Advertisement
Review Article| Volume 15, ISSUE 2, P219-234, June 2022

Homologous Recombination Deficiency and Ovarian Cancer Treatment Decisions

Practical Implications for Pathologists for Tumor Typing and Reporting

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Surgical Pathology Clinics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lord C.J.
        • Ashworth A.
        PARP inhibitors: Synthetic lethality in the clinic.
        Science. 2017; 355: 1152-1158
        • Pennington K.P.
        • Walsh T.
        • Harrell M.I.
        • et al.
        Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.
        Clin Cancer Res. 2014; 20: 764-775
      1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. Version 3.2021.
        (Accessed October 4, 2021)
        • Miller R.E.
        • Leary A.
        • Scott C.L.
        • et al.
        ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer.
        Ann Oncol. 2020; 31: 1606-1622
        • Hoppe M.M.
        • Sundar R.
        • Tan D.S.P.
        • et al.
        Biomarkers for homologous recombination deficiency in cancer.
        J Natl Cancer Inst. 2018; 110: 704-713
        • Liu J.F.
        • Konstantinopoulos P.A.
        • Matulonis U.A.
        PARP inhibitors in ovarian cancer: current status and future promise.
        Gynecol Oncol. 2014; 133: 362-369
        • Konstantinopoulos P.A.
        • Norquist B.
        • Lacchetti C.
        • et al.
        Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline.
        J Clin Oncol. 2020; 38: 1222-1245
        • Norquist B.M.
        • Brady M.F.
        • Harrell M.I.
        • et al.
        Mutations in homologous recombination genes and outcomes in ovarian carcinoma patients in GOG 218: an NRG oncology/gynecologic oncology group study.
        Clin Cancer Res. 2018; 24: 777-783
        • Stover E.H.
        • Fuh K.
        • Konstantinopoulos P.A.
        • et al.
        Clinical assays for assessment of homologous recombination DNA repair deficiency.
        Gynecol Oncol. 2020; 159: 887-898
        • Radhakrishnan S.K.
        • Jette N.
        • Lees-Miller S.P.
        Non-homologous end joining: emerging themes and unanswered questions.
        DNA Repair (Amst). 2014; 17: 2-8
        • Watkins J.A.
        • Irshad S.
        • Grigoriadis A.
        • et al.
        Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers.
        Breast Cancer Res. 2014; 16: 211
        • Nesic K.
        • Wakefield M.
        • Kondrashova O.
        • et al.
        Targeting DNA repair: the genome as a potential biomarker.
        J Pathol. 2018; 244: 586-597
        • Fuh K.
        • Mullen M.
        • Blachut B.
        • et al.
        Homologous recombination deficiency real-time clinical assays, ready or not?.
        Gynecol Oncol. 2020; 159: 877-886
        • Lord C.J.
        • Ashworth A.
        The DNA damage response and cancer therapy.
        Nature. 2012; 481: 287-294
        • Pilie P.G.
        • Tang C.
        • Mills G.B.
        • et al.
        State-of-the-art strategies for targeting the DNA damage response in cancer.
        Nat Rev Clin Oncol. 2019; 16: 81-104
        • Konstantinopoulos P.A.
        • Ceccaldi R.
        • Shapiro G.I.
        • et al.
        Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer.
        Cancer Discov. 2015; 5: 1137-1154
        • Satoh M.S.
        • Lindahl T.
        Role of poly(ADP-ribose) formation in DNA repair.
        Nature. 1992; 356: 356-358
        • Bryant H.E.
        • Schultz N.
        • Thomas H.D.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Ashworth A.
        • Lord C.J.
        • Reis-Filho J.S.
        Genetic interactions in cancer progression and treatment.
        Cell. 2011; 145: 30-38
        • Dobzhansky T.
        Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura.
        Genetics. 1946; 31: 269-290
        • Stover E.H.
        • Konstantinopoulos P.A.
