abstract:

Tumor BRCA1 Reversion Mutation Arising During Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance

BACKGROUND:

In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 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 BRCA1/2-mutant breast cancer patients with poor response to neoadjuvant platinum-based therapy.

METHODS:

PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin and iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n=80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was re-sequenced in the residual surgical breast tumor tissue.

RESULTS:

Nineteen patients had a deleterious germline BRCA1/2 mutation and 4 had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA and W1712X mutations, respectively, with loss of heterozygosity at these loci in the pre-treatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14 amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy four months later revealed the identical reversion mutation, and the patient subsequently died of metastatic breast cancer.

CONCLUSIONS:

We report a BRCA1 reversion mutation in a newly diagnosed triple-negative breast cancer patient that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse and death.