Summary

This phase III trial compares the effect of radiation therapy combined with hormonal therapy versus hormonal therapy alone in treating patients with low risk, early stage breast cancer with Oncotype Dx Recurrence =< 18. Oncotype DX is a laboratory test which results in a score that is used to help predict whether breast cancer will spread to other parts of the body or come back. Radiation therapy uses high doses of radiation to kill cancer cells and shrink tumors but may result in some side effects. Hormones called estrogen and progesterone may contribute to the growth of breast tumor cells. Hormone therapy, also called endocrine therapy, may stop the growth of tumor cells by blocking or removing these hormones. This clinical trial may help researchers understand if patients with low-risk, early stage breast cancer who have Oncotype recurrence score of =< 18 can safely omit radiation therapy and only be treated with hormonal therapy without losing any radiation treatment benefit.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior rate of invasive or non-invasive ipsilateral breast tumor recurrence (IBTR) compared to breast conservation with breast radiation and endocrine therapy.

SECONDARY OBJECTIVES:
I. To evaluate whether breast conservation surgery and endocrine therapy inclusive of any second breast conservation surgery for salvage of IBTR results in a non-inferior rate of overall breast conservation compared to breast conserving surgery, endocrine therapy, and radiation for IBTR.
II. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior rate of invasive ipsilateral breast tumor recurrence (IIBTR) compared to breast conservation, breast radiation, and endocrine therapy.
III. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior relapse free interval (RFI) compared to breast conservation, breast radiation, and endocrine therapy.
IV. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior distant disease-free survival (DDFS) compared to breast conservation, breast radiation, and endocrine therapy.
V. To evaluate whether breast conservation surgery and endocrine therapy results in a non-inferior overall survival (OS) compared to breast conservation, breast radiation, and endocrine therapy.
VI. To evaluate whether there is a difference in patient-reported breast pain in women who do and do not receive breast radiation.
VII. To evaluate whether there is a difference in patient-reported worry about recurrence in women who do and do not receive breast radiation.
VIII. To evaluate whether adherence to endocrine therapy following breast conservation surgery alone is non inferior compared to endocrine therapy with breast conservation surgery and breast radiation.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Within 12 weeks of the last breast cancer surgery, patients undergo external beam radiation therapy. Patients also receive endocrine therapy for a minimum of 5 years initiated before, during, or after completion of radiation therapy at the discretion of the investigator. Endocrine therapy may include tamoxifen, anastrozole, letrozole, exemestane, or luteinizing hormone-releasing hormone (LHRH) agonist/antagonist. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo mammogram or magnetic resonance imaging (MRI) as well as optional blood sample collection throughout the trial.

ARM II: Patients receive endocrine therapy for a minimum of 5 years at the discretion of the investigator. Endocrine therapy may include tamoxifen, anastrozole, letrozole, exemestane, or LHRH agonist/antagonist. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo mammogram or MRI as well as optional blood sample collection throughout the trial.

After completion of study treatment, patients are followed up every 6 months for 24 months, and then every 12 months from year 3 through year 10 after randomization.

Eligibility

1. The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry/Step 1 and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
2. The patient must be >= 50 years and < 70 years of age
3. The trial is open to female and male patients
4. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. The patient must have undergone a lumpectomy and the margins of the resected specimen or re-excision must be histologically free of invasive tumor and breast 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. (Patients with margins positive for breast lobular carcinoma in situ [LCIS] are eligible without additional resection)
6. The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination
7. Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection)
8. 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 (=< 2 cm). * By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible)
9. Oncotype DX Recurrence Score of =< 18 on diagnostic core biopsy or resected specimen. * For patients with a T1a tumor (=< 0.5 cm in size), or patients at Canadian provinces or approved international sites where Oncotype DX Recurrence Score testing would not be covered, who do not already have an Oncotype DX Recurrence Score at pre-entry/Step 1, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory. Tumor size sample must be = 0.2 cm for analysis * The Oncotype RS can be run on the biopsy core or surgical specimen. The patient cannot have initiated endocrine therapy prior to tissue collection. * An Oncotype RS is required for eligibility, however, for a patient whose tumor has already had a MammaPrint test completed as part of usual care when being considered for enrollment and is in the binary “low” category will meet this eligibility criteria and an Oncotype RS does not need to be performed
10. The tumor must have been determined to be estrogen receptor (ER) and/or progesterone receptor (PgR) positive assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guideline Recommendations for hormone receptor testing. Patients with >= 1% ER or PgR staining by immunohistochemistry (IHC) are considered positive
11. The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines
12. Patients may be premenopausal or postmenopausal at the time of pre-entry/Step 1. For study purposes, postmenopausal is defined as: * Age 56 or older with no spontaneous menses for at least 12 months prior to pre-entry/Step 1; or a documented hysterectomy; or * Age 55 or younger with no spontaneous menses for at least 12 months prior to pre-entry/Step 1 (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or * Documented bilateral oophorectomy
13. The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry/Step 1 must be no more than 70 days
14. The patient must have recovered from surgery with the incision completely healed and no signs of infection
15. Bilateral mammogram or MRI within 6 months prior to pre-entry/Step 1
16. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
17. Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician’s discretion