%0 Journal Article
%T Moving From Mutation to Actionability
%A Amit M. Oza
%A Ilaria Colombo
%A Katherine C. Kurnit
%A Shannon N. Westin
%J About the Ed Book | ASCO Educational Book
%D 2018
%R https://doi.org/10.1200/EDBK_199665
%X THE ROLE OF TARGETED THERAPY IN GYNECOLOGIC CANCERS Section: ChooseTop of pageAbstractTHE ROLE OF TARGETED THER... <<NGS GENE PANELSReferences Over the last decade, remarkable advances have been achieved in the ˇ°omicsˇ± technologies, (genomic, proteomic, transcriptomic) enabling rapid DNA and RNA sequencing and changing the paradigm of cancer treatment that is now moving from a ˇ°one-size-fits-allˇ± strategy to personalized medicine. Identification of predictive biomarkers has become a touchstone for drug development with the aim of matching patients to a specific targeted treatment that is no longer based on disease site or histologic subtype but on the specific actionable molecular aberration. The advent of high-throughput sequencing technologies had led to identification of an incredibly high number of somatic mutations with the added challenge of distinguishing ˇ°driverˇ± from ˇ°passengerˇ± mutations.1 The fundamental principle of precision medicine lies in the possibility to directly or indirectly act on these mutations, identify predictive biomarkers, and improve treatment effectiveness by matching the right treatment to the right patient. Following the characterization of molecular landscapes of ovarian, endometrial, and cervical cancers by The Cancer Genome Atlas (TCGA), many different targeted therapies have been investigated and some approved for the treatment of gynecologic cancers.2-4 However, efficacy, type of actionability, and presence of biomarkers to guide patient selection are different between agents (Fig. 1). FIGURE 1. Efficacy, Type of Actionability, and Presence of Biomarkers in Gynecologic Cancers Driver Mutations and Direct Actionability PARP inhibitors. Repair of DNA damage is necessary to maintain genomic stability, promote cell survival, and replication. Base excision repair pathways are involved in the repair of single strand DNA breaks where PARP plays a role. Inhibition of PARP leads to accumulation of double-stranded DNA breaks normally repaired by homologous recombination (error-free pathway) or by nonhomologous end joining (error-prone pathway).5 Different enzymes are recruited to repair double-stranded DNA breaks, such as BRCA1, BRCA2, and other homologous recombination proteins. Germline or somatic mutations in BRCA1/2 or defects in other homologous recombination repair system genes (e.g., EMSY, RAD51, ATM, ATR, Fanconi Anemia, BARD1, BRIP1, PALB2, CHEK2, PTEN, MRE11A and others), are known as homologous recombination deficiency (HRD) and observed in 50% to 60% of high-grade serous ovarian cancer (HGSOC) cases.2 The presence
%U http://ascopubs.org/doi/full/10.1200/EDBK_199665