Cancers arising in BRCA1 mutation carriers are highly sensitive to cisplatin due to somatic inactivation of the wild-type BRCA1 allele. Accordingly, BRCA1-driven OCs usually respond well to NACT and therefore almost always undergo complete cytoreduction. However, despite this seemingly effective treatment and continuation of platinum therapy in the adjuvant setting, almost all BRCA1-associated OCs inevitably relapse.
We compared BRCA1 LOH status in paired OC samples before and after NACT.
BRCA1 LOH was detected in 19/28 chemonaive OCs. Surprisingly, heterozygous status was restored in 13/19 (68%) samples after median of 3 cycles of NACT. The analysis of linked SNPs demonstrated that the restoration of BRCA1 proficiency is not due to the second mutation in the BRCA1 gene, but due to selection of pre-existing BRCA1-proficient cells. Furthermore, the persistence of isolated BRCA1-heterozygous cells in the chemonaïve OCs was confirmed by FISH analysis. Absence of BRCA1 LOH in post-NACT samples could not be explained by errors in tumor microdissection, as residual cancer tissues still retained TP53 mutation. Relapsed OC tissues were analyzed in 4 patients, who experienced the restoration of BRCA1 heterozygosity during NACT; the return to the BRCA1-deficient state during platinum-free interval was observed in 3 of these cases.
1) Loss of the remaining BRCA1 allele is not the first molecular event in the pathogenesis of BRCA1-associated cancers: it is likely to occur only after TP53 gene inactivation. 2) BRCA1-driven chemonaive cancers still contain a fraction of BRCA1-proficient cells even if they demonstrate LOH in a gross tumor mass. Therefore, drugs targeting BRCA1 deficiency are unlikely to be curative if applied alone. 3) The ratio between BRCA1-deficient and -proficient cells undergoes rapid changes during platinum therapy and platinum-free intervals. 4) Continuation of platinum therapy in the adjuvant setting for the tumors with restored BRCA1 status does not have a biologic rationale. 5) Intratumoral interactions between BRCA1-deficient and -proficient cells deserve further investigation.
N.N. Petrov Institute of Oncology.
Russian Science Foundation (grant number 14-25-00111).
All authors have declared no conflicts of interest.