Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma

Abstract

Background

Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence.

Methods

We investigated the association of gBRCA1/2, sBRCA1/2 and non-BRCA HRR gene mutations with HGSOC patient survival using two patient cohorts (cohort 1, n = 174 matched FFPE tumour and normal with panel-based sequencing; cohort 2, n = 279 matched fresh tumour and normal with whole genome sequencing). TCGA-OV samples (n = 316) were used for external validation.

Results

Patients with HRR-mutant tumours (BRCA1, BRCA2, non-BRCA HRR-mutant) demonstrated prolonged survival across both cohorts (cohort 1: multivariable hazard ratio [multiHR] 0.53 [0.32–0.87]; cohort 2: multiHR 0.36 [0.25–0.51]). gBRCA1/2 and sBRCA1/2 were associated with a similar survival benefit compared to the HRR-wildtype group in the combined cohort (cohort 1 +2) (gBRCA1/2: multiHR 0.50 [0.34–0.71]; sBRCA1/2: multiHR 0.41 [0.25–0.68]). These findings were recapitulated using the TCGA-OV dataset (gBRCA1/2: multiHR 0.56 [0.34–0.91]; sBRCA1/2: multiHR 0.48 [0.25–0.92]). Non-BRCA HRR mutations were associated with marked survival advantage (multiHR vs HRR-wildtype 0.22 [0.11–0.45]). The survival advantage in BRCA1-mutant cases (germline or somatic) was less marked (multiHR for non-BRCA HRR-mutant vs BRCA1-mutant 0.41 [0.19–0.90]). gBRCA1/2, sBRCA1/2 and non-BRCA HRR mutations were all associated with high HRDetect scores measuring HRR deficiency (median 1.00 versus 0.56 in HRR-wildtype, P < 0.01).

Conclusion

gBRCA1/2 and sBRCA1/2 are equivalent in their association with prolonged survival. Non-BRCA HRR gene mutations may be associated with markedly favourable survival in HGSOC.