310), and letrozole (286-217) m/z 
transitions will be monitored in multiple reaction monitoring mode. 
Anastrozole-O­ glucuronide 1 and 2 will be denoted based on 
differences in retention time. 
 


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15.0 
Drug Information 
15.1 
Anastrozole (Arimidex®) 
15.11  Background  
Anastrozole is a nonsteroidal, competitive inhibitor of the aromatase enzyme 
system which binds to the heme group of aromatase, a cytochrome P450 enzyme 
that catalyzes the conversion of androgens to estrogens.  
15.12 Formulation and storage 
Anastrozole is commercially available as 1 mg tablets. Store at controlled room 
temperature 20-25˚C (68-77˚F) [see USP Controlled Room Temperature]. 
15.13 Administration 
Administer orally with or without food. Refer to the treatment section for specific 
administration instructions. 
15.14 Pharmacokinetic information 
Absorption: Absorption of anastrozole is rapid and maximum plasma 
concentrations typically occur within 2 hours of dosing under fasted conditions.   
Food reduces the rate but not the overall extent of anastrozole absorption. 
Distribution: Plasma concentrations approach steady-state levels at about 7 days 
of once daily dosing. Anastrozole is 40% bound to plasma proteins in the 
therapeutic range. 
Metabolism: Metabolism of anastrozole occurs by N-dealkylation, hydroxylation 
and glucuronidation. 
Excretion: Eighty-five percent of radiolabeled anastrozole was recovered in 
feces and urine. Hepatic metabolism accounts for approximately 85% of 
anastrozole elimination. Renal elimination accounts for approximately 10% of 
total clearance. The mean elimination half-life of anastrozole is 50 hours. 
15.15 Potential drug interactions 
Cytochrome P450: None 
15.16  Known potential adverse events 
Consult the package insert for the most current and complete information. 
Common adverse reactions include hot flashes, asthenia, arthritis, pain, 
arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, 
osteoporosis, fractures, back pain, insomnia, headache, bone pain, peripheral 
edema, increased cough, dyspnea and lymphedema.  
15.17 Drug procurement 
Anastrozole 1 mg is commercially available: Patients will be given a prescription 
for anastrozole to be filled at the pharmacy of their choice. 
Anastrozole 10 mg: Study medication will be provided by the Mayo Clinic 
Breast Cancer SPORE. 
15.18 Nursing guidelines 
15.181 
May take with food if needed for nausea. Instruct patient to report 
unrelieved nausea or vomiting. 


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15.182 
Instruct patient that hot flashes may occur. Manage hot flashes with 
non-hormonal interventions (e.g. venlafaxine XR 75 mg daily). 
15.183 
Assess for changes in bowel patterns. Manage diarrhea with non-
prescription drugs. Instruct patient to report unrelieved diarrhea. 
15.184 
Headache may occur. Can be managed with non-prescription 
analgesics. Instruct patient to report headaches that are not relieved. 
15.185 
Vaginal dryness may occur. Instruct patient in the use of lubricating 
agents. 
15.186 
Mild swelling may occur in the arms and legs. Instruct patient to 
elevate extremities when at rest to relieve the swelling. 
15.187 
While thrombophlebitis is rare, instruct patient to report any pain, 
redness, marked swelling in the arms and/or legs, dizziness, or 
shortness of breath to their health care provider immediately or seek 
medical attention in an emergency room. 
15.2 
Letrozole (Femara®) 
15.21 Background  
Letrozole is a nonsteroidal, competitive inhibitor of the aromatase enzyme 
system which binds to the heme group of aromatase, a cytochrome P450 enzyme 
that catalyzes the conversion of androgens to estrogens.  
15.22 Formulation and storage 
Letrozole is commercially available as 2.5 mg tablets.  Store at 77°F (25°C); 
excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room 
Temperature]. 
15.23 Administration 
Administer orally with or without food.  
Refer to the treatment section for specific administration instructions.   
15.24 Pharmacokinetic information 
Distribution: Vd: ~1.9 L/kg 
Protein binding: weak 
Metabolism: Hepatic via CYP3A4 and CYP2A6 into an inactive carbinol 
metabolite 
Half-life elimination: Terminal: ~ 2 days 
Excretion: Urine (90%; 6% as unchanged drug, 75% as glucuronide 
carbinol metabolite, 9% as unidentified metabolites) 
15.25 Potential Drug Interactions 
Cytochrome P450: Substrate of CY2A6 (minor), CYP3A4 (minor). 
Inhibitor of CYP2A6 (strong), CYP2C19 (moderate) 
15.26 Known potential adverse events:  
Consult the package insert for the most current and complete information.  
Common adverse events include cataracts, eye irritation, palpitations, 
cardiac failure, tachycardia, dysaesthesia, arterial thrombosis, memory 
impairment, irritability, nervousness, urticaria, increased urinary 


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frequency, leukopenia, stomatitis, pyrexia, vaginal discharge, appetite 
increase, dryness of skin and mucosa and disturbances in taste and thirst. 
15.27 Drug procurement 
Commercial supplies. Patients will be given a prescription for letrozole to be 
filled at the pharmacy of their choice. 
15.28 Nursing Guidelines 
15.281 
Manage hot flashes with non-hormonal interventions (e.g., venlafaxine 
XR 75 mg daily). 
15.282 
Manage pain (arthralgias). Instruct patient to report unrelieved pain. 
15.283 
May take with food if needed for nausea. Instruct patient to report 
unrelieved nausea or vomiting. 
15.284 
Assess for changes in bowel patterns. Manage diarrhea or constipation 
with non-prescription drugs. Tell patients to report unrelieved diarrhea 
or constipation. 
15.285 
If patient experiences difficulty breathing or sudden onset chest pain, 
instruct them to seek emergency medical attention immediately. 
15.286 
Monitor for signs of edema, instruct patient to report any swelling in 
legs, feet, or hands. 
 


