Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

High efficacy of cisplatin neoadjuvant therapy in a prospective series of patients carrying BRCA1 germ-line mutation.

Development of malignancies in BRCA1 germ-line mutation carriers usually involves somatic inactivation of the remaining BRCA1 allele. This feature leads to a tumor-specific deficiency of double-strand DNA break repair and underlies pronounced sensitivity of BRCA1-driven cancers to cisplatin. BRCA1-specific activity of cisplatin has been repeatedly demonstrated in cell culture and animal experiments; however, corresponding clinical evidence remains limited. We applied neoadjuvant monotherapy by cisplatin (75-100 mg/m(2), 4-6 cycles) to six breast cancer patients carrying BRCA1 5382insC mutation. Pronounced reduction in tumor size was observed in all treated women. Three patients (T2N0M0, T4N2M0 and T4N2M0) showed pathologic complete response, two women (T4N0M0 and T2N1M0) had partial pathologic response, and one woman (T3N2M0) declined surgery. This study and available literature data suggest that cisplatin is a preferable option for systemic treatment of BRCA1-related hereditary breast cancer.