Nivolumab use for BRCA gene mutation carriers with recurrent epithelial ovarian cancer: A case series

Abstract

Tumors deficient in DNA mismatch repair are known to display increased susceptibility to immune checkpoint inhibitors due to accumulation of DNA damage and increased neoantigen load. This suggests that deficiency in the BRCA-related DNA repair mechanism may also be a surrogate marker for immunotherapy response. The aim of this study was to examine the efficacy of the immune checkpoint inhibitor, nivolumab, in women with BRCA gene mutations and recurrent müllerian cancer. This retrospective case series followed six BRCA carriers who received nivolumab monotherapy (3.0 mg/kg, intravenous, day 1 and 15, every 4 weeks) as salvage therapy for recurrent epithelial ovarian (n = 5) and fallopian tubal (n = 1) cancers. Toxicity, treatment response, and survival were examined. Median age was 57 (range 51–64). BRCA1 and 2 mutations were equally distributed. All had high-grade serous histology, and all but one had advanced-stage disease at initial diagnosis. The majority had platinum-resistant disease (n = 4). All received salvage therapy prior to nivolumab therapy (median 3 lines), including PARP inhibitors (n = 3). The median number of nivolumab treatment cycles was 9, including 2 women receiving 18 cycles. Three women developed nivolumab-related toxicities, most commonly grade 2 hypothyroidism (n = 2). Median follow-up time was 13.4 months, and there were 3 complete responses, 1 partial response, and 2 patients with progressive disease. Objective response rate was 67% (4 out of 6). In conclusion, our study suggests that nivolumab monotherapy is well-tolerated and may be an effective salvage therapy for BRCA mutation carriers with recurrent epithelial ovarian, fallopian tubal, and primary peritoneal cancers.

Aberrant upregulation of PDK1 in ovarian cancer cells impairs CD8+ T cell function and survival through elevation of PD-L1

“…51 Cases with BRCA mutations showed overall increased mutational burden harboring higher response rates to immunotherapies, including immune checkpoint blockade. 52 However, comparison of the expression patterns of PD-L1 and PDK1 in cases with mutant and wild-type BRCA in this study revealed no influence of BRCA mutation on PD-L1 or PDK1 levels in ovarian cancer.…”

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

“…BRCA and homologous recombination deficiency (HRD) status were also evaluated in the KEYNOTE-100 study, but no differences were observed between responders and non-responders [35]. However, in a small series of mutated BRCA patients with recurrent EOC, the use of salvage therapy with nivolumab resulted in an ORR of 67% (4 of 6 patients) [51].…”

DNA Repair Gene Mutations as Predictors of Immune Checkpoint Inhibitor Response beyond Tumor Mutation Burden

“… 3 Non-MMR DNA repair pathways may increase somatic mutation rates, but their association with ICI response has not been examined systematically. 10 …”