Introduction/Background Tubo-ovarian carcinomas (OCs) are highly sensitive to platinum-based neoadjuvant chemotherapy (NACT) but almost never demonstrate complete pathologic response.
Methodology We analyzed paired primary and residual tumor tissues from 30 patients with hereditary BRCA1/2-driven OCs (BRCA1: 17; BRCA2: 13), who were treated by carboplatin/paclitaxel NACT (median number of cycles: 3, range 3–6). BRCA1/2 and TP53 genes were analyzed by the next-generation sequencing (NGS). The ratio between TP53 mutation-specific vs. wild-type reads was considered to monitor the proportion of tumor and non-tumor cells in the tissue sample. Assuming that all BRCA1/2 wild-type reads come from cells with retention of heterozygosity (ROH), one can calculate the percentage of cells with loss-of-heterozygosity (LOH). Excess of mutated vs. wild-type BRCA1/2 reads was interpreted as the LOH. We compared LOH in tumor tissues before and after NACT.
Results All 30 OCs had BRCA1/2 LOH in primary tumor and carried somatic TP53 mutation. Five (17%) tumor pairs showed transition from LOH to ROH during NACT presumably affecting all or the vast majority of residual tumor cells. Another 16 (53%) tumors demonstrated significant reduction of the percentage of tumor cells with LOH suggesting the expansion of BRCA1/2-proficient clones in the post-NACT tumor tissue. There were no signals of emergence of a second open reading frame (ORF) restoring BRCA1/2 mutation.
Conclusion Chemonaive BRCA1/2-driven carcinomas often contain a fraction of tumor cells with preserved BRCA1/2 heterozygosity. NACT can cause a selection of pre-existing BRCA1/2-proficient tumor cells, without gaining secondary reversal BRCA1/2 mutations.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.