Summary

This phase III trial compares the addition of chemotherapy to usual treatment (ovarian function suppression plus hormonal therapy) to usual treatment alone in treating premenopausal estrogen receptor (ER)-positive/HER2-negative breast cancer patients who are at high risk of their cancer returning. One of the likely benefits of chemotherapy is that it can stop the ovaries from releasing eggs and hormones in women who are premenopausal. This study may help researchers determine if adding chemotherapy to ovarian suppression and hormonal therapy has similar effectiveness to ovarian suppression and hormonal therapy alone in preventing cancer from returning.

Objectives

PRIMARY OBJECTIVE:
I. To determine whether adjuvant chemotherapy (ACT) added to ovarian function suppression (OFS) plus endocrine therapy (ET) is superior to OFS plus ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early- stage breast cancer (EBC) patients with estrogen receptor (ER)-positive, HER2-negative tumors and 21-gene recurrence score (RS) between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).

SECONDARY OBJECTIVES:
I. To determine whether ACT added to OFS plus ET is superior to OFS plus ET in improving invasive disease-free survival (IDFS) among premenopausal, EBC patients with ER-positive, HER2-negative tumors and 21-gene RS between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).
II. To determine whether ACT added to OFS plus ET is superior to OFS plus ET in improving overall survival (OS) among premenopausal, EBC patients with ER-positive, HER2-negative tumors and 21-gene RS between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).
III. To determine whether ACT added to OFS plus ET is superior to OFS plus ET in improving distant recurrence-free interval (DRFI) among premenopausal, EBC patients with ER-positive, HER2-negative tumors and 21-gene RS between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).
IV. To determine whether ACT added to OFS plus ET is superior to OFS plus ET in improving breast cancer-free interval (BCFI) among premenopausal, EBC patients with ER-positive, HER2-negative tumors and 21-gene RS between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).
V. To determine whether patients who receive ACT added to OFS plus ET will have more severe menopausal symptoms, measured by the Functional Assessment of Cancer Therapy-Endocrine Symptoms Subscale (FACT ESS)-19 score, compared to those who do not receive ACT.
VI. To determine whether patients who receive ACT added to OFS plus ET will have increased pain during aromatase inhibitor (AI) therapy compared to patients who do not receive ACT.

EXPLORATORY OBJECTIVES:
I. To determine if there are differences in adherence to long-term OFS plus ET by treatment arm assignment.
II. To determine if there are differences in the degree of ovarian suppression between treatment arms.
III. To determine if ACT added to OFS plus ET increases the long-term toxicities of OFS plus ET in premenopausal women with EBC.
IV. To determine whether patients who receive ACT added to OFS plus ET will have similar selected quality of life (QOL) outcomes during OFS plus ET compared to patients who do not receive ACT.
V. To assess if survival outcomes differ by race/ethnicity.
VI. To determine if body mass index (BMI) contributes to outcome in this study population.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive a gonadotropin-releasing hormone (GnRH) agonist via injection and an AI orally (PO) per the study investigator's choice. Treatment with AI continues for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients also undergo mammogram or magnetic resonance imaging (MRI) scans during screening and then every 12 months on study and during follow up, and dual X-ray absorptiometry (DEXA) scans every 2 years on study. Patients may also undergo collection of tumor tissue within 90 days after randomization and at time of disease recurrence, and collection of blood samples before randomization, at 12, 24, 36, 48, and 60 months, and at time of disease recurrence.

ARM 2: Patients receive adjuvant chemotherapy regimen, a GnRH agonist via injection, and an AI PO per the study investigator's choice. Treatment with AI continues for up to 5 years in the absence of disease progression or unacceptable toxicity. Patients also undergo mammogram or MRI scans during screening and then every 12 months on study and during follow up, and DEXA scans every 2 years on study. Patients may also undergo collection of tumor tissue within 90 days after randomization and at time of disease recurrence, and collection of blood samples before randomization, at 12, 24, 36, 48, and 60 months, and at time of disease recurrence.

After completion of study treatment, patients are followed every 12 months for 10 years.

Eligibility

1. The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
2. Female patients must be >= 18 years of age
3. Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as: * Age 50 years or under with spontaneous menses within 12 months; or * Age > 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or * Patients with amenorrhea due to intrauterine device (IUD) or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or * Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range
4. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 (or Karnofsky >= 60%)
5. Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy
6. Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy
7. Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy
8. For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection.)
9. For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy radiation therapy [RT] of the chest wall will be administered.)
10. Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND)
11. The following staging criteria must be met postoperatively according to American Joint Committee on Cancer (AJCC) 8th edition criteria: * By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.) * By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c). * Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes * Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1
12. Oncotype DX RS requirements: * If node-negative: ** Oncotype DX RS must be RS 21-25, or ** Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size > 3 cm, intermediate histologic grade with primary tumor size > 2 cm, or high histologic grade with primary tumor size > 1 cm * If 1-3 nodes involved: ** Oncotype DX RS must be < 26 *** Patients with a “Low Risk” or “MP1” MammaPrint result must have eligibility assessed with an Oncotype DX RS at pre-entry. Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible
13. The tumor must be ER and/or PgR-positive by current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines based on local testing results. Patients with >= 1% ER and/or PgR staining by immunohistochemistry (IHC) will be classified as positive
14. The tumor must be HER2-negative by current ASCO/CAP guidelines based on local testing results
15. The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry must be no more than 16 weeks
16. Short course of endocrine therapy of less than 6 weeks duration before pre-entry is acceptable either as neoadjuvant or adjuvant therapy. An Oncotype DX RS must be performed on core biopsy specimen obtained prior to initiation of neoadjuvant endocrine therapy if received
17. Patients with a prior or concurrent non-breast malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. This would include prior cancers treated with curative intent
18. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
19. Radiation therapy should be used according to standard guidelines; the intended radiation therapy should be declared prior to pre-entry

Treatment Sites in Georgia