Tumor <i>BRCA1</i> Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance

Abstract

<b>Purpose:</b> In germline <i>BRCA1</i> or <i>BRCA2</i> (<i>BRCA1/2</i>) mutation carriers, restoration of tumor <i>BRCA1/2</i> function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed patients with <i>BRCA1/2</i>-mutant breast cancer with poor response to neoadjuvant platinum-based therapy.<b>Experimental Design:</b> PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and iniparib in patients with stage I-IIIA triple-negative or <i>BRCA1/2</i> mutation-associated breast cancer (<i>n</i> = 80). All patients underwent comprehensive <i>BRCA1/2</i> genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, <i>BRCA1/2</i> status was resequenced in the residual surgical breast tumor tissue.<b>Results:</b> Nineteen patients had a deleterious germline <i>BRCA1/2</i> mutation, and four had moderate residual disease at surgery. <i>BRCA1/2</i> sequencing of residual tissue was performed on three patients. These patients had <i>BRCA1</i> 1479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a new <i>BRCA1</i> mutation was detected in the residual disease. This resulted in a 14-amino acid deletion and restoration of the <i>BRCA1</i> reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer.<b>Conclusions:</b> We report a <i>BRCA1</i> reversion mutation in a patient newly diagnosed with triple-negative breast cancer that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse, and death. <i>Clin Cancer Res; 23(13); 3365-70. ©2017 AACR</i>.