Summary

This randomized phase III trial studies if not giving regional radiotherapy is just as good as using regional radiotherapy in keeping breast cancer from coming back in patients with estrogen receptor (ER) positive, HER2 negative node positive low risk breast cancer who have undergone breast conserving surgery or mastectomy. Women with ER positive breast cancer normally will receive endocrine therapy and some may receive chemotherapy to help prevent the cancer from coming back. Many women will also receive radiotherapy to the whole breast/chest area and the surrounding lymph glands (called regional radiotherapy). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. It is not known whether patients with low risk breast cancer need to receive regional radiotherapy. As a result, some women may be getting regional radiotherapy who do not need it and be exposed to the side effects of their treatment without benefit. This study will help to determine if regional radiotherapy can be omitted for low risk ER positive node positive breast cancer patients.

Objectives

PRIMARY OBJECTIVE:
I. To compare the breast cancer recurrence-free interval (BCRFI) between patients that received regional radiation therapy (RT) or not, defined as time from randomization to time of invasive recurrent disease in the ipsilateral chestwall, breast, regional nodes, distant sites or death due to breast cancer (BC).

SECONDARY OBJECTIVES:
I. To compare the invasive disease-free survival (DFS) between patients that received regional RT or not.
II. To compare the breast cancer mortality between patients that received regional RT or not.
III. To compare the overall survival (OS) between patients that received regional RT or not.
IV. To compare the locoregional recurrence-free interval (LRRFI) between patients that received regional RT or not.
V. To compare the distant recurrence-free interval (DRFI) between patients that received regional RT or not.
VI. To compare the toxicity between patients that received regional RT or not.
VII. To compare arm volume and mobility measurements between patients that received regional RT or not.
VIII. To compare patient reported outcomes (PROs) and the quality of life (QOL) between patients that received regional RT or not. (Enrollment completed August 2,2022)
IX. To compare the cost effectiveness between patients that received regional RT or not. (Enrollment completed August 2,2022)

TERTIARY OBJECTIVES:
I. To establish a comprehensive tumor bank linked to a clinical database for the further study of predictive and prognostic biomarkers in breast cancer.
II. To evaluate the ability of intrinsic subtype measured by immunohistochemistry (IHC) to predict BCRFI, LRRFI, DRFI and the effect of regional RT on these outcomes.
III. To evaluate other radiation sensitivity signatures to prognosticate and predict effect of regional RT.
IV. To describe the prevalence of detectable baseline circulating tumor deoxyribonucleic acid (DNA) (ctDNA) in node positive low risk estrogen receptor (ER) positive breast cancer and evaluate its prognostic ability.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Following breast conserving surgery (BCS), patients receive whole breast irradiation (WBI) daily Monday to Friday for 16-21 or 25-32 fractions. Patients who underwent mastectomy do not receive RT.

ARM 2: Following BCS, patients receive WBI plus RT to the regional nodes (supraclavicular, non-dissected axillary, and internal mammary) daily Monday to Friday for 16-21 or 25-32 fractions. Patients who have had a mastectomy receive RT to the chest wall and regional nodes (supraclavicular, non-dissected axillary, and internal mammary).

Patients undergo blood sample collection throughout the study.

