• A patient cannot be considered eligible for this study unless ALL of the following conditions are met.

‣ The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry and, for patients treated in the U.S., authorization permitting release of personal health information.

⁃ Female patients must be greater than or equal to 18 years of age.

⁃ 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 greater than 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 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.

⁃ The patient must have an ECOG performance status of less than or equal to 2 (or Karnofsky greater than or equal to 60%).

⁃ 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.

⁃ 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.

⁃ Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy.

⁃ For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS (ductal carcinoma in situ) 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 LCIS (lobular carcinoma in situ) are eligible without additional resection.)

⁃ For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT (radiation therapy) of the chest wall will be administered.)

⁃ Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND).

⁃ The following staging criteria must be met postoperatively according to 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.

⁃ Oncotype DX RS (recurrence score) 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 greater than 3 cm, intermediate histologic grade with primary tumor size greater than 2 cm, or high histologic grade with primary tumor size greater than 1 cm.

⁃ If 1-3 nodes involved:

⁃ Oncotype DX RS must be less than 26.

‣ \* Patients with a Low Risk or MP1 MammaPrint (a genomic test that analyzes the activity of certain genes in early-stage breast cancer) result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). 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.

⁃ The tumor must be ER and/or PgR-positive (progesterone receptor) by current ASCO/CAP guidelines based on local testing results. Patients with greater than or equal to 1% ER and/or PgR staining by IHC will be classified as positive.

⁃ The tumor must be HER2-negative by current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines based on local testing results.

⁃ The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry must be no more than 16 weeks.

⁃ 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.

⁃ 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.

⁃ HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

⁃ Radiation therapy should be used according to standard guidelines; the intended radiation therapy should be declared prior to pre-entry.