Can a subset of patients with HER2+ metastatic breast cancer be cured?

PROJECT SUMMARY Because of the development of highly effective HER2-targeted therapies over the past two decades, most patients now diagnosed with stage I-III HER2+ breast cancer (BC) are cured. These therapies have benefitted patients who develop distant recurrence as well as the increasing proportion presenting with de novo HER2+

metastatic breast cancer (MBC). Indeed, a subset of these patients does exceptionally well, remaining on first- line therapy indefinitely without evidence of disease progression. But, for these patients, the usual clinical paradigm is non-curative. Though retrospective studies show some clinical predictors of durable response to

anti-HER2 treatments, there are currently no validated, predictive biomarkers. Though patients may have no evidence of disease for years on systemic therapy, there currently is no standard approach for stopping therapy. Tracking minimal residual disease (MRD) in the blood via cell-free DNA (cfDNA) may provide an important

approach to optimize treatment in patients with HER2+ MBC and will allow us to explore whether a subset of such patients might be cured of breast cancer. Together with collaborators at the Broad Institute, we have developed and tested an ultrasensitive blood test to detect MRD that involves tracking a large fingerprint of

patient-specific tumor mutations in cfDNA. We have applied this assay to patients with both early and advanced BC, showing a strong relationship between an MRD positive test and disease recurrence or progression. We plan to use this novel assay, in conjunction with a retrospective, cross-sectional study and a prospective clinical

trial, to define the role of MRD in HER2+ MBC. Dr. Parsons is a medical oncologist specializing in breast cancer, seeking K08 support for mentored time with Dr. Ian Krop at Dana-Farber Cancer Institute, with Dr. Ben Park at Vanderbilt as a co-mentor. Her overarching career goal is to improve outcomes for patients with breast cancer through the use of blood-based biomarkers.

She aims to become a clinical investigator who translates findings in the lab into meaningful diagnostics to improve care of breast cancer patients. The proposed scientific aims, together with her training plan, will enable her to acquire the knowledge, skills and approaches to help her to become a successful investigator. Here she

focuses on HER2+ metastatic breast cancer (MBC) for its limited, but important scope, as an example of breast cancer more broadly and the possibility of MRD assessment to help guide therapeutic intervention. She will apply an approach developed to detect MRD to this setting, with the intention of expanding it to breast cancer more

broadly in the future.