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DNA damage repair in ovarian cancer: unlocking the heterogeneity.

ABSTRACT: Treatment for advanced ovarian cancer is rarely curative; three quarters of patients with advanced disease relapse and ultimately die with resistant disease. Improving patient outcomes will require the introduction of new treatments and better patient selection. Abrogations in the DNA damage response (DDR) may allow such stratifications.A defective DNA-damage response (DDR) is a defining hallmark of high grade serous ovarian cancer (HGSOC). Indeed, current evidence indicates that all HGSOCs harbour a defect in at least one major DDR pathway. However, defective DDR is not mediated through a single mechanism but rather results from a variety of (epi)genetic lesions affecting one or more of the five major DNA repair pathways. Understanding the relationship between these pathways and how these are abrogated will be necessary in order to facilitate appropriate selection of both existing and novel agents.Here we review the current understanding of the DDR with regard to ovarian, and particularly high grade serous, cancer, with reference to existing and emerging treatments as appropriate.

SUBMITTER: Gee ME

PROVIDER: S-EPMC6011341 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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DNA damage repair in ovarian cancer: unlocking the heterogeneity.

Gee Mary Ellen ME Faraahi Zahra Z McCormick Aiste A Edmondson Richard J RJ

Journal of ovarian research 20180620 1

Treatment for advanced ovarian cancer is rarely curative; three quarters of patients with advanced disease relapse and ultimately die with resistant disease. Improving patient outcomes will require the introduction of new treatments and better patient selection. Abrogations in the DNA damage response (DDR) may allow such stratifications.A defective DNA-damage response (DDR) is a defining hallmark of high grade serous ovarian cancer (HGSOC). Indeed, current evidence indicates that all HGSOCs harb ...[more]

PMID: 29925418

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Project description:Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15-25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.

Dataset Information

DNA damage repair in ovarian cancer: unlocking the heterogeneity.

Publications

DNA damage repair in ovarian cancer: unlocking the heterogeneity.

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