This study is being done to see if anti-HER2 treatment be safely stopped in patients with HER2-positive metastatic breast cancer (MBC) that have had exceptional response to treatment. Exceptional response" is considered as cancer progression being controlled for three years or more since starting anti-HER2 treatment.

This is a single arm, phase II study of cessation of anti-HER2 systemic therapy in exceptional responders with HER2-positive metastatic breast cancer (MBC), defined as individuals free of disease progression after at least 3 years of first-line treatment.

This research study will include two different groups (cohorts) of patients. Those not wanting to stop anti-HER2 maintenance treatment will be included in a non-randomized, observational cohort (cohort 1). Those willing to stop maintenance anti-HER2 treatment you will be included in cohort 2.

This study is trying to understand whether blood samples that may contain traces of DNA from cancer, known as "circulating tumor DNA" or "ctDNA" are able to help identify which patients can successfully stop treatment without a change in their cancer.

The research study procedures include: an initial screening phase followed by periodic visits with blood work, questionnaires, and body scans.

It is expected that about 82 people will take part in this research study (52 in cohort 2 (stopping treatment), 30 in cohort 1 (continuing treatment). This study is expected to last 1 year with 10 years of follow up.

The Susan G. Komen Foundation, the Gateway for Cancer Research - both nonprofit foundations supporting cancer research - and the National Institutes of Health are supporting this research study by providing funds. This study is also being supported by Johns Hopkins University on behalf of the Translational Breast Cancer Research Consortium (TBCRC). The TBCRC is a group of academic medical centers across the United States that work together to conduct breast cancer research.

Inclusion Criteria:

• Age ≥18 years

• Participants must have histologically or cytologically confirmed unresectable locally advanced or metastatic invasive breast carcinoma that is HER2-positive by American Society of Clinical Oncology/College of American Pathologists 2018 criteria, as assessed by standard institutional guidelines (central testing is not required). Both estrogen receptor (ER)-positive/HER2-positive and ER-negative/HER2-positive will be eligible.

• Participants with ER-positive disease should continue endocrine therapy.

• Participants must be currently receiving first-line anti-HER2 therapy (any regimen) for metastatic disease and must have been on this therapy for at least 3 years without evidence of progressive disease according to RECIST 1.1 criteria. The following exceptions apply:

• Patients with history of brain-only progressive disease previously treated with local therapy (surgery and/or radiation therapy) are eligible, provided they meet all the following study criteria:

  • Asymptomatic
  • Not requiring anti-convulsant for symptomatic control
  • Not requiring corticosteroids
  • No evidence of interim central nervous system (CNS) progression between the completion of CNS-directed therapy and screening radiographic study
  • Minimum of 2 years (24 months) between completion of CNS-directed therapy and study start

• Participants with history of oligo-progression (i.e., progressive disease of a single lesion) outside CNS treated with local treatment and/or change of endocrine therapy only are eligible, provided they meet the following criteria:

  • No evidence of interval progression between completion of local treatment or endocrine therapy change and screening radiographic study
  • Minimum 2 years (24 months) between completion of local therapy or treatment switch and study start

• CT scan within 30 days of study start without definite evidence of progressive disease in the opinion of the treating investigator.

• Available, representative archival formalin-fixed paraffin-embedded (FFPE) tumor tissue block from primary and/or metastatic site. If tissue block is unavailable, 20 unstained 10uM slides will be accepted (less than 20 slides may be acceptable with documentation of Sponsor-Investigator approval and would not require an eligibility exception). Tumor tissue must be received by coordinating site prior to study enrollment.

• ECOG performance status 0-1

• For intervention arm only (cohort 2): willingness to stop anti-HER2 systemic therapy

• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

• Ability to understand the study requirements and document informed consent indicating awareness of the investigational nature and the risks of this study

• Participants with another prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of this trial are eligible

Exclusion Criteria:

• Participants who are receiving any investigational agents to treat breast cancer
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• All English- speaking patients will participate in the PRO measures. Patients that do not read or understand English are eligible to participate but will be exempt from the patient completed questionnaires

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Data can be shared no earlier than 1 year following the date of publication

Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu