Ovarian cancer treatment in mutation carriers/BRCAness

abstract

 Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5-year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. 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 deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks, thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase 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 by using non-platinum 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 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.