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16.0 
Statistical Considerations and Methodology  
16.1 
Study Design 
This goal of this study is to assess whether women with inadequate estrogen suppression 
after 8-10 weeks of adjuvant anastrozole 1 mg daily (ANA1) would benefit from 
increasing their dose of anastrozole to 10 mg daily (ANA10). Two analytic approaches 
will be taken to address this objective. The first approach focuses on the set of patients 
who are adherent to treatment schedule, that is, if at least 80% of the planned dose is 
taken will adequate estrogen suppression be achieved. The second approach focuses on 
intentions, that is, among those patients who start an 8-10 week course of anastrozole 
10 mg daily what proportion will have achieved adequate estrogen suppression at 
treatment discontinuation. Patients who fail to provide a blood sample after discontinuing 
treatment will be considered not to have achieved adequate estrogen suppression. 
The study was designed to assess in the adherent cohort whether the estrogen suppression 
rate with anastrozole 10 mg daily for 8-10 weeks (ES-ANA10) after inadequate estrogen 
suppression of 8-10 weeks of adjuvant anastrozole 1 mg daily is at most 25% against the 
alternative that it is at least 50%.  
Inadequate estrogen suppression is defined as E1>1.3 pg/ml and E2>0.5 pg/ml after 8-
10 weeks of treatment with an aromatase inhibitor. 
Based on preliminary findings from MA27, we expect approximately 20% of women 
with ER+ primary breast cancer to have inadequate estrogen suppression with anastrozole 
1 mg daily for 8-10 weeks. Thus, if 160 patients were enrolled then we would expect 32 
of them to have IES-ANA1. There may be a few patients who refuse to switch to 
anastrozole 10 mg daily for 8-10 weeks followed by a blood draw for E1 and E2 testing. 
Assuming at most 3 women will refuse to continue or fail to adhere to treatment, 
29 patients who are adherent to treatment will be available to evaluate the primary aim. 
With a sample size of 29 patients in the adherence cohort, a one-sided binomial test of 
proportions with a significance level of 0.05 will have a 87% chance of rejecting the null 
hypothesis that the estrogen suppression rate with anastrozole 10 mg daily for 8-10 weeks 
is at most 25% when the true estrogen suppression rate with anastrozole 10 mg daily for 
8-10 weeks is at least 50%. Specifically, the null hypothesis is rejected if the number of 
women who are ES-ANA10 is 12 or more among these 29 patients. 
16.2 
Analyses 
16.21 Primary Analysis 
The primary analysis will include all patients with inadequate estrogen 
suppression after 8-10 weeks of adjuvant anastrozole 1 mg daily who provide a 
blood sample after completing 8-10 weeks of  anastrozole 10 mg daily will be 
included in the analysis of the primary endpoint. Patients who fail to provide a 
blood sample after discontinuing anastrozole 10 mg daily for 8-10 weeks 
Adverse events will be graded and their attributions assigned using NCI CTCAE 
v5.0. 
For each cohort, point and interval estimates for the estrogen suppression rate 
with anastrozole 10 mg daily for 8-10 weeks will be constructed using the 
properties of the binomial distribution. 


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16.3 
Accrual rate and enrollment 
Accrual Rate: MCR – anticipate 300 patients per year meeting eligibility criteria and 
100 patients per year agreeing to participate in the clinical trial. 
Total Expected Accrual: 160 minimum to obtain 32 patients who reach Cycle 3 with 
29 patients evaluable for study endpoints 
16.4 
Stopping rules 
16.41 Feasbility stopping rule 
The percentage of patients who have inadequate estrogen suppression 
(E1>1.3 pg/ml and E2>0.5 pg/ml) will be examined after every 25th patients has 
completed 8-10 weeks of anastrozole at the 1 mg daily dose. If this percentage is 
10% or less among these 25 patients and all the previously enrolled patients is 
10% or less, the trial will temporarily halt for the study team to review study data 
to make a trial recommendation to FDA and IRB. 
16.42 Safety Stopping rule: 
Adverse events will be examined at the completion of each treatment. Enrollment 
to the trial will be temporarily halted if: 
(a) During or at completion of treatment Cycle 1 with anastrozole 1 mg daily, 
2 or more of the first 6 patients or 30% or more of the patients treated with 
the agent have developed a Grade 4 cytopenia or some other Grade 3-4 
adverse event during or at completion of that agent 
(b) During or at completion of treatment Cycle 2 with anastrozole 10 mg daily, 
if 2 or more of the first 6 patients develops a DLT (as specified in Section 7.0 
of the protocol) within 28-35 days of starting ANA10. The study will remain 
closed to enrollment to allow the study team to review toxicity data 
thoroughly and make decisions regarding changes to the protocol. If at most 
one of these 6 patients develops a DLT within 28-35 days of starting 
ANA10, re-registration will reopen. 
After at least 7 patients have been re-registered and have begun ANA10, 
30% or more of the patients treated with the agent have developed a Grade 4 
cytopenia or some other Grade 3-4 adverse event during or at completion of 
that agent 
(c) During or at completion of treatment Cycle 3 with letrozole 2.5  mg daily, 
2 or more of the first 6 patients or 30% or more of the patients treated with 
the agent have developed a Grade 4 cytopenia or some other Grade 3-4 
adverse event during or at completion of that agent 
(d) A patient death on protocol treatment or within 30 days of discontinuing all 
protocol treatment that is considered possibly, probably or definitely related 
to treatment. 
The study team will review study data and then make a trial recommendation to 
FDA and IRB. 
16.5 
Analysis Plan for Secondary Outcome and Translational Endpoint  
Descriptive statistics will be used to describe the distribution of E1 and E2 concentrations 
following ANA10 and letrozole. The percent change in E1 and E2 concentrations from 
pre-AI levels will be determined and graphically depicted using spider plots. 


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16.6 
Data & Safety Monitoring 
16.61 Safety review 
The principal investigator(s) and the study statistician will review the study 
monthly to identify accrual, adverse event, and any endpoint problems that might 
be developing. 
The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring Board 
(DSMB) is responsible for reviewing accrual and safety data for this trial at least 
biannually, based on reports provided by the MCCC Statistical Office. 
16.7 
Subset Analyses for Minorities 
16.71 Study availability 
This study will be available to all eligible female patients, regardless of race or 
ethnic origin. 
16.72 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
 
 


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16.73 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Expected sizes of racial by gender subsets are 
shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
 
5 
Not Hispanic or Latino 
155 
 
155 
Ethnic Category: Total of all subjects 
160 
0 
160 
Racial Category 
American Indian or Alaskan Native 
 
 
 
Asian 
7 
 
7 
Black or African American 
6 
 
6 
Native Hawaiian or other Pacific Islander 
 
 
 
White 
147 
 
147 
Racial Category: Total of all subjects 
160 
0 
160 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0 
Pathology Considerations/Tissue Biospecimens: None 
 


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18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up -- None 
See Section 4.  
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation  
This study requires supporting documentation for diagnosis prior to study entry. These 
documents should be submitted within 14 days of registration. Patient medication diaries 
will be uploaded to Medidata Rave. 
18.6 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition to this, the Overdue Materials report is available on the 
Cancer Center Systems homepage. 
19.0  
Budget 
19.1 
Costs charged to patient 
• 
Routine clinical care 
• 
Anastrozole 1mg and letrozole 
19.2 
Tests to be research funded 
• 
Routine blood testing prior to ANA10 
• 
Safety assessment visits for ANA10: 1) for first 6 patients; 2) 30 days after last dose 
• 
Nurse visit and routine blood testing prior to Cycle 3 
• 
Research testing on blood samples 
19.3 
Other budget concerns 
Mayo Clinic Breast Cancer SPORE will provide funding to support the costs of running 
this study. 
Mayo Clinic Breast Cancer SPORE will provide anastrozole 10 mg (ANA10) for use in 
this study.  
 


