SpecificBRCAand immune configurations determine optimal response to platinum-based chemotherapy in triple negative breast and ovarian carcinomas

• DOI: 10.1101/2021.08.19.456799
• Publication Date: 2021-08-19T23:25:17Z
• Authors: Francesca Menghi; Kalyan Banda; Pooja Kumar; Robert Straub; Lacey Dobrolecki; Isabel V. Rodriguez; Susan E. Yost; Harshpreet Chandok; Marc R. Radke; Angela S. Zhu; George Somlo; Yuan Yuan; Michael T. Lewis; Elizabeth M. Swisher; Edison T. Liu
• Keywords: Triple-negative breast cancer

SUMMARY Loss of homologous recombination repair (HRR) via germline and somatic BRCA1 or BRCA2 gene mutations promoter methylation has been associated with better response to platinum agents PARP inhibitors, in both triple negative breast cancer (TNBC) ovarian carcinoma (OvCa). A major conundrum arising from recent clinical studies is why cancers ( meth) respond more poorly as compared those bearing BRCA mut), given the biologically equivalent HRR deficiency states. We dissected this problem through detailed genomic analyses primary TNBC OvCa cohorts, well experimentation patient-derived xenograft (PDX) models genetically engineered cell lines. Using precise scar tandem duplicator phenotype a indicator deficiency, we found that, all mut meth share an degree BRCA1-linked rearrangements. Nonetheless, consistently that patients cancers, but not had significantly outcomes when proficient cancers. When fully methylated PDX TNBCs were exposed single short course chemotherapy unmethylated allele emerged resultant tumors increase expression. separate analysis PDXs derived treatment naïve featured complete promoter, whereas post-chemotherapy invariably only partial methylation. lower rates vivo platinum-based therapy clonal expansions partially PDX, confirmed reduced level was due demethylation one alleles outgrowth non-methylated clone. Clinically, OvCas high levels expression approaching These data suggest unlike where achieved are ‘fixed’, highly adaptive genotoxin exposure likely recover expression, which may explain their poorer therapeutic response. further increased immune transcriptional signal, especially elevated M1 macrophage signature, enhanced cohorts underscoring importance characterizing molecular heterogeneity enhance predictive precision assigning probabilities OvCa.