Summary

This phase III trial compares the usual treatment of breast radiation and HER2-targeted drugs following surgery and chemotherapy to using the usual treatment approach without radiation in treating patients with low-risk HER2-positive breast cancer. The usual approach is defined as care most people get for this type of cancer. The usual approach for patients who have undergone surgery, chemotherapy, and HER2-targeted therapy and are not in a study is treatment with radiation therapy to the breast and continuing HER2-targeted therapy. HER2-targeted drugs attach to the HER2 receptor proteins on the surface of breast tumor cells and block the HER2 receptors from receiving growth signals in HER2-positive breast cancer. By blocking the growth signals, HER2-targeted drugs can slow or stop the growth of HER2-positive breast cancer. Radiation therapy uses high energy sources of radiation to kill tumor cells and shrink tumors. The usual approach for patients who have undergone surgery, chemotherapy, and HER2-targeted therapy and are not in a study is treatment with radiation therapy to the breast and continuing HER2-targeted therapy. Omitting radiation from the usual treatment approach may avoid the potential short-term and long-term risks of radiation in patients with low-risk HER2-positive breast cancer and may have the same effect as the usual approach in preventing cancer from coming back (recurrence ).

Objectives

PRIMARY OBJECTIVE:
I. To compare the recurrence-free interval (RFI) among patients with early-stage, low risk HER2 positive (HER2+) breast cancer who undergo breast conserving surgery and receive HER2-directed therapy, and are randomized to not receive adjuvant breast radiotherapy versus those who are randomized to receive adjuvant radiotherapy per the current standard of care.

SECONDARY OBJECTIVES:
I. To estimate 7-year cumulative incidence ipsilateral breast recurrence (IBR) for radiation omitting arm and test the hypothesis that the 7-year IBR rate is <7% for patients not receiving adjuvant breast radiotherapy.
II. To estimate time to ipsilateral breast recurrence (IBR) by treatment arm.
III. To determine the time to local regional recurrence (LRR) by treatment arm.
IV. To determine disease-free survival (DFS) by treatment arm.
V. To determine overall survival (OS) by treatment arm.
VI. To evaluate whether there is a difference in patient-reported breast pain in patients who do and do not receive breast radiation in cohort A and cohort B.
VII. To evaluate whether there is a difference in patient-reported worry about recurrence in patients who do and do not receive breast radiation in cohort A and cohort B.

EXPLORATORY OBJECTIVE:
I. To explore important measures of quality of life that would reasonably be expected to vary by study arm, including cosmesis, breast-related functional status, fatigue, breast and skin symptoms, and global quality of life.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive breast radiation therapy and HER2-targeted therapy such as pertuzumab or trastuzumab subcutaneously (SC) or intravenously (IV) while on the study. Patients also undergo mammogram or magnetic resonance imaging (MRI) throughout the trial.

ARM 2: Patients receive HER2-targeted therapy such as pertuzumab or trastuzumab SC or IV while on the study. Patients also undergo mammogram or MRI throughout the trial.

Patients are followed every 6 months from randomization through year 3 and then annually from year 3 through 10.

Eligibility

1. The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information.
2. The trial is open to female and male patients who have undergone breast conserving surgery and completed a minimum of 4 cycles (12 weeks) of neoadjuvant or adjuvant chemotherapy in combination with HER2-targeted therapy.
3. The patient must be >= 40 years of age.
4. The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 ,1, or 2/Karnofsky performance status above 60.
5. Histologically or cytologically confirmed invasive breast carcinoma.
6. The tumor must have been determined to be HER2-positive by current American Society of Clinical Oncology/ College of American Pathologists (ASCO/CAP) guidelines based on local testing results.
7. The tumor must have estrogen receptor (ER) and progesterone receptor (PgR) status assessed locally using current ASCO/CAP Guidelines.
8. Patient must have undergone axillary staging, either sentinel node biopsy (SNB) or axillary lymph nodal dissection (ALND). In neoadjuvant patients, SNB following neoadjuvant therapy is strongly recommended. SNB prior to neoadjuvant therapy is discouraged, but patients are permitted if node negative (pN0).
9. The following staging criteria must be met according to American Joint Committee on Cancer (AJCC) 8th edition criteria: Adjuvant cohort * By pathologic evaluation, the patient’s primary tumor must be =< 2 cm and ipsilateral nodes must be pN0. Surgical lumpectomy margins must be negative for invasive cancer and ductal carcinoma in situ (no ink on tumor).
10. The following staging criteria must be met according to AJCC 8th edition criteria: Neoadjuvant cohort * Prior to neoadjuvant therapy, the patient’s primary tumor must be =< 3 cm by imaging studies, with negative axillary nodes (cN0) based on axillary ultrasound, computed tomography, positron emission tomography, or magnetic resonance imaging (U/S, CT, PET or MRI). Physical examination is not sufficient documentation of cN0 status. * Must be ypT0N0 at surgery (lumpectomy); patients with residual non-invasive disease (ductal carcinoma in situ [DCIS]) in the surgical specimen (ypTis), are NOT eligible.
11. For the Adjuvant cohort, adjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.
12. For the Neoadjuvant cohort, neoadjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy. * Patients who did not receive chemotherapy in the neoadjuvant setting are not eligible, even if they achieved pathologic complete response (pCR) with their preoperative treatment; nor would these patients become eligible by receiving chemotherapy after surgery.
13. In patients assigned to radiation therapy, treatment should start =< 12 weeks from surgery on the Neoadjuvant cohort and =< 8 weeks from the completion of chemotherapy on the Adjuvant cohort. Patients should continue HER2-targeted therapy during assigned study treatment (radiation or observation).
14. Bilateral mammogram or MRI within 52 weeks prior to randomization.
15. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with an undetectable viral load within 6 months of randomization are eligible for this trial.