        • Matulonis U.A.
        • et al.
        Biomarkers of response and resistance to DNA repair targeted therapies.
        Clin Cancer Res. 2016; 22: 5651-5660
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • et al.
        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: 2654-2663
        • Walsh T.
        • Casadei S.
        • Lee M.K.
        • et al.
        Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.
        Proc Natl Acad Sci U S A. 2011; 108: 18032-18037
        • Norquist B.M.
        • Harrell M.I.
        • Brady M.F.
        • et al.
        Inherited Mutations in Women With Ovarian Carcinoma.
        JAMA Oncol. 2016; 2: 482-490
        • Cancer Genome Atlas Research Network
        Integrated genomic analyses of ovarian carcinoma.
        Nature. 2011; 474: 609-615
        • Noordermeer S.M.
        • van Attikum H.
        PARP inhibitor resistance: a tug-of-war in BRCA-Mutated cells.
        Trends Cell Biol. 2019; 29: 820-834
        • Wang Y.
        • Bernhardy A.J.
        • Cruz C.
        • et al.
        The BRCA1-Delta11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin.
        Cancer Res. 2016; 76: 2778-2790
        • Abkevich V.
        • Timms K.M.
        • Hennessy B.T.
        • et al.
        Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer.
        Br J Cancer. 2012; 107: 1776-1782
        • Popova T.
        • Manie E.
        • Rieunier G.
        • et al.
        Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation.
        Cancer Res. 2012; 72: 5454-5462
        • Birkbak N.J.
        • Wang Z.C.
        • Kim J.Y.
        • et al.
        Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents.
        Cancer Discov. 2012; 2: 366-375
        • Timms K.M.
        • Abkevich V.
        • Hughes E.
        • et al.
        Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes.
        Breast Cancer Res. 2014; 16: 475
        • Swisher E.M.
        • Lin K.K.
        • Oza A.M.
        • et al.
        Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.
        Lancet Oncol. 2017; 18: 75-87
        • Coleman R.L.
        • Fleming G.F.
        • Brady M.F.
        • et al.
        Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.
        N Engl J Med. 2019; 381: 2403-2415
        • Moore K.N.
        • Secord A.A.
        • Geller M.A.
        • et al.
        Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial.
        Lancet Oncol. 2019; 20: 636-648
        • Mirza M.R.
        • Monk B.J.
        • Herrstedt J.
        • et al.
        Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.
        N Engl J Med. 2016; 375: 2154-2164
        • Ledermann J.
        • Harter P.
        • Gourley C.
        • et al.
        Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer.
        N Engl J Med. 2012; 366: 1382-1392
        • Moore K.
        • Colombo N.
        • Scambia G.
        • et al.
        Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
        N Engl J Med. 2018; 379: 2495-2505
        • Pujade-Lauraine E.
        • Ledermann J.A.
        • Selle F.
        • et al.
        Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 1274-1284
        • Ray-Coquard I.
        • Pautier P.
        • Pignata S.
        • et al.
        Olaparib plus bevacizumab as first-line maintenance in ovarian cancer.
        N Engl J Med. 2019; 381: 2416-2428
        • Gonzalez-Martin A.
        • Pothuri B.
        • Vergote I.
        • et al.
        Niraparib in patients with newly diagnosed advanced ovarian cancer.
        N Engl J Med. 2019; 381: 2391-2402
        • Ledermann J.A.
        • Oza A.M.
        • Lorusso D.
        • et al.
        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: 710-722
        • Coleman R.L.
        • Oza A.M.
        • Lorusso D.
        • et al.
        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: 1949-1961
        • Kristeleit R.
        • Shapiro G.I.
        • Burris H.A.
        • et al.
        A phase I-II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors.
        Clin Cancer Res. 2017; 23: 4095-4106
        • Kobel M.
        • Kalloger S.E.
        • Huntsman D.G.
        • et al.
