3025 - Primary ovarian carcinomas arising in BRCA1 mutation carriers contain a small fraction of BRCA1-proficient cells, which rapidly repopulate tumor mass during neoadjuvant chemotherapy but become outgrown by BRCA1-deficient clones during platinum-free intervals

Background

Somatic loss of the wild-type allele is a key event in the pathogenesis of BRCA1-driven carcinomas. BRCA1 deficiency renders pronounced sensitivity of these tumors to platinum compounds and PARP inhibitors.

Methods

We analyzed BRCA1 loss of heterozygosity (LOH) in serial ovarian cancer (OC) samples, which were obtained from BRCA1 germ-line mutation carriers before neoadjuvant chemotherapy (NACT), at surgery and at disease relapse.

Results

26/36 (72%) OC had BRCA1 LOH before NACT. 15 (58%) of these 26 tumors showed retention of the normal BRCA1 allele after NACT. The analysis of linked SNPs and FISH assay strongly indicated, that the restoration of BRCA1 function is caused not by the second mutation, but by the selection of pre-existing BRCA1-proficient cells. Tumor relapses were available in 7 patients with BRCA1 LOH in the chemonaive tumor and/or BRCA-proficiency in the residual post-NACT neoplasm; 6 (86%) of these relapses had BRCA1 LOH thus resembling the primary tumor. Secondary open reading frame (ORF) restoring BRCA1 mutation was detected in 1 recurrent OC. Serial samples retained same TP53 mutation during the treatment course. Whole exome sequencing revealed that chemonaive, post-NACT and relapsed tumors had both shared and individual mutations.

Conclusions

1) BRCA1 LOH is not the first event in the pathogenesis of BRCA1-driven cancer: gain of TP53 mutation probably precedes BRCA1 inactivation in order to prevent apoptosis; 2) Chemonaïve BRCA1-driven tumors contain a small fraction of BRCA1-proficient cells, which rapidly repopulate the tumor lump during the first weeks of therapy; 3) Change of BRCA1 status during NACT may call to reconsider the existing approaches to adjuvant therapy, as the residual post-NACT tumor masses are likely to be platinum-resistant; 4) The balance between BRCA1-deficient and BRCA1-proficient cells is a subject of fluctuations, depending whether therapy is applied or not; 5) Clinical trials on BRCA1-driven OCs need to address the issue of intratumoral heterogeneity of BRCA1 status.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Russian Science Foundation (grant 19-15-00168).

Disclosure

All authors have declared no conflicts of interest.