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20.0 
References 
1. Ingle JN. Overview of adjuvant trials of aromatase inhibitors in early breast cancer. Steroids 2011;76:765-7. 
2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors vs tamoxifen in early 
breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 2015. 
3. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003;348:2431-42. 
4. Ryan KJ. Biological aromatization of steroids. J Biol Chem 1959;234:268-72. 
5. Corbin CJ, Graham-Lorence S, McPhaul M, Mason JI, Mendelson CR, Simpson ER. Isolation of a full-length 
cDNA insert encoding human aromatase system cytochrome P-450 and its expression in nonsteroidogenic cells. 
Proc Natl Acad Sci U S A 1988;85:8948-52. 
6. Bulun SE, Chen D, Moy I, Brooks DC, Zhao H. Aromatase, breast cancer and obesity: a complex interaction. 
Trends Endocrinol Metab 2012;23:83-9. 
7. Geisler J, King N, Dowsett M, et al. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase 
inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. 
Br J Cancer 1996;74:1286-91. 
8. Geisler J, King N, Anker G, et al. In vivo inhibition of aromatization by exemestane, a novel irreversible 
aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res 1998;4:2089-93. 
9. Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE. Influence of letrozole and anastrozole on total body 
aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, 
cross-over study. J Clin Oncol 2002;20:751-7. 
10. Geisler J, Helle H, Ekse D, et al. Letrozole is superior to anastrozole in suppressing breast cancer tissue and 
plasma estrogen levels. Clin Cancer Res 2008;14:6330-5. 
11. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early 
breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol 2013;31:1398-404. 
12. Smith I, Yardley D, Burris H, et al. Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole 
in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results 
of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J Clin Oncol 
2017;35:1041-8. 
13. Ingle JN, Kalari KR, Buzdar AU, et al. Estrogens and their precursors in postmenopausal women with early 
breast cancer receiving anastrozole. Steroids 2015;99:32-8. 
14. Rose S, Laan MJ. Why match? Investigating matched case-control study designs with causal effect estimation. 
Int J Biostat 2009;5:Article 1. 
15. Liu X. Classification accuracy and cut point selection. Stat Med 2012;31:2676-86. 
16. Therneau T, Grambsch P. Modeling survival data:  Extending the Cox model 2000;Springer New York. 
17. Nelson RE, Grebe SK, DJ OK, Singh RJ. Liquid chromatography-tandem mass spectrometry assay for 
simultaneous measurement of estradiol and estrone in human plasma. Clin Chem 2004;50:373-84. 
18. Mauras N, Ross JL, Gagliardi P, et al. Randomized Trial of Aromatase Inhibitors, Growth Hormone, or 
Combination in Pubertal Boys with Idiopathic, Short Stature. J Clin Endocrinol Metab 2016;101:4984-93. 
19. Ketha H, Girtman A, Singh RJ. Estradiol assays--The path ahead. Steroids 2015;99:39-44. 
20. Ingle JN, Buzdar AU, Schaid DJ, et al. Variation in anastrozole metabolism and pharmacodynamics in women 
with early breast cancer. Cancer Res 2010;70:3278-86. 
21. Buzdar AU, Jonat W, Howell A, et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal 
women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from 
two mature phase III trials. Arimidex Study Group. Cancer 1998;83:1142-52. 
22. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in 
postmenopausal women. J Natl Cancer Inst 2003;95:1218-26. 
  
 


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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
From http://www.ecog.org/general/perf_stat.html 
 
 


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Appendix II Patient Medication Diary 
Anastrozole – Cycle 1  
Patient initials (optional) _ 
 
Study ID Number  
 
Please complete this diary on a daily basis. Record the date & time  that you took your anastrozole 
in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
Take anastrozole in the morning. On the days you are scheduled to have your blood drawn do not 
take your dose until after your study visit & instructed by the study team. 
Week 1) Week of: _________________________ 
Anastrozole 1 mg 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 2) Week of: _________________________ 
Anastrozole 1 mg 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 3) Week of: _________________________ 
Anastrozole 1 mg 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 4) Week of: _________________________ 
Anastrozole 1 mg 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 5) Week of: _________________________ 
Anastrozole 1 mg 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 6) Week of: _________________________ 
Anastrozole 1 mg 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 


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Week 7) Week of: _________________________ 
Anastrozole 1 mg 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 8 Week of: _________________________ 
Anastrozole 1 mg 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 9) Week of: _________________________ 
Anastrozole 1 mg 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 10) Week of: _________________________ 
Anastrozole 1 mg 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Patient signature: ___________________________________________ Date: ______________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please contact:  ______________________ 
Telephone #: ______________________________________ 
 
Study Coordinator Use Only 
Number of pills returned ______ 
Number of Bottles  returned: _______ 
 
Discrepancy Yes____/No____ 
Verified by __________________ 
Date_______________ 


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Anastrozole –Cycle 2 
Patient initials (optional) _ 
 
Study ID Number  
 
Please complete this diary on a daily basis. Record the date & time  that you took your 
anastrozole in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
Take anastrozole in the morning. On the days you are scheduled to have your blood drawn do not 
take your dose until after your study visit & instructed by the study team. 
Week 1) Week of: _________________________ 
Anastrozole 10 mg 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 2) Week of: _________________________ 
Anastrozole 10 mg 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 3) Week of: _________________________ 
Anastrozole 10 mg Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 4) Week of: _________________________ 
Anastrozole 10 mg Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 5) Week of: _________________________ 
Anastrozole 10 mg 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 6) Week of: _________________________ 
Anastrozole 10 mg 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 


