Abstract
With the advent of next-generation sequencing (NGS), The Cancer Genome Atlas (TCGA) research network has given gynecologic cancers molecular classifications, which impacts clinical practice more and more. New cancer treatments that identify and target pathogenic abnormalities of genes have been in rapid development. The most prominent progress in gynecologic cancers is the clinical efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors, which have shown breakthrough benefits in reducing hazard ratios (HRs) (HRs between 0.2 and 0.4) of progression or death from BRCA1/2 mutated ovarian cancer. Immune checkpoint inhibition is also promising in cancers that harbor mismatch repair deficiency (dMMR)/microsatellite instability (MSI). In this review, we focus on the druggable genetic alterations in gynecologic cancers by summarizing literature findings and completed and ongoing clinical trials.
Highlights
According to the Global Cancer Statistics 2020, cervical cancer, corpus cancer, and ovarian cancer were the fourth, sixth, and seventh in incidence and fourth, eleventh, and seventh in mortality rates among female malignancies [1]
We focus on the druggable genetic alterations in gynecologic cancers by summarizing literature findings and the clinical efficacy of clinical trials
poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), the first synthetic lethal drugs that are the first clinically approved, are targeting in homologous recombination deficiency (HRD) cancers, which have the defect in the homologous recombination repair pathway, the conservative mechanism of repair of double-strand breaks (DSBs) [20]
Summary
According to the Global Cancer Statistics 2020, cervical cancer, corpus cancer, and ovarian cancer were the fourth, sixth, and seventh in incidence and fourth, eleventh, and seventh in mortality rates among female malignancies [1]. EOC has more frequent mutations in TP53, FOXM1, RB, PI3K/RAS, NOTCH pathway, and homologous recombination (HR) alterations. 2. Alterations in Homologous Recombination Pathway as a Biomarker and Target of Cancer Therapies 2.1. 50% of epithelial ovarian cancers (EOC) harbor genetic and epigenetic alterations of the HR pathway genes [8]. Ovarian cancer patients with germline BRCA mutations had a better survival rate with a generally favorable response to platinum-based chemotherapy, compared to patients who were BRCA-wild type [8,12,13,14,15]. PARP inhibitors (PARPi), the first synthetic lethal drugs that are the first clinically approved, are targeting in HRD cancers, which have the defect in the homologous recombination repair pathway, the conservative mechanism of repair of DSBs [20]. Talazoparib has been approved for adults with deleterious or suspected deleterious germline BRCA-mutated, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer, but with limited evidence in EOCs [20,44,45]
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