Background: Patients who have residual disease after neoadjuvant chemotherapy (NAC) have a higher risk of metastatic recurrence. Residual disease likely includes therapy-resistant subclones of breast cancer cells, which untreated lead to metastases. The aim of this study was to identify additional adjuvant therapies based on genomic profiling of residual disease post NAC therapy.

Methods: Next-generation sequencing of tumor samples from patients (pts) with residual invasive breast cancer after NAC was performed using a Tempus xT, 595 gene panel on matched tumor-normal samples. All samples were obtained from the University of Chicago Breast Cancer tissue bank. Clinical information was obtained from electronic health records and the cancer registry.

Results: Of 23 evaluable patients enriched for African Americans, 65% were HER2-positive, 22% TNBC and 13% ER+/HER2-. At a median follow up of 2.9 years, 8 pts (35%) have recurred and 8 were dead. We identified 119 clinically actionable variants in 22 tumors, and the most commonly altered genes were TP53 (18 alterations, 74% of cases), ERBB2 (8, 26%), PIK3CA (7, 30%), CDK4 (4, 17%), MCL1 (4, 17%), and MDM2 (4, 17%). Of significance, 67% of HER2-positive pts had no detectable ERBB2 copy number gain in the residual tumor. 78% of pts had at least one potential druggable target according to CIViC and/or OncoKB: 19 variants in HER2-positive, 8 in HER2-negative. The mean estimated tumor mutation burden (TMB) was 4.34 m/MB (range: 0-26.7), and 13% were considered TMB-high ( > 9 m/MB). No patients had high-microsatellite instability type residual tumors.

Conclusions: Many potentially targetable alterations reside in residual disease of both HER2-positive and -negative breast cancer after NAC. Post-NAC treatment targeting these harbored alterations and post-NAC immunotherapy could have impact on the prognosis of breast cancer patients who have residual disease after NAC.

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