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Week 7) Week of: _________________________ 
Anastrozole 10 mg Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 8 Week of: _________________________ 
Anastrozole 10 mg Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 9) Week of: _________________________ 
Anastrozole 10 mg 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week 10) Week of: _________________________ 
Anastrozole 10 mg 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Patient signature: ___________________________________________ Date: ______________ 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please contact: ______________________ 
Telephone #: ______________________________________ 
 
Study Coordinator Use Only 
Number of pills returned ______ Number of Bottles  returned: _______  
Discrepancy Yes____/No____ 
Verified by __________________ 
Date_______________ 


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Letrozole – Cycle 3 
Patient initials (optional) _ 
 
Study ID Number  
 
Please complete this diary on a daily basis. Write in the amount of the dose of letrozole that you 
took in the appropriate “Day” box. 
On the days that you do not take any study drug, please write in “0”. If you forget to take your 
daily dose, please write in “0”, but remember to take your prescribed dose at the next regularly 
scheduled time. 
Take letrozole in the morning. On the days you are scheduled to have your blood drawn do not 
take your dose until after you have had your blood drawn. 
Week of: _________________________ 
Letrozole 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 


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Week of: _________________________ 
Letrozole 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Week of: _________________________ 
Letrozole 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
MM/DD/YY 
 
 
 
 
 
 
 
Time 
 
 
 
 
 
 
 
Patient signature: ___________________________________________ Date: _____________ 
My next scheduled visit is: _______________________________ 
If you have any questions, please contact: ______________________ 
Telephone #: ______________________________________ 
 
Study Coordinator Use Only 
Number of pills returned ______ 
Number of bottles returned: _______  
Discrepancy Yes____/No____ 
Verified by __________________ 
Date_______________ 
 

ICF_000.pdf: 
 
 
 
 
Study Title:  
MC1931 Pharmacodynamic Study of Estrogen Suppression Threshold-Directed Therapy (ESTDT) 
of Anastrozole as Adjuvant Therapy for Early Stage Breast Cancer 
 
NCT04294225 
 
Document Date: 11/22/2022 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
IRB#: 19-006637 00       e-Sign  
Page 1 of 20 
IRB Doc. Ctrl # 10013.33 
 
 
 
 
 
 
 
Name and Clinic Number 
Protocol #: MC1931 
Version #: Initial 
Version Date: 21Nov2022 
RESEARCH PARTICIPANT CONSENT AND PRIVACY 
AUTHORIZATION FORM 
 
Study Title: MC1931 Pharmacodynamic Study of Estrogen Suppression Threshold-Directed 
Therapy (ESTDT) of Anastrozole as Adjuvant Therapy for Early Stage Breast 
Cancer  
 
IRB#:  
19-006637  
 
Principal Investigator: Tufia C. Haddad, M.D., and Colleagues 
 
 
Key Study Information 
 
 
This section provides a brief summary of the study. It is important for you to understand why 
the research is being done and what it will involve before you decide. Please take the time to 
read the entire consent form carefully and talk to a member of the research team before 
making your decision. You should not sign this form if you have any questions that have not 
been answered. 
It’s Your Choice 
This is a research study. Being in this research study is your choice; 
you do not have to participate. If you decide to join, you can still stop 
at any time. You should only participate if you want to do so. You will 
not lose any services, benefits or rights you would normally have if 
you choose not to take part. 
Research Purpose 
The purpose of this research is to find out more about how anastrozole 
works to prevent recurrence of breast cancer. 
 
You have been asked to take part in this research because you have 
been diagnosed with estrogen receptor positive breast cancer and have 
been recommended to start adjuvant endocrine treatment with an 
aromatase inhibitor. 
What’s Involved 
Study participation involves taking an aromatase inhibitor (AI) called 
anastrozole (the brand name is Arimidex®) for 8-10 weeks. Then your 
blood will be checked to see if:  
1) the anastrozole is in your blood, and  
2) the anastrozole is having an effect on your blood estrogen 
levels. 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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If the anastrozole is working fine and lowering your blood estrogen 
levels, then you will be done with the study. 
 
If the anastrozole is not working well, then you will be asked to take a 
higher dose of anastrozole for 8-10 weeks and have your blood 
checked again. After this higher dose regimen, you will take 8-10 
weeks of a different aromatase inhibitor, letrozole (the brand name is 
Femara®), for 8-10 weeks and have your blood checked a third time. 
After this blood test you will be done with the study. Your oncologist 
will determine if you should remain on letrozole following the study. 
Key Information 
This study will take less time than most research studies and about the 
same amount of time as regular care for your cancer or maybe a bit 
less. 
Post-menopausal women diagnosed with estrogen-receptor positive 
breast cancer are often prescribed aromatase inhibitors to control the 
amount of estrogen in their bodies to prevent the cancer from coming 
back. 
The risks from the aromatase inhibitors are the same whether you are 
on a study or not. The most common risks are those associated with a 
loss of estrogen: hot flashes, hair thinning, vaginal dryness, joint or 
bone stiffness or aches. 
Learn More 
If you are interested in learning more about this study, read the rest of 
this form carefully. The information in this form will help you decide 
if you want to participate in this research or not. A member of our 
research team will talk with you about taking part in this study before 
you sign this form. If you have questions at any time, please ask us. 
 
 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Making Your Decision 
 
 
Taking part in research is your decision. Take your time to decide. Feel free to discuss the 
study with your family, friends, and healthcare provider before you make your decision. 
Taking part in this study is completely voluntary and you do not have to participate. 
 
If you decide to take part in this research study, you will sign this consent form to show that 
you want to take part. We will give you either a printed or electronic copy of this form to 
keep. A copy of this form will be put in your medical record. 
 
