Advances in our understanding of cancer biology have led to a rapid expansion of molecularly targeted therapeutics for gynecological cancers over the last decade. Concurrently, it is becoming increasingly evident that gynaecological cancers are genetically heterogeneous diseases. Importantly, this genetic heterogeneity appears to underpin the variation in outcomes observed in these malignancies.

For example, the BRCA1/2 tumor suppressor genes are critical for the maintenance of cellular genomic stability through the error-free repair of DNA double-strand breaks (DSBs) via the high-fıdelity homologous-recombination repair (HR) pathway. Loss of BRCA1/2 function may occur because of somatic mutations or epigenetic silencing. Improved prognosis in terms of progression-free survival (PFS) and overall survival (OS), with higher partial response (PR) and complete response (CR) rates to platinum containing regimens and longer treatment-free intervals, has been observed in retrospective studies of patients who are BRCA1/2-mutant carriers (BMOC) with ovarian cancer compared with patients who are non-BMOC. This “BRCAness” phenotype, with superior outcomes following platinum based therapy in patients with BMOC, has been attributed to HR defıciency in the absence of BRCA1/2 function. This results in an impaired ability of BRCA-defıcient tumor cells to repair platinum-induced DSBs, which confers increased sensitivity to chemotherapy. Similarly, inhibition of poly(ADP-ribose) polymerase (PARP) enzymes (which repair single-stranded DNA breaks mainly through the base excision repair pathway) in HR-defıcient cells by PARP inhibitors (PARPi) results in DSBs that are subjected to low fıdelity repair by nonhomologous end joining. The absence of high-fıdelity DNA-repair mechanisms following PARPi treatment in HR-deficient cells leads to synthetic lethality through an accumulation of DNA damage that result in mitotic catastrophe and cell death. Following successful clinical trials, the PARP inhibitors have now been approved by the FDA and EMA for use in patients with BMOC and platinum sensitive recurrent ovarian cancer.

Conversely, EOC subtypes, such as ovarian clear cell carcinomas, that are less frequently associated with HR defects, appear to be much more chemoresistant and present a considerable clinical challenge in patients with advanced disease. For these chemoresistant gynaecological malignancies, there is an urgent need to optimise currently available treatments and develop new therapeutic strategies. In this talk, we will use the aforementioned examples to discuss the development of precision medicine based on insights gleaned from the molecular features of ovarian cancers.