Chemotherapy for Patients with BRCA1 and BRCA2 –Mutated Ovarian Cancer: Same or Different?

Abstract

Retrospective studies have shown an improved prognosis, higher response rates to platinum-containing regimens, and longer treatment-free intervals between relapses in patients with BRCA 1 and BRCA 2 ( BRCA1/2)–mutated ovarian cancer (BMOC) compared with patients who are not carriers of this mutation. These features of BMOC are attributed to homologous-recombination repair (HR) deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks (DSBs), thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase (PARP) enzyme inhibition and other DNA-damaging chemotherapeutic agents such as pegylated liposomal doxorubicin (PLD). Therefore, the chemotherapeutic approach for patients with BMOC should focus on treatment with platinum-based chemotherapy at first-line and recurrent-disease settings and measures to increase the platinum-free interval following early platinum-resistant relapse (i.e., progression-free survival of less than 6 months from last platinum-based chemotherapy) by using nonplatinum cytotoxic agents, with the aim of reintroducing platinum again at a later date. The role of first-line intraperitoneal platinum-based therapy in the specific context of BMOC also merits further analysis. Other than platinum, alternative DNA-damaging agents (including PLD and trabectedin) also may have a therapeutic role in patients with recurrent BMOC. The recent approval of olaparib for clinical use in Europe and the United States will also affect chemotherapeutic strategies for these patients. Further work to clarify the precise relationship between BRCA1/2 mutation genotype and clinical phenotype is crucial to delineating the optimal therapeutic choices in the future for patients with BMOC.KEY POINTSImproved prognosis and response to platinum-based chemotherapy are hallmarks of BRCA1/2-mutated ovarian cancer (BMOC).Increased platinum sensitivity is attributed to underlying homologous-recombination repair deficiency in BMOC, leading to impaired ability to repair platinum-induced double-strand breaks, thereby conferring increased sensitivity to chemotherapy.Chemotherapeutic strategies for patients with BMOC should focus on platinum-based chemotherapy at first-line and recurrent-disease settings, and include measures to increase the platinum-free interval in patients with early platinum-resistant relapse (i.e., progression-free survival of < 6 months from last platinum-based chemotherapy) by using nonplatinum cytotoxic agents, with the aim of reintroducing platinum at a later date.In recurrent disease, patients with BMOC appear to have increased sensitivity to pegylated liposomal doxorubicin and other DNA-damaging agents, including trabectedin and mitomycin C, also may have a therapeutic role.With recent approval for the use of the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib in BMOC in Europe and the United States, further work to define the optimal choice, timing, and sequence of chemotherapy and/or PARPi therapy will be crucial to improve outcomes for patients with BMOC.