Homologous Recombination Deficiency Assays in Epithelial Ovarian Cancer: Current Status and Future Direction

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Nov 1

PMID 34722237

Citations 18

Authors

Ying-Cheng Chiang

Po-Han Lin

Wen-Fang Cheng

Affiliations

Soon will be listed here.

Abstract

Epithelial ovarian cancer (EOC) patients are generally diagnosed at an advanced stage, usually relapse after initial treatments, which include debulking surgery and adjuvant platinum-based chemotherapy, and eventually have poor 5-year survival of less than 50%. In recent years, promising survival benefits from maintenance therapy with poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) has changed the management of EOC in newly diagnosed and recurrent disease. Identification of mutations and/or homologous recombination deficiency (HRD) is critical for selecting patients for PARPi treatment. However, the currently available HRD assays are not perfect predictors of the clinical response to PARPis in EOC patients. In this review, we introduce the concept of synthetic lethality, the rationale of using PARPi when HRD is present in tumor cells, the clinical trials of PARPi incorporating the HRD assays for EOC, the current HRD assays, and other HRD assays in development.

Citing Articles

Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer.

Chiang Y, Huang H, Kuo K, Hwu W, Lin P J Ovarian Res. 2025; 18(1):19.

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Germ cell-specific gene 2 accelerates cell cycle in epithelial ovarian cancer by inhibiting GSK3α-p27 cascade.

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References

Domchek S, Aghajanian C, Shapira-Frommer R, Schmutzler R, Audeh M, Friedlander M . Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016; 140(2):199-203. PMC: 4992984. DOI: 10.1016/j.ygyno.2015.12.020. View

Ozols R . Update on the management of ovarian cancer. Cancer J. 2002; 8 Suppl 1:S22-30. View

Cunningham J, Cicek M, Larson N, Davila J, Wang C, Larson M . Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. PMC: 4168524. DOI: 10.1038/srep04026. View

Xu G, Chapman J, Brandsma I, Yuan J, Mistrik M, Bouwman P . REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature. 2015; 521(7553):541-544. PMC: 4671316. DOI: 10.1038/nature14328. View

Alsop K, Fereday S, Meldrum C, DeFazio A, Emmanuel C, George J . BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012; 30(21):2654-63. PMC: 3413277. DOI: 10.1200/JCO.2011.39.8545. View

Watkins J, Irshad S, Grigoriadis A, Tutt A . Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res. 2014; 16(3):211. PMC: 4053155. DOI: 10.1186/bcr3670. View

George A, Kaye S, Banerjee S . Delivering widespread BRCA testing and PARP inhibition to patients with ovarian cancer. Nat Rev Clin Oncol. 2016; 14(5):284-296. DOI: 10.1038/nrclinonc.2016.191. View

Frampton G, Fichtenholtz A, Otto G, Wang K, Downing S, He J . Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 2013; 31(11):1023-31. PMC: 5710001. DOI: 10.1038/nbt.2696. View

Lord C, Ashworth A . The DNA damage response and cancer therapy. Nature. 2012; 481(7381):287-94. DOI: 10.1038/nature10760. View

10.

Prasad V . Why the US Centers for Medicare and Medicaid Services (CMS) should have required a randomized trial of Foundation Medicine (F1CDx) before paying for it. Ann Oncol. 2017; 29(2):298-300. DOI: 10.1093/annonc/mdx786. View

11.

Wilson A, Stubbs M, Liu P, Ruggeri B, Khabele D . The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer. Gynecol Oncol. 2018; 149(3):575-584. PMC: 5986599. DOI: 10.1016/j.ygyno.2018.03.049. View

12.

Cruz C, Castroviejo-Bermejo M, Gutierrez-Enriquez S, Llop-Guevara A, Ibrahim Y, Gris-Oliver A . RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann Oncol. 2018; 29(5):1203-1210. PMC: 5961353. DOI: 10.1093/annonc/mdy099. View

13.

Ledermann J, Oza A, Lorusso D, Aghajanian C, Oaknin A, Dean A . Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020; 21(5):710-722. PMC: 8210534. DOI: 10.1016/S1470-2045(20)30061-9. View

14.

Quinet A, Carvajal-Maldonado D, Lemacon D, Vindigni A . DNA Fiber Analysis: Mind the Gap!. Methods Enzymol. 2017; 591:55-82. DOI: 10.1016/bs.mie.2017.03.019. View

15.

Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte A, Lee J . Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016; 535(7612):382-7. PMC: 4959813. DOI: 10.1038/nature18325. View

16.

Norquist B, Wurz K, Pennil C, Garcia R, Gross J, Sakai W . Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011; 29(22):3008-15. PMC: 3157963. DOI: 10.1200/JCO.2010.34.2980. View

17.

Coleman R, Oza A, Lorusso D, Aghajanian C, Oaknin A, Dean A . Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 390(10106):1949-1961. PMC: 5901715. DOI: 10.1016/S0140-6736(17)32440-6. View

18.

Kawamoto T, Araki K, Sonoda E, Yamashita Y, Harada K, Kikuchi K . Dual roles for DNA polymerase eta in homologous DNA recombination and translesion DNA synthesis. Mol Cell. 2005; 20(5):793-9. DOI: 10.1016/j.molcel.2005.10.016. View

19.

Stover E, Fuh K, Konstantinopoulos P, Matulonis U, Liu J . Clinical assays for assessment of homologous recombination DNA repair deficiency. Gynecol Oncol. 2020; 159(3):887-898. DOI: 10.1016/j.ygyno.2020.09.029. View

20.

Waks A, Cohen O, Kochupurakkal B, Kim D, Dunn C, Buendia Buendia J . Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer. Ann Oncol. 2020; 31(5):590-598. PMC: 7946408. DOI: 10.1016/j.annonc.2020.02.008. View