Introduction/Background Somatic loss of the wild-type BRCA1 allele is a key event in pathogenesis of BRCA1-driven cancers rendering their pronounced sensitivity to platinum and PARP inhibitors.

Methodology We compared the somatic status of BRCA1 and some other genes in serial ovarian cancer (OC) samples, which were obtained before neoadjuvant chemotherapy (NACT), during surgery and at disease relapse from BRCA1 mutation carriers.

Results 26/36 (72%) OC had BRCA1 loss of heterozygosity (LOH) before NACT. 15/26 (58%) of the tumors, which had LOH at the beginning of the treatment, 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. Exome analysis revealed that chemonaive, post-NACT and relapsed tumors had both shared and individual mutations.

Conclusion

1. BRCA1 LOH is not the first event in the pathogenesis of BRCA1–driven cancer: gain of TP53 mutation probably precedes BRCA1 inactivation;

2. Treatment–naïve 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;

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.

Disclosure This work has been supported by the Russian Science Foundation, grant 19-15-00168.