For purposes of this form, Mayo Clinic refers to Mayo Clinic in Arizona, Florida and 
Rochester, Minnesota; Mayo Clinic Health System; and all owned and affiliated clinics, 
hospitals, and entities. 
 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Name and Clinic Number 
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Contact Information 
 
 
If you have questions about … 
You can contact … 
 Study tests and procedures 
 Materials you receive 
 Research-related appointments  
 Research-related concern or complaint 
 Research-related injuries or emergencies 
 Withdrawing from the research study 
Principal Investigator: 
Tufia C. Haddad, M.D. 
Brenda J. Ernst, M.D. (AZ)  
Konstandinos Sideras, M.D. (FL) 
 
Phone:  
(507) 284-2511 
AZ: (480) 301-8000 
FL: (904) 953-2000  
 
Institution Name and Address: 
Mayo Clinic 
200 First St SW 
Rochester MN 55905 
 
Mayo Clinic  
5777 E Mayo Boulevard  
Phoenix, AZ 85054  
 
Mayo Clinic  
4500 San Pablo Road  
Jacksonville, FL 32224  
 Rights of a research participant 
Mayo Clinic Institutional Review Board (IRB) 
Phone: (507) 266-4000 
Toll-Free: (866) 273-4681 
 Rights of a research participant 
 Any research-related concern or complaint 
 Use of your Protected Health Information 
 Stopping your authorization to use your 
Protected Health Information 
 Withdrawing from the research study 
Research Participant Advocate (RPA) 
(The RPA is independent of the Study Team) 
Phone: (507) 266-9372 
Toll-Free: (866) 273-4681 
E-mail: researchparticipantadvocate@mayo.edu 
 Billing or insurance related to this research 
study 
Patient Account Services 
Toll-Free: (844) 217-9591  
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Other Information: 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
A description of this research study will be available on ClinicalTrials.Mayo.edu. This website 
will not include information that can identify you. You can search this website at any time. 
 
 
Why are you being asked to take part in this research study? 
 
 
You are being asked to be in this study because you have been diagnosed with estrogen receptor 
positive breast cancer and you have been recommended adjuvant endocrine therapy with an 
aromatase inhibitor. 
 
The plan is to have about 240 women take part in this study at Mayo Clinic. 
 
 
Why is this research study being done? 
 
 
This study is being done to find out why some women do not respond well to the aromatase 
inhibitor, anastrozole (Arimidex®). Everyone in this study will receive anastrozole.  
 
Those women who do not lower their estrogen levels with anastrozole will receive a course of a 
higher dose of anastrozole as well as subsequent course of a different aromatase inhibitor, 
letrozole (Femara®). Anastrozole (1mg daily) and letrozole (2.5 mg daily) are approved by the 
FDA for treatment of women diagnosed with estrogen receptor (ER) positive breast cancer. 
Anastrozole (10mg daily) dose is considered “investigational” by the FDA, because the safety 
and efficacy of this dose are unknown. Anastrozole (10mg) daily is not approved by the FDA. 
 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Information you should know 
 
 
Who is Funding the Study? 
This study is being funded by the Mayo Clinic Breast Cancer Specialized Program of Research 
Excellence (SPORE) and the Mayo Clinic Cancer Center. 
 
 
How long will you be in this research study? 
 
 
You will be in this research study for up to 6 months. 
 
 
What will happen to you while you are in this research study? 
 
 
Before You Start this Study 
If you agree to be in this study, you will sign this informed consent document. 
 
All patients will need to have the following exams, tests, or procedures to find out if you can be 
in the study. These exams, tests, or procedures are part of regular clinical care and may be done 
even if you do not join the study: 
• Physical exam including complete medical history, height, weight and vital signs (blood 
pressure, pulse, temperature) 
• Assessment of your performance status (ability to carry out daily activities) 
• Routine blood tests 
 
During this Study 
We will also collect blood samples (about 2.5 tablespoons) for research before you start 
treatment. 
 
You will start treatment with anastrozole, which is a tablet (pill) you take once per day with 
water. 
 
If you miss a dose of anastrozole, take it as soon as possible. However, if it is almost time for 
your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take a 
double dose. 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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You will take anastrozole once every day for 8-10 weeks. You will need to keep a diary of when 
you take anastrozole and bring the diary and the medication bottles with you to your 
appointments. 
 
After about 8 weeks, you will have blood testing to see if the anastrozole is in your blood and to 
check the levels of two types of estrogen in your blood. The two types of estrogen are E1 
(estrone) and E2 (estradiol). It is expected that anastrozole will lower E1 and E2 levels. 
 
If your blood E1 and E2 levels are sufficiently lowered by anastrozole, you will be done with the 
study. Your regular cancer doctor will determine if you should keep taking the anastrozole. 
 
If your E1 and E2 levels are not sufficiently lowered by anastrozole, you will be offered to take a 
higher dose of anastrozole (10mg) (ANA10). If you are eligible and choose to take the higher 
dose, you will take it every day for 8-10 weeks. You will need to keep a diary of when you take 
anastrozole and bring the diary and the medication bottles with you to your appointments.  
 
After about 2-4 weeks a nurse will call you to see how you are doing and refill your supply of 
ANA10.  
 
If you are one of the first six patients to take the higher dose of anastrozole (ANA10), you will 
need to return to the clinic about 4-5 weeks after you start ANA10 to see the study team. You 
will have your blood drawn for safety testing. If everything is okay, your supply of ANA10 will 
be refilled. 
 
After about 8 weeks, you will have research blood testing. Then you will discontinue the higher 
dose of anastrozole and start taking a different aromatase inhibitor, letrozole, which is a tablet 
you take once every day with water. You will take letrozole every day for 8-10 weeks. You will 
need to keep a diary of when you take letrozole and bring the diary and the medication bottles 
with you to your appointments. 
 
You will need to come to the clinic about 30 days after your last dose of anastrozole (10 mg 
daily) for blood testing and to review any symptoms you may have. 
After about 8 weeks of taking letrozole, you will have blood testing for research, and then you 
will be done with the study. Your regular cancer doctor will determine if you should keep taking 
letrozole or another drug. 
 
Tests done only for research purposes are not meant to provide clinical information or help care 
for you. The results are only important for research. Therefore, the results of tests done with your 
information and samples will not be provided to you. In the rare event that a finding might affect 
the health of you or your family, we will contact you and you can choose whether to receive or 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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refuse the information. If you decide to follow up and further medical testing or care is needed, 
the costs will be billed to you or your insurance. 
 
 
What are the possible risks or discomforts from being in this research study? 
 
