Abstract
SummarySince the introduction of poly-ADP-ribose polymerase (PARP) inhibitor therapy for epithelial ovarian cancer (EOC) patients, testing for aberrations of homologous recombination (HR) repair as a predictive biomarker of therapy response has become an area of particular clinical interest. As HR represents a crucial repair pathway of otherwise possibly lethal DNA double strand breaks, its deficiency triggers a phenotypic behavior of tumor cells resulting in the accumulation of genetic damage. PARP inhibitors target this emerging genomic instability by fostering DNA strand breaks. Whereas testing for mutations of the tumor-suppressor genes BRCA 1 and BRCA 2 as a pivotal part of the HR apparatus has entered clinical routine, approximately 30% more high-grade EOC patients harbor aberrations of the HR pathway other than BRCA mutations and may therefore respond to PARP inhibition therapy. In recent years, several double-blind, placebo-controlled trials investigating sizeable patient cohorts have reported positive results of PARP inhibitor therapy response in HR-positive patient subgroups. Therefore, introducing HR testing in both the primary and recurrent setting as a biomarker for PARP inhibitor response may expand the range of patients who may profit from this therapeutic option beyond BRCA-mutated tumors.
Highlights
The ability to restore double strand breaks (DSB) depends on the activity of the homologous recombination repair (HR) apparatus, which copies the respective undamaged, homologous DNA of the sister chromatid to reconstruct the corrupted double strand during S and G2 phase
BRCAm BRCA mutated, HR (95%CI) hazard ratio (95% confidence interval), HR deficient (HRd) homologous recombination repair deficient, PFS progression-free survival aBRCAm was defined as a detected germline or somatic mutation of the BRCA 1 and/or BRCA 2 gene bBRCAm was defined as a BRCA 1 and/or 2 germline mutation cHRd was defined as a detection of a whole-genome loss of heterozygosity of at least 16% in a next-generation sequencing assay dHRd was defined as a tumor score of ≥42 on the myChoice HRD Plus assay (Myriad Genetics) and/or BRCA tumor or germline mutation eHRd was defined as a tumor score of ≥42 on the myChoice HRD Plus assay (Myriad Genetics) and and/or BRCA tumor mutation inhibitors rendered HR repair both a possible target and biomarker in the treatment of epithelial ovarian cancer (EOC)
As HRd cancer cells are more sensitive to lesser DNA damages favoring subsequent DSBs, poly-ADP-ribose polymerase (PARP) inhibition-induced excess of single strand breaks leads to accumulation of DSB HRd tumor cells cannot repair [2]
Summary
Received: 24 February 2020 / Accepted: 31 March 2020 / Published online: 21 April 2020. Summary Since the introduction of poly-ADP-ribose polymerase (PARP) inhibitor therapy for epithelial ovarian cancer (EOC) patients, testing for aberrations of homologous recombination (HR) repair as a predictive biomarker of therapy response has become an area of particular clinical interest. Whereas testing for mutations of the tumor-suppressor genes BRCA 1 and BRCA 2 as a pivotal part of the HR apparatus has entered clinical routine, approximately 30% more high-grade EOC patients harbor aberrations of the HR pathway other than BRCA mutations and may respond to PARP inhibition therapy. Introducing HR testing in both the primary and recurrent setting as a biomarker for PARP inhibitor response may expand the range of patients who may profit from this therapeutic option beyond BRCA-mutated tumors. Keywords Ovarian cancer · PARP inhibitor · Homologous recombination · Double strand break
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