Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients with Stage II-III Breast Cancer Undergoing Surgery

PRIMARY OBJECTIVES:

I. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine treatment increases the proportion of endocrine sensitive tumors relative to patients treated with anastrozole.

II. To determine whether fulvestrant in combination with anastrozole, administered for 24 weeks as neoadjuvant endocrine treatment, increases the proportion of endocrine sensitive tumors relative to patients treated with anastrozole.

III. If both of the fulvestrant containing arms are found to have an endocrine sensitive disease rate at least 10% higher than that of the anastrozole arm, we will assess whether the endocrine sensitive disease rate is greater with the combination of anastrozole and fulvestrant than with fulvestrant alone.

IV. To assess whether the 5-year recurrence free survival (RFS) rate among women treated with anastrozole with a modified preoperative endocrine prognostic index (PEPI) score 0 following 24 weeks of neoadjuvant therapy is at most 90%.

V. For the fulvestrant containing regimens, a point and interval estimate of the 5 year RFS will be obtained.

SECONDARY OBJECTIVES:

I. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between the fulvestrant arm and the anastrozole arm.

II. To examine the differences in surgical outcome, clinical and radiological response rates, and safety profile between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole.

III. To examine the rate of pathologic complete response (pCR) of 12 weeks of neoadjuvant paclitaxel in patients with endocrine resistant disease following 4-weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole).

IV. To examine the rate of pathologic complete response (pCR) among those patients with endocrine resistant disease, following 4 weeks or 12-weeks of neoadjuvant endocrine therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and anastrozole), who choose not to receive neoadjuvant paclitaxel, but another standard neoadjuvant taxane and /or anthracycline containing regimen or cyclophosphamide, methotrexate, fluorouracil (CMF).

V. To summarize the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade > 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting.

VI. To assess time to breast cancer recurrence for patients with endocrine resistant tumors defined by tumor marker of proliferation Ki-67 (Ki67) > 10% at week 4, Ki67 > 10% at week 12 and modified preoperative endocrine prognostic index (PEPI) score of non-zero on neoadjuvant endocrine therapy, with all three groups combined or separated.

VII. To determine the impact of NF1 gene copy loss and stop/gain mutations on short and long-term neoadjuvant/adjuvant endocrine therapy outcomes.

VIII. To assess whether women with circulating tumor-derive deoxyribonucleic acid (ctDNA) present after 4 weeks of neoadjuvant endocrine therapy (NET) is less likely to achieve modified (m)PEPI 0 or pCR among those with week 4 Ki67 =< 10% and continued on NET.

IX. To examine whether the proportion of women with ctDNA present at week 4 differs between those with week 4 Ki67 >10% on NET and those with week 4 Ki67 =< 10%.

X. To assess whether residual cancer curden (RCB) class differs with respect to the presence of ctDNA after week 4 NET among those with a week 4 Ki67 levels > 10% who switched to neo-adjuvant chemotherapy.

CORRELATIVE SCIENCE OBJECTIVES:

I. To assess whether the degree of tumor Ki67 suppression at week 4 and surgery differs between patients randomized to fulvestrant and those randomized to anastrozole.

II. To assess whether the degree of tumor Ki67 suppression at week 4 and surgery differs between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole.

III. To examine the impact of tumor estrogen receptor (ER) expression level post-neoadjuvant endocrine therapy on RFS in each treatment arm separately.

IV. To examine whether RFS differs with respect to pathologic tumor stage (T1 versus [vs.] T2) post-neoadjuvant endocrine therapy in the subgroup of women with a modified PEPI score of 0.

V. To examine whether rate of endocrine resistant tumors or RFS differs with respect to the degree of week 4 Ki67 suppression.

VI. To examine whether the rate of week 4 Ki67 level > 10%, the rate of endocrine resistant tumors or RFS differs with respect to pre-treatment gene expression profile.

VII. To examine whether gene expression profiles at week 4 can further refine the patient population who have modified PEPI score non-0 or shorter RFS.

VIII. To assess the pCR/residual cancer burden (RCB)-1 rate in each of the following cohorts:

VIIIa. Those who chose to switch to paclitaxel after finding their week 4 Ki67 was > 10%.

VIIIb. Those who chose to switch to paclitaxel after finding their week 12 Ki67 was > 10%.

VIIIc. Those patients who chose to switch to a standard neoadjuvant taxane and/or anthracycline containing regimen or CMF (rather than paclitaxel) after finding their week 4 Ki67 was > 10%.

