Adding Surgery and Radiation to the Usual Treatment for HER2-Positive Breast Cancer That Had Already Spread at Diagnosis

Overview

This phase III trial evaluates the effect of adding locoregional therapy (surgery and radiation) and metastasis-directed stereotactic body radiation therapy (SBRT) to standard systemic therapy following standard HER2-targeted systemic therapy, compared to standard systemic therapy alone, in treating patients with HER2-positive stage IV breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or to a limited number of sites (oligometastatic). The usual approach for patients with (oligo)metastatic HER2-positive breast cancer is systemic drug treatment, which means medicines that travel through the whole body to treat both the breast and any areas where the cancer has spread. There are a number of approved HER2-targeted systemic therapy regimens available to patients. These typically include immunotherapy and/or chemotherapy. Immunotherapy drugs may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Unlike systemic therapy, locoregional therapies like surgery and radiation are focused treatments at the site of disease, delivered with the intent of sparing healthy tissues. Breast surgeries such as breast conserving therapy or total mastectomy are procedures in which the cancerous breast tissue (and healthy breast tissue in the case of total mastectomy) are surgically removed from the body. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Adding locoregional therapy, as well as metastasis-directed SBRT, to standard systemic therapy may help patients with (oligo)metastatic, HER2-positive stage IV breast cancer live longer overall or before their cancer progresses, and may help more patients achieve no evidence of disease, when compared to standard systemic therapy alone.

PRIMARY OBJECTIVES: I. To compare overall survival (OS) between participants with de novo stage IV oligometastatic HER2+ breast cancer who experience at least a partial response (PR) after initial systemic therapy similar to those used in stage III disease with curative intent, and are randomized to a multimodality approach including definitive locoregional therapy with surgery and radiotherapy and ablative intent stereotactic radiotherapy to detectable metastatic lesions followed by additional HER2-directed systemic therapy, similar to those used for residual disease after neoadjuvant therapy, (Cohort A, Arm 1) versus those who are randomized to physician's choice standard of care HER2-directed systemic therapies without local and metastasis directed ablative therapies (Cohort A, Arm 2). (Randomized Cohort A) II. To evaluate the distribution of progression-free survival (PFS) and overall survival (OS) among participants with de novo stage IV oligometastatic HER2+ breast cancer who do not experience a response after systemic therapy. (Observational Cohort B) SECONDARY OBJECTIVES: I. To compare progression-free survival (PFS) in Cohort A, Arm 1 (randomized to multimodality therapy) versus Cohort A, Arm 2 (randomized to standard of care HER2-directed systemic therapy). (Randomized Cohort) II. To compare PFS in Cohort A, Arm 1 per protocol (received all multimodality therapy as planned) versus Cohort A, Arm 2. (Randomized Cohort) III. To compare OS in Cohort A, Arm 1 per protocol (received all multimodality therapy as planned) versus Cohort A, Arm 2. (Randomized Cohort) IV. To assess duration of standard of care first line systemic therapy received from time of response assessment in Cohort B. (Observational Cohort) BANKING OBJECTIVE: I. To bank specimens for future correlative studies. OUTLINE: STEP 1: Patients receive physician's choice of HER2-targeted systemic therapy according to National Comprehensive Cancer Network (NCCN)/American Society of Clinical Oncology (ASCO) guidelines until completion of at least 12 weeks (4 cycles) or up to 24 weeks (8 cycles) of HER2-targeted therapy prior to Step 2 registration. Patients with brain metastases may also undergo stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) at the discretion of the treating physician. STEP 2: Patients with partial or complete response in the breast following completion of Step 1 are assigned to Cohort A. Patients with clinically stable or progressive disease following completion of Step 1 are assigned to Cohort B. COHORT A: Patients are randomized to 1 of 2 arms. ARM 1: LOCOREGIONAL THERAPY: Patients undergo breast surgery (either breast conserving therapy or total mastectomy) within 4-6 weeks of completion of Step 1 systemic therapy. Within 8 weeks of breast surgery, patients undergo locoregional radiation therapy (RT) to the breast, with or without RT to the breast/chest wall and/or regional lymph nodes, over 5-16 fractions. Patients may undergo RT boost to the lumpectomy bed over 4-5 fractions at the discretion of the treating physician. STEREOTACTIC BODY RADIATION THERAPY (SBRT): Within 4-6 weeks of completion of locoregional therapy, patients undergo SBRT, with or without concurrent adjuvant therapy (pertuzumab and trastuzumab, or trastuzumab emtansine \[T-DM1\], or trastuzumab deruxtecan \[T-DXd\] with or without pertuzumab), to all targetable metastatic lesions every other day for 1, 3, or 5 fractions over a maximum of 3 weeks. POST-LOCOREGIONAL THERAPY AND SBRT: Following recovery from surgery, patients resume systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines for at least 1 year in the absence of disease progression or unacceptable toxicity. Patients who are estrogen receptor positive may also receive endocrine therapy, with or without CDK4/6 inhibitors, at the discretion of the treating physician for at least 5 years, in the absence of disease progression or unacceptable toxicity. ARM 2: Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines for at least 1 year in the absence of disease progression or unacceptable toxicity. Patients may receive locoregional therapy and/or SBRT according to standard of care only if required for palliative purposes. COHORT B: Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines in the absence of disease progression or unacceptable toxicity. All patients also undergo echocardiography (ECHO), magnetic resonance imaging (MRI), mammography, ultrasound, computed tomography (CT), and/or positron emission tomography (PET)/CT throughout the trial. Patients may undergo optional biopsy and/or collection of blood samples throughout the trial. After completion of study treatment, patients registered to Step 2 are followed up for 10 years.