        Differences in tumor type in low-stage versus high-stage ovarian carcinomas.
        Int J Gynecol Pathol. 2010; 29: 203-211
      2. WHO Classification of Tumours Editorial Board. Female genital tumours. Lyon (France): International Agency for Research on Cancer; 2020. (WHO classification of tumours series, 5th ed.; vol. 4).

        • Kobel M.
        • Rahimi K.
        • Rambau P.F.
        • et al.
        An immunohistochemical algorithm for ovarian carcinoma typing.
        Int J Gynecol Pathol. 2016; 35: 430-441
        • Kobel M.
        • Luo L.
        • Grevers X.
        • et al.
        Ovarian carcinoma histotype: strengths and limitations of integrating morphology with immunohistochemical predictions.
        Int J Gynecol Pathol. 2019; 38: 353-362
        • Lee S.
        • Piskorz A.M.
        • Le Page C.
        • et al.
        Calibration and Optimization of p53, WT1, and napsin A Immunohistochemistry Ancillary Tests for Histotyping of Ovarian Carcinoma: Canadian Immunohistochemistry Quality Control (CIQC) Experience.
        Int J Gynecol Pathol. 2016; 35: 209-221
        • Wright A.A.
        • Bohlke K.
        • Armstrong D.K.
        • et al.
        Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: society of gynecologic oncology and American society of clinical oncology clinical practice guideline.
        Gynecol Oncol. 2016; 143: 3-15
        • Bansal A.
        • Srinivasan R.
        • Rohilla M.
        • et al.
        Morphologic and immunocytochemical features of high-grade serous carcinoma of ovary in ascitic fluid effusion and fine-needle aspiration cytology.
        Am J Clin Pathol. 2020; 154: 103-114
        • Stewart C.J.R.
        • Crum C.P.
        • McCluggage W.G.
        • et al.
        Guidelines to aid in the distinction of endometrial and endocervical carcinomas, and the distinction of independent primary carcinomas of the endometrium and adnexa from metastatic spread between these and other sites.
        Int J Gynecol Pathol. 2019; 38: S75-S92
        • Leskela S.
        • Romero I.
        • Rosa-Rosa J.M.
        • et al.
        Molecular heterogeneity of endometrioid ovarian carcinoma: an analysis of 166 cases using the endometrial cancer subrogate molecular classification.
        Am J Surg Pathol. 2020; 44: 982-990
        • Parra-Herran C.
        • Lerner-Ellis J.
        • Xu B.
        • et al.
        Molecular-based classification algorithm for endometrial carcinoma categorizes ovarian endometrioid carcinoma into prognostically significant groups.
        Mod Pathol. 2017; 30: 1748-1759
        • D'Alessandris N.
        • Travaglino A.
        • Santoro A.
        • et al.
        TCGA molecular subgroups of endometrial carcinoma in ovarian endometrioid carcinoma: A quantitative systematic review.
        Gynecol Oncol. 2021; 163: 427-432
        • DeLair D.
        • Oliva E.
        • Kobel M.
        • et al.
        Morphologic spectrum of immunohistochemically characterized clear cell carcinoma of the ovary: a study of 155 cases.
        Am J Surg Pathol. 2011; 35: 36-44
        • Kobel M.
        • Kalloger S.E.
        • Carrick J.
        • et al.
        A limited panel of immunomarkers can reliably distinguish between clear cell and high-grade serous carcinoma of the ovary.
        Am J Surg Pathol. 2009; 33: 14-21
        • Chui M.H.
        • Momeni Boroujeni A.
        • Mandelker D.
        • et al.
        Characterization of TP53-wildtype tubo-ovarian high-grade serous carcinomas: rare exceptions to the binary classification of ovarian serous carcinoma.
        Mod Pathol. 2021; 34: 490-501
        • McCluggage W.G.
        • Lyness R.W.
        • Atkinson R.J.
        • et al.
