Ovarian cancers (OC) arising in BRCA1 germ-line mutation carriers usually demonstrate high sensitivity to neoadjuvant chemotherapy (NACT), but almost inevitably relapse even after complete cytoreduction and continuation of systemic platinum treatment after surgery.
Changes in the somatic BRCA1 loss-of-heterozygosity (LOH) status were monitored in OC samples obtained before NACT, after NACT and at disease relapses.
Loss of the wild-type BRCA1 allele was documented in 19 out 28 chemonaive OC samples included in the study. Surprisingly, 13 (68%) of these 19 OC demonstrated the retention of BRCA1 heterozygosity in the tumor tissue, which was surgically removed after median 3 cycles of NACT. TP53 mutations were easily detectable in some of the post-NACT samples thus confirming the good quality of microdissection. FISH assay and the analysis of adjacent SNPs revealed that the reversion of LOH status was attributed to selection of preexisting BRCA1-proficient clones but not to the second mutation in BRCA1 gene. Four tumor relapses were available for analysis; 3 out of these 4 tumors “restored” BRCA1 LOH during platinum-free interval. Next-generation sequencing analysis identified additional molecular events associated with evolution of OC clones upon platinum exposure and during treatment-free periods.
Isolated BRCA1 proficient cells are still present in chemonaive ovarian carcinomas with BRCA1 LOH, indicating that the somatic loss of the wild-type BRCA1 is not necessarily the first event in the pathogenesis of hereditary OC. These clones rapidly expand during even short-term systemic therapy. BRCA1-deficient cells have selective advantage in the absence of drug exposure and repopulate the tumor mass during platinum-free intervals. These fluctuations of BRCA1 LOH status explain why conventional platinum-based therapy, being capable to produce excellent tumor responses in BRCA1 germ-line mutation carriers, is not curative when considering long-term outcomes.
Clinical trial identification
Legal entity responsible for the study
Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg
Russian Scientific Fund (grant 14-25-00111)
All authors have declared no conflicts of interest.