Origin of residual tumor masses in {BRCA}1/2-driven ovarian carcinomas treated by neoadjuvant chemotherapy: selection of preexisting {BRCA}1/2-proficient tumor cells but not the gain of second {ORF}-restoring mutation

{INTRODUCTION}: Tubo-ovarian carcinomas ({OCs}) are highly sensitive to platinum-based neoadjuvant chemotherapy ({NACT}) but almost never demonstrate complete pathologic response. {METHODS}: We analyzed paired primary and residual tumor tissues from 30 patients with hereditary {BRCA}1/2-driven {OCs} ({BRCA}1: 17; {BRCA}2: 13), who were treated by carboplatin/paclitaxel {NACT} (median number of cycles: 3, range 3-6). {BRCA}1/2 and {TP}53 genes were analyzed by the next-generation sequencing ({NGS}). The ratio between {TP}53 mutation-specific vs. wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample, and the ratio between {BRCA}1/2 mutated and wild-type reads was used to estimate the presence of cells with the loss or retention of heterozygosity ({LOH} or {ROH}, respectively). {RESULTS}: All 30 {OCs} had {BRCA}1/2 {LOH} in primary tumor and carried somatic {TP}53 mutation. Twenty-eight {OCs} had sufficient tumor cell cellularity in the post-{NACT} tissue to evaluate the ratio between mutated and wild-type {BRCA}1/2 alleles. Five (18\%) out of 28 informative tumor pairs showed transition from {LOH} to {ROH} during {NACT} presumably affecting all or the vast majority of residual tumor cells. There were no signals of the emergence of a second open reading frame ({ORF}) restoring {BRCA}1/2 mutation. {CONCLUSION}: Chemonaive {BRCA}1/2-driven carcinomas may contain a fraction of tumor cells with preserved {BRCA}1/2 heterozygosity. {NACT} can cause a selection of pre-existing {BRCA}1/2-proficient tumor cells, without gaining secondary reversal {BRCA}1/2 mutations.