 
Risks and side effects of anastrozole (Arimidex®) 
Very common risks of anastrozole (events occurring more than 10% of the time) 
• Hot flashes - sensation of warmth and flushing accompanied by sweating in the chest, 
shoulders, neck, and head 
• Joint pain and stiffness (arthralgia) 
• Feeling weak (asthenia) or tired (fatigue) 
• Thinning of the bones which may lead to a break in the bone (osteopenia, osteoporosis) 
 
Common risks of anastrozole (events occurring 1-10% of the time) 
• Loss of appetite 
• Nausea (feeling sick to your stomach) 
• Headache 
• Increased cholesterol in the blood 
• Drowsiness or excessive sleepiness (somnolence) 
• Pain, burning, or tingling in the hand (carpal tunnel syndrome) 
• Loose stools (diarrhea) 
• Vomiting 
• Changes in liver enzymes as seen on blood tests (ALT, AST) 
• Mild hair loss (alopecia) 
• Allergic reaction that may involve swelling of the face, lips, or tongue (hypersensitivity 
reactions) 
• Bone pain 
• Vaginal dryness 
• Vaginal bleeding (typically occurs in the first few weeks of treatment – if it persists, tell 
your doctor) 
• Muscle pain 
• Skin rash 
 
Uncommon risks of anastrozole (events occurring <1% of the time) 
• Changes in liver enzymes as see on blood tests (GGT and bilirubin) 
• Inflammation of the liver (hepatitis) 
• Hives or rash 


 
 
Approval Date:  
November 22, 2022 
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• Trigger finger – a thumb or finger which locks into a bent position 
• Increased calcium in the blood (hypercalcemia) 
 
Rare but serious risks of anastrozole (events occurring 0.01-1.0% of the time) 
• Red skin rash with raised swollen papules (erythema multiforme) 
• Skin rash caused by hypersensitivity reactions 
• Small areas of bleeding (red or purple patches) in the skin; very rarely accompanied by 
joint, stomach, and kidney pain, or blood in the urine (Henoch-Schonlein Purpura) 
 
Very Rare risks of anastrozole (events occurring less than 0.01% of the time) 
• Extremely severe skin reaction with ulcers or blisters (Stevens-Johnson syndrome) 
• Serious allergic reaction (anaphylaxis) – may involve hives, itching, shortness of breath, 
swelling of the lips or throat, difficulty breathing, may be life-threatening 
 
If either of these happen to you, call an ambulance or see a doctor immediately – you may need 
urgent medical treatment. 
 
Risks and side effects of letrozole (Femara®) 
Some of these side effects, such as hot flashes, hair loss or vaginal bleeding, may be due to the lack 
of estrogen in your body. 
 
Very Common risks of letrozole (events occurring more than 10% of the time) 
• Hot flashes 
• Fatigue 
• Excessive sweating (diaphoresis) 
• Bone or joint aches and pains 
• Thinning of the bones which may lead to a break in the bone (osteopenia, osteoporosis) 
 
Common risks of letrozole (events occurring 1 to 10% of the time) 
• Increased cholesterol in the blood (hypercholesterolemia) 
• Skin rash 
• Headache 
• Dizziness, feeling lightheaded 
• Sense of discomfort or unease (malaise) 
• Feeling sick to your stomach (nausea) 
• Throwing up (vomiting) 
• Sour stomach (indigestion) 
• Difficulty passing stool (constipation) 
• Loose, frequent stools (diarrhea) 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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• Increased or decreased appetite 
• Muscle pain 
• Swelling of arms, hands, legs, or feet (edema) 
• Feeling down or blue (depression) 
• Weight gain 
• Hair thinning or loss (alopecia) 
• High blood pressure (hypertension) 
• Abdominal pain 
• Dry skin 
• Vaginal bleeding or spotting 
 
Uncommon risks of letrozole (events occurring less than 1% of the time) 
• Anxiety 
• Nervousness 
• Irritability 
• Drowsiness or Excessive sleepiness (somnolence) 
• Difficulty falling or staying asleep (insomnia) 
• Impairment of sensation, especially of touch 
• Blurred vision 
• Eye irritation 
• Heart palpitations 
• Rapid heartbeat (tachycardia) 
• Itching, hives (urticaria) 
• Vaginal discharge 
• Vaginal dryness 
• Joint swelling and pain (arthritis) 
• Breast pain 
• Fever 
• Excessive thirst 
• Changes in taste 
• Dry mouth 
• Dryness of mucous membranes (like those lining nose and mouth) 
• Weight loss 
• Infection of the bladder and or kidney (urinary tract infection) 
• Frequent urination 
• Cough 
• Increased level of liver enzymes in the blood 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Rare risks of letrozole (events occurring 0.01-1% of the time) 
• Weakness, paralysis or loss of feeling in any part of the body (particularly arm or leg), 
loss of coordination, nausea, or difficulty speaking or breathing (sign of a brain disorder, 
e.g. stroke)  
• Sudden oppressive chest pain (sign of a heart disorder)  
• Difficulty breathing, chest pain, fainting, rapid heart rate, bluish skin discoloration, or 
sudden arm, leg or foot pain (signs that a blood clot may have formed)  
• Swelling and redness along a vein which is extremely tender and possibly painful when 
touched  
• Severe fever chills, or mouth ulcers due to infections (lack of white blood cells).  
• Severe persistent blurred vision  
 
You should inform the doctor immediately if you experience any of the following symptoms 
during treatment. 
• Swelling mainly of the face and throat (signs of allergic reaction) 
• Yellow skin and eyes, nausea, loss of appetite, dark-colored urine (signs of hepatitis) 
• Rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (signs of skin 
disorder) 
 
Risks for Pregnancy and Nursing 
Because you are post-menopausal, there is very little risk that you might become pregnant. 
However because the drugs used in this study can affect an unborn fetus or nursing child, you 
must not get pregnant or nurse a child while on this study. If you become pregnant, you need to 
tell your doctor immediately. 
 
Standard of Care Risks  
Your doctor will discuss the risks of other tests and procedures, which are part of regular care for 
your cancer. 
 
Blood draws  
The risks of drawing blood include pain, bruising, lightheadedness, and/or fainting, or rarely, 
infection at the site of the needle stick. 
 
Genetic Information Nondiscrimination Act (GINA)  
The Genetic Information Nondiscrimination Act (GINA) may help protect you from health 
insurance or employment discrimination based on genetic information.  
 
 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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The law provides that health insurance companies and group health plans  
• may not ask for genetic information from this research and  
• may not use genetic information when making decision about eligibility or premiums 
 
The law will not stop health insurance companies from using genetic information to decide 
whether to pay claims. The law also will not help you get other types of insurance (such as: life, 
disability or long-term care).  
 
Risks Associated with Genomic Testing  
Despite the GINA protections and the best efforts of the research team, there may still be a risk if 
information about you were to become known to people outside of this study. 
 