VIIId. Those patients who chose to switch to a standard neoadjuvant taxane and/or anthracycline containing regimen or CMF (rather than paclitaxel) after finding their week 12 Ki67 was > 10%.

IX. To evaluate cycle 1, day 2 tumor biopsy following the initiation of paclitaxel to develop early molecular markers of tumor response to paclitaxel.

X. To evaluate tumor tissue, serum, and plasma specimens collected at baseline, on-therapy, and at surgery, and blood collected during follow-up and at recurrence for biomarker discovery (through methods including but not limited to gene expression profiling, patterns of gains or losses of deoxyribonucleic acid [DNA], tumor whole genome and targeted DNA and ribonucleic acid [RNA] sequencing and proteomics) in studies that aim to understand signaling pathways associated with endocrine therapy and taxane therapy sensitivity and resistance.

XI. To compare the RCB profile between NF1-low and NF1-normal tumors triaged to neoadjuvant chemotherapy.

XII. Exploratory objectives for ctDNA analysis:

XIIa. To examine the association between the presence of pre-NET ctDNA and each of the following patient and disease characteristics: age, race, body mass index, cTstage, cN stage, pre-NET Ki67, tumor grade, histology, breast cancer intrinsic subtype, gene expression or mutation profiles, week 4 Ki67 levels =< 10% , week 4 Ki67 =< 2.7% (complete cell cycle arrest).

XIIb. To assess whether the presence of pre-NET ctDNA decreases the likelihood to achieve mPEPI 0 + pCR among patients with week 4 Ki67 levels =< 10% who completed NET or subsequently discontinued NET due to disease progression.

XIIc. To estimate the proportion of women who maintain ctDNA positivity or attain ctDNA positivity after completion of 4 weeks, or after 24 weeks of NET.

XIId. To assess whether the presence of ctDNA at completion of NET decreases the duration of breast cancer-free interval among patients with week 4 Ki67 levels =< 10% who completed NET.

XIIe. To assess whether the duration of breast cancer-free interval is decreased in those with ctDNA present at week 4 NET among patients with a week 4 Ki67 levels > 10% who switched to neo-adjuvant chemotherapy.

XIIf. To assess whether RCB class or duration of breast cancer-free interval differs with respect to the presence of ctDNA at the completion of NCT among those with a week 4 Ki67 levels > 10% who switched to NCT.

XIIg. To determine the sensitivity, specificity, and lead-time interval for ctDNA detection during follow up after surgery for distant disease recurrence among high risk patients.

XIIh. To assess the ctDNA positivity rate at 5 years after surgery and its association with late recurrence among women with a week 4 Ki67 levels =< 10% who completed NET.

XIIi. To assess the ctDNA positivity rate at 5 years after surgery and its association with late recurrence among women with a week 4 Ki67 levels > 10% who switched to neoadjuvant chemotherapy.

XIIj. To examine changes in ctDNA quantity over time up to surgery during neoadjuvant therapy among patients with week 4 Ki67 > 10%, those with week 4 Ki67 =< 10%, and mPEPI and RCB categories.

XIIk. To compare mutation profiles of ctDNA at metastatic recurrence with persistent/emerging mutations in tumor tissues at surgery post neoadjuvant therapy to identify driver mechanisms of recurrence.

OUTLINE: Patients are randomized to 1 of 3 treatment arms. (Effective 11/01/2018, Arms II and III will be closed to enrollment and all new patients will be assigned to Arm I.)

ARM I: Patients receive anastrozole orally (PO) once daily (QD) on days 1-28. Treatment repeats every 4 weeks for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery between days 7-28 of cycle 6.

ARM II: Patients receive fulvestrant intramuscularly (IM) on days 1 and 15 (cycle 1) and day 1 (cycles 2-6). Treatment repeats every 4 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo surgery between days 7-28 of cycle 6.

ARM III: Patients receive anastrozole as in Arm I and fulvestrant IM as in Arm II and undergo surgery between days 7-28 of cycle 6.

MODIFIED PEPI 0 VALIDATION PHASE: Patients with endocrine therapy resistant disease, defined by Ki67 > 10% at the 4-week biopsy receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, 15, and 22. Beginning 3-6 weeks later, patients undergo surgery. Treatment repeats every 4 weeks for 3 cycles at the discretion of the treating physician.

After completion of study treatment, patients are followed up yearly for 6-10 years, then up to 10 years thereafter.