Eligibility

1. Patients must be women with newly diagnosed histologically proven invasive carcinoma of the breast with no evidence of metastases, staged as per site standard of care
2. Patients must have been treated by breast conserving surgery (BCS) or mastectomy Patients must have been treated by breast conserving surgery (BCS) or mastectomy with clear margins of excision * Patients treated by BCS with focally positive margins for invasive breast cancer or ductal carcinoma in situ (DCIS) (involving < 3 high power fields) are eligible if additional surgery is not possible, e.g. posterior margin positive and deep resection margin abuts the chest wall or anterior margin positive and superficial resection margin abuts the skin; boost radiotherapy must be administered for positive margins as described above
3. Post-mastectomy positive margins for invasive breast cancer and/or DCIS is not allowed
4. Multifocal disease (i.e. the presence of two or more foci of breast cancer within the same breast quadrant) and multicentric disease (i.e. the presence of two or more foci of breast cancer in different quadrants of the same breast) are allowed
5. Patients with T3N0 disease are eligible
6. Patients with disease limited to nodal micrometastases are eligible
7. Patients with nodal macrometastases (> 2 mm) treated by axillary dissection must have 1-3 positive axillary nodes (macrometastases, > 2 mm) * Note patients with additional nodal micrometastases (> 0.2-2mm) or isolated tumour cells (=< 0.2 mm) are eligible
8. Patients with nodal macrometastases (> 2 mm) treated by sentinel lymph node biopsy (SLNB) alone must have only 1-2 positive axillary nodes (macrometastases, > 2 mm) * Note patients with additional nodal micrometastases (> 0.2-2mm) or isolated tumour cells (=< 0.2 mm) are eligible
9. Patients must be ER >= 1% and HER2 negative on local testing
10. Patients must have an Oncotype DX recurrence score =< 25 obtained from testing of breast tumor tissue from a core biopsy or from the surgical specimen * If the patient does not already have Oncotype DX recurrence score, specimen (unstained blocks or slides) must be sent to the Exact Sciences centralized laboratory in Redwood City, California * Oncotype DX testing must be performed on a core biopsy PRIOR to commencement of neoadjuvant endocrine therapy
11. Patient must consent to provision of, and investigator(s) must agree to submit to the Canadian Cancer Trials Group (CCTG) Central Tumour Bank, a representative formalin fixed paraffin block of tumor tissue in order that the specific correlative marker assays described in the protocol may be conducted; where tissue exists but local center regulations prohibit submission of blocks of tumor tissue, the approval of the CCTG must be sought prior to randomization of the first patient to allow cores (two 2 mm cores of tumor from the block) and slides (20 x 5 micron thick unstained slides) of representative tumor tissue to be substituted; where tumor tissue is available, failure to submit any tissue samples will result in the patient being considered ineligible
12. Patient must consent to provision of samples of blood in order that the specific correlative marker assays described in the protocol may be conducted
13. Patients must have had endocrine therapy initiated or planned for >= 5 years; premenopausal women will receive ovarian ablation plus aromatase inhibitor therapy or tamoxifen if adjuvant chemotherapy was not administered; for all patients, endocrine therapy can be given concurrently or following RT
14. Patients may or may not have had adjuvant chemotherapy
15. RT must commence within 16 weeks of definitive surgery if the patient is not treated with chemotherapy; if adjuvant chemotherapy is given, RT must begin within 12 weeks after the last dose; (Note: adjuvant chemotherapy may be ongoing at the time of randomization) * Note: Definitive surgery is defined as the last breast cancer-related surgery
16. Patient’s Eastern Cooperative Oncology Group (ECOG) performance status must be 0, 1 or 2
17. Patient’s age must be >= 35 years
18. For the first 736 eligible English or French-speaking subjects who have agreed to optional questionnaire completion (note: enrollment completed 2022AUG02): Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life, health utilities and lost productivity questionnaires in either English or French; the baseline assessment must be completed within required timelines, prior to registration/randomization; inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) or refusal to complete the questionnaires will not make the patient ineligible for the study; participation in questionnaire completion is mandatory for centers, but optional for patients
19. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements; each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate * A similar process must be followed for sites outside of Canada as per their respective cooperative group’s procedures
20. Patients must be accessible for treatment and follow-up; investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up
21. In accordance with CCTG policy, protocol treatment is to begin within 6 weeks of patient randomization
22. Women of childbearing potential must have agreed to use an effective contraceptive method; a woman is considered to be of "childbearing potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, she is responsible for beginning contraceptive measures * Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected; for example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumor production of human chorionic gonadotropin (hCG), as seen with some cancers; patient will be considered eligible if an ultrasound is negative for pregnancy

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