Genetic information is unique to you, even without your name or other identifiers. For this 
reason, genetic information like DNA may be used to identify you and possibly your family 
members. We have procedures (such as, labeling your biospecimens with a password protected 
code known only to select research staff) to prevent people working with your DNA from 
discovering if it belongs to you. However, there is the risk this can happen as new ways of 
tracing genetic information are being developed that may make re-identification of genetic 
information possible. 
 
Unforeseeable Risks  
Side effects may range from mild to severe. Other drugs may be given to make side effects less 
serious and less uncomfortable. Talk to the researcher and/or your healthcare provider about side 
effects and ask any other questions.  
 
This study involves testing your DNA, which is the genetic information you inherited from your 
parents (also known as genetic testing). This testing may include whole genome sequencing 
(mapping your entire genetic code). You will not be notified of the genetic test results and they 
will not be put into your medical record. 
 
 
Are there reasons you might leave this research study early? 
 
 
You may decide to stop at any time. You should tell the Principal Investigator if you decide to 
stop and you will be advised whether any additional tests may need to be done for your safety.  
 
 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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In addition, the Principal Investigator or Mayo Clinic may stop you from taking part in this study 
at any time: 
• if it is in your best interest,  
• if you don’t follow the study procedures,  
• if the study is stopped.  
 
If you leave this research study early, or are withdrawn from the study, no more information 
about you will be collected; however, information already collected about you in the study may 
continue to be used. 
 
We will tell you about any new information that may affect your willingness to stay in the 
research study. 
 
 
What if you are injured from your participation in this research study? 
 
 
Where to get help: 
 
If you think you have suffered a research-related injury, you should promptly notify the Principal 
Investigator listed in the Contact Information at the beginning of this form. Mayo Clinic will 
offer care for research-related injuries, including first aid, emergency treatment and follow-up 
care as needed. 
 
Who will pay for the treatment of research related injuries? 
Care for such research-related injuries will be billed in the ordinary manner, to you or your 
insurance. You will be responsible for all treatment costs not covered by your insurance, 
including deductibles, co-payments and coinsurance. The study will not offer free medical care 
or payment for any bad side effects from taking part in this study. 
+ 
 
What are the possible benefits from being in this research study? 
 
 
This study may not make your health better. However, it may allow you and your cancer doctor 
to know if your body responds well to anastrozole. It may also allow other patients with breast 
cancer to benefit in the future from what we learn in this research study. 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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What alternative do you have if you choose not to participate  
in this research study? 
 
 
You don’t have to be in this study to receive treatment for your condition. Your other choices 
may include: treatment for your cancer without being on a study, treatment on a different 
research study, or no treatment. Talk to the Principal Investigator or your doctor if you have any 
questions about any of these alternative treatments or procedures. 
 
 
What tests or procedures will you need to pay for if you take part  
in this research study? 
 
 
You won’t need to pay for tests and procedures which are done just for this research study. These 
tests and procedures are:  
• Research testing on blood samples 
• Routine blood testing at the end of normal dose anastrozole (1mg) 
 
If you are assigned to higher dose of anastrozole (10mg) and start Cycle 2, you won’t need to 
pay for the following tests and procedures done just for this study: 
• Supply of higher dose of anastrozole (10mg) for 8-10 weeks 
• Clinic visit and routine and research blood testing at the end of Cycle 2 and 30 days after 
your last dose of higher dose anastrozole (10mg) 
 
If you are one of the first 6 patients to continue on to Cycle 2 in the study and take the higher 
dose of anastrozole (10 mg), you won’t need to pay for the following tests and procedures which 
are done just for this study: 
• Routine and research blood testing for safety while you are taking anastrozole 10 mg 
• Clinic visit during Cycle 2 between Days 28 and 35 just for this research study 
 
You and/or your insurance will need to pay for all other tests and procedures that are part of this 
research study and/or needed for your clinical care including copayments and deductibles.  
 
You and/or your insurance will need to pay for (standard dose) anastrozole and letrozole used in 
this study, because they are part of regular care for your cancer.  
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Before you take part in this study, you should call your insurer to find out if the cost of these 
tests and/or procedures will be covered. You will have to pay for any costs not covered by your 
insurance. 
 
If you have billing or insurance questions call Patient Account Services at the telephone 
number provided in the Contact Information section of this form. 
 
 
Will you be paid for taking part in this research study? 
 
 
You will not be paid for taking part in this study. 
 
There is a very small chance that some commercial value may result from the use of your 
donated samples. This could include new products like a drug or a test to diagnose a disease. If 
that happens, you won't be offered a share in any profits. 
 
 
Will your information or samples be used for future research? 
 
 
Your information and samples will be sent to the Sponsor, Mayo Clinic. The Sponsor can use 
your data and samples for research purposes only as described in the research study. Your data 
and samples will be sent to the Sponsor in a coded format, which protects your identity. Mayo 
Clinic may destroy the samples at any time without telling you. We will test your blood as part  
of this study. In addition, we would like to keep your study information and samples for future 
research. You can still take part in this study without giving permission to use your data and 
samples for future research. If you agree to give your sample, it will be the property of Mayo 
Clinic. 
 
Researchers at Mayo Clinic who aren't involved with this study may ask to use your sample for 
future research. Researchers at other institutions may also ask for a part of your sample for future 
studies. Your sample will be sent to researchers in a coded format, which protects your identity.  
 
Some future studies may examine your DNA, which is the genetic information you inherited 
from your parents (genetic testing). If there are findings which may be useful for your health 
care, the researchers may contact Mayo Clinic, so Mayo Clinic can give you the option of 
learning the results. You would be given general information on the potential risks, benefits, and 
costs of choosing to learn about the findings. 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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To support future research, de-identified genetic information may be placed in databases 
accessible by the internet. Some of the information may be available to anyone using the 
internet, and some will be released only to approved researchers. Combined study information 
(including genomic summary results) may be published, but the information will not identify 
you. 
 
Even though information traditionally used to identify you will not be shared, people may 
develop ways in the future to allow someone to link your genetic information back to you. For 
this reason, confidentiality cannot be guaranteed. It is also possible that re-identified information 
could be used in discriminating ways, and there could be additional unknown risks. We will 
make every effort to protect your confidentiality. 
 
