Tumor Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance.

In germline or () mutation carriers, restoration of tumor 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 -mutant breast cancer with poor response to neoadjuvant platinum-based therapy. PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and iniparib in patients with stage I-IIIA triple-negative or mutation-associated breast cancer ( = 80). All patients underwent comprehensive genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, status was resequenced in the residual surgical breast tumor tissue. Nineteen patients had a deleterious germline mutation, and four had moderate residual disease at surgery. sequencing of residual tissue was performed on three patients. These patients had 1479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a new mutation was detected in the residual disease. This resulted in a 14-amino acid deletion and restoration of the reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer. We report a 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. .