        Morphological effects of chemotherapy on ovarian carcinoma.
        J Clin Pathol. 2002; 55: 27-31
        • Chew I.
        • Soslow R.A.
        • Park K.J.
        Morphologic changes in ovarian carcinoma after neoadjuvant chemotherapy: report of a case showing extensive clear cell changes mimicking clear cell carcinoma.
        Int J Gynecol Pathol. 2009; 28: 442-446
        • Miller K.
        • Price J.H.
        • Dobbs S.P.
        • et al.
        An immunohistochemical and morphological analysis of post-chemotherapy ovarian carcinoma.
        J Clin Pathol. 2008; 61: 652-657
        • Espinosa I.
        • Gallardo A.
        • D'Angelo E.
        • et al.
        Simultaneous carcinomas of the breast and ovary: utility of Pax-8, WT-1, and GATA3 for distinguishing independent primary tumors from metastases.
        Int J Gynecol Pathol. 2015; 34: 257-265
        • Kobel M.
        • Ronnett B.M.
        • Singh N.
        • et al.
        Interpretation of P53 immunohistochemistry in endometrial carcinomas: toward increased reproducibility.
        Int J Gynecol Pathol. 2019; 38: S123-S131
        • Kobel M.
        • Piskorz A.M.
        • Lee S.
        • et al.
        Optimized p53 immunohistochemistry is an accurate predictor of TP53 mutation in ovarian carcinoma.
        J Pathol Clin Res. 2016; 2: 247-258
        • Rabban J.T.
        • Garg K.
        • Ladwig N.R.
        • et al.
        Cytoplasmic Pattern p53 immunoexpression in pelvic and endometrial carcinomas with TP53 mutation involving nuclear localization domains: an uncommon but potential diagnostic pitfall with clinical implications.
        Am J Surg Pathol. 2021; 45: 1441-1451
        • Singh N.
        • Piskorz A.M.
        • Bosse T.
        • et al.
        p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies.
        J Pathol. 2020; 250: 336-345
        • Altman A.D.
        • Nelson G.S.
        • Ghatage P.
        • et al.
        The diagnostic utility of TP53 and CDKN2A to distinguish ovarian high-grade serous carcinoma from low-grade serous ovarian tumors.
        Mod Pathol. 2013; 26: 1255-1263
      3. FoundationOne CDx Specimen Instructions.
        (Available at:)
      4. Myriad myChoice CDx Specimen Instructions.
        (Available at:)
        • Fujiwara M.
        • McGuire V.A.
        • Felberg A.
        • et al.
        Prediction of BRCA1 germline mutation status in women with ovarian cancer using morphology-based criteria: identification of a BRCA1 ovarian cancer phenotype.
        Am J Surg Pathol. 2012; 36: 1170-1177
        • Howitt B.E.
        • Hanamornroongruang S.
        • Lin D.I.
        • et al.
        Evidence for a dualistic model of high-grade serous carcinoma: BRCA mutation status, histology, and tubal intraepithelial carcinoma.
        Am J Surg Pathol. 2015; 39: 287-293
        • Hussein Y.R.
        • Ducie J.A.
        • Arnold A.G.
        • et al.
        Invasion patterns of metastatic extrauterine high-grade serous carcinoma with BRCA germline mutation and correlation with clinical outcomes.
        Am J Surg Pathol. 2016; 40: 404-409
        • Reyes M.C.
        • Arnold A.G.
        • Kauff N.D.
        • et al.
        Invasion patterns of metastatic high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency.
        Mod Pathol. 2014; 27: 1405-1411
        • Soslow R.A.
        • Han G.
        • Park K.J.
        • et al.
        Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.
        Mod Pathol. 2012; 25: 625-636
        • Bartosch C.
        • Clarke B.
        • Bosse T.
        Gynaecological neoplasms in common familial syndromes (Lynch and HBOC).
        Pathology. 2018; 50: 222-237