Please read the following statements and mark your choices:  
 
1. I permit my information and samples to be stored and used in future research to learn about, 
prevent or treat cancer:  
 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
2. I permit my information and samples to be stored and used in future research to learn about, 
prevent, or treat any other health problems (for example: causes of diabetes, heart disease, 
and Alzheimer’s):  
 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
3. I agree to have my coded genetic information and coded medical information placed in 
password-protected secured databases for research analyses. 
 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
You may withdraw your consent for future use of your information and/or samples at any 
time, by writing to the Principal Investigator at the address provided in the “Contact 
Information" section of this consent form. 
 
Your information and/or samples would be removed from any repository where they are stored, 
if possible. Information and/or samples already distributed for research use will not be retrieved. 
QST-NSTD1Y
QST-NSTD1N
QST-NSTD2Y
QST-NSTD2N
QST-NSTD3Y
QST-NSTD3N


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
IRB#: 19-006637 00       e-Sign  
Page 17 of 20 
IRB Doc. Ctrl # 10013.33 
 
 
 
 
 
 
 
Name and Clinic Number 
Protocol #: MC1931 
Version #: Initial 
Version Date: 21Nov2022 
Because we cannot predict how your sample will be used in the future, we cannot promise that 
samples can be retrieved and destroyed. 
 
It is possible that information identifying your samples or your data could be removed. These 
samples and data will no longer be linked to you. If that were to happen, the samples and data 
could be used for future research studies or given to another researcher without asking for your 
permission. 
 
 
How will your privacy and the confidentiality of your records be protected? 
 
 
Mayo Clinic is committed to protecting the confidentiality of information obtained about you in 
connection with this research study. All of your research samples given to Mayo Clinic will be 
labeled with a code number and kept in locked storage. Only your study team will be able to link 
your samples with your identity. No one working with your samples will know your identity. If 
the results of the research are made public, information that identifies you will not be used. 
 
During this research, information about your health will be collected. Under Federal law called 
the Privacy Rule, health information is private. However, there are exceptions to this rule, and 
you should know who may be able to see, use and share your health information for research and 
why they may need to do so. Information about you and your health cannot be used in this 
research study without your written permission. If you sign this form, it will provide that 
permission (or “authorization”) to Mayo Clinic. 
 
Your health information may be collected from: 
• Past, present and future medical records. 
• Research procedures, including research office visits, tests, interviews and 
questionnaires. 
 
Your health information will be used and/or given to others to: 
• Do the research. 
• Report the results. 
• See if the research was conducted following the approved study plan, and applicable rules 
and regulations. 
 
Your health information may be used and shared with: 
• Mayo Clinic research staff involved in this study 
• Other Mayo Clinic staff involved in your clinical care 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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IRB Doc. Ctrl # 10013.33 
 
 
 
 
 
 
 
Name and Clinic Number 
Protocol #: MC1931 
Version #: Initial 
Version Date: 21Nov2022 
• The sponsor(s) of this study and the people or groups hired by the sponsor(s) to help 
perform this research 
• The Mayo Clinic Institutional Review Board that oversees the research 
• Federal and State agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health and other United States 
agencies) or government agencies in other countries that oversee or review research 
• A group that oversees the data (study information) and safety of this research 
 
How your information may be shared with others: 
While taking part in this study, you will be assigned a code that is unique to you, but does not 
include information that directly identifies you. This code will be used if your study information 
is sent outside of Mayo Clinic. The groups or individuals who receive your coded information 
will use it only for the purposes described in this consent form. 
 
If the results of this study are made public (for example, through scientific meetings, reports or 
media), information that identifies you will not be used. 
 
In addition, individuals involved in study oversight and not employed by Mayo Clinic may be 
allowed to review your health information included in past, present, and future medical and/or 
research records. This review may be done on-site at Mayo Clinic or remotely (from an off-site 
location). These records contain information that directly identifies you. However, the 
individuals will not be allowed to record, print, copy (using paper, digital, photographic or other 
methods), or remove your identifying information from Mayo Clinic. 
 
Is your health information protected after it has been shared with others? 
Mayo Clinic asks anyone who receives your health information from us to protect your privacy; 
however, once your information is shared outside Mayo Clinic, we cannot promise that it will 
remain private and it may no longer be protected by the Privacy Rule. 
 
 
Your Rights and Permissions 
 
 
Participation in this study is completely voluntary. You have the right not to participate at all. 
Even if you decide to be part of the study now, you may change your mind and stop at any time. 
You do not have to sign this form, but if you do not, you cannot take part in this research study. 
 
Deciding not to participate or choosing to leave the study will not result in any penalty. Saying 
‘no’ will not harm your relationship with your own doctors or with Mayo Clinic. 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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IRB Doc. Ctrl # 10013.33 
 
 
 
 
 
 
 
Name and Clinic Number 
Protocol #: MC1931 
Version #: Initial 
Version Date: 21Nov2022 
If you cancel your permission for Mayo Clinic to use or share your health information, your 
participation in this study will end and no more information about you will be collected; 
however, information already collected about you in the study may continue to be used. 
 
You can cancel your permission for Mayo Clinic to use or share your health information at any 
time by sending a letter to the address below: 
 
Mayo Clinic 
Office for Human Research Protection 
ATTN: Notice of Revocation of Authorization 
201 Building 4-60 
200 1st Street SW 
Rochester, MN 55905 
 
Alternatively, you may cancel your permission by emailing the Mayo Clinic Research 
Participant Advocate at: researchparticipantadvocate@mayo.edu. 
 
Please be sure to include in your letter or email: 
• The name of the Principal Investigator, 
• The study IRB number and /or study name, and 
• Your contact information. 
 
Your permission for Mayo Clinic to use and share your health information lasts forever, unless 
you cancel it. 
 
 


 
 
Approval Date:  
November 22, 2022 
Not to be used after: January 27, 2023 
 
 
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Name and Clinic Number 
Protocol #: MC1931 
Version #: Initial 
Version Date: 21Nov2022 
 
 
Enrollment and Permission Signatures 
 
 
Your signature documents your permission to take part in this research.  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
Printed Name  
 
 
Date (mm/dd/yyyy) 
 
 
Time (hh:mm am/pm)  
 
 
 
 
 
 
 
 
_______________________________ 
Signature 
 
 
 
Person Obtaining Consent  
• I have explained the research study to the participant. 
• I have answered all questions about this research study to the best of my ability. 
 
 
 
Printed Name  
 
 
Date (mm/dd/yyyy) 
 
 
Time (hh:mm am/pm) 
 
 
_______________________________ 
Signature 
prtPOCName
dtePOCSig
sigPOC
chkEsi
dteParticipantSig
sigParticipant
prtParticipantName
sigWitness