Increased synthetic cytotoxicity of combinatorial chemo-radiotherapy in homologous recombination deficient tumors

Abstract

BackgroundHomologous recombination deficient (HRD) tumors are exquisitely sensitive to platinum-based chemotherapy and when combined with RT, leads to improved overall survival in multiple cancer types. Whether a subset of tumors with distinct molecular characteristics demonstrate increased benefit from cisplatin and RT (c-RT) is unclear. We hypothesized that HRD tumors, whether associated with BRCA mutations or genomic scars of HRD, exhibit exquisite sensitivity to c-RT, and that HRD may be a significant driver of c-RT benefit. MethodsSensitivity to c-RT was examined using isogenic and sporadic breast cancer cell lines. HRD was assessed using four assays: RT-induced Rad51 foci, a DR-GFP reporter assay, a genomic scar (large scale state transitions, LST), and clonogenic survival assays (CSA). Whole genome sequencing of 4 breast tumors from a phase 2 clinical trial of neoadjuvant c-RT in triple negative breast cancer (TNBC) was performed and defined HRD utilizing HRDetect. ResultsBRCA1/2 deficient cell lines displayed functional HRD based on the Rad51 functional assay, with c-RT to RT or cisplatin interaction ratios (IR) of 1.11 and 26.84 for the BRCA1 isogenic pair at 2uM Cisplatin and 6Gy, respectively. The highest LST lines demonstrated HRD and synthetic cytotoxicity to c-RT with IR at 2Gy and Cisplatin 20uM of 7.50, and the lowest LST line with IR of 0.65. Of 4 evaluable patients on the Phase 2 trial, one achieved pathologic complete response (pCR) with corresponding HRD based on multiple genomic scar scores including HRDetect and LST scores, compared with patients without pCR. ConclusionsHRD breast cancers, whether identified by BRCA1/2 mutation status, functional tests or mutational signatures, appear to be significantly more sensitive to c-RT compared to isogenic controls or tumors without HRD mutational signature. HRD tumors may be exquisitely sensitive to c-RT and warrants further clinical investigation to guide a precision oncology approach.