Origin of Residual Tumor Masses in BRCA1/2-Driven Ovarian Carcinomas Treated by Neoadjuvant Chemotherapy: Selection of Preexisting BRCA1/2-Proficient Tumor Cells but Not the Gain of Second ORF-Restoring Mutation

<b><i>Introduction:</i></b> Tubo-ovarian carcinomas (OCs) are highly sensitive to platinum-based neoadjuvant chemotherapy (NACT) but almost never demonstrate complete pathologic response. <b><i>Methods:</i></b> We analyzed paired primary and residual tumor tissues from 30 patients with hereditary <i>BRCA1/2</i>-driven OCs (<i>BRCA1</i>: 17; <i>BRCA2</i>: 13), who were treated by carboplatin/paclitaxel NACT (median number of cycles: 3, range: 3–6). <i>BRCA1/2</i> and <i>TP53</i> genes were analyzed by the next-generation sequencing. The ratio between <i>TP53</i> mutation-specific versus wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample, and the ratio between <i>BRCA1/2-</i>mutated and wild-type reads was used to estimate the presence of cells with the loss or retention of heterozygosity (LOH or ROH, respectively). <b><i>Results:</i></b> All 30 OCs had <i>BRCA1/2</i> LOH in primary tumor and carried somatic <i>TP53</i> mutation. Twenty-eight OCs had sufficient tumor cell cellularity in the post-NACT tissue to evaluate the ratio between mutated and wild-type <i>BRCA1/2</i> 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-restoring <i>BRCA1/2</i> mutation. <b><i>Conclusion:</i></b> Chemonaive <i>BRCA1/2</i>-driven carcinomas may contain a fraction of tumor cells with preserved <i>BRCA1/2</i> heterozygosity. NACT can cause a selection of pre-existing <i>BRCA1/2</i>-proficient tumor cells, without gaining secondary reversal <i>BRCA1/2</i> mutations.