Research Article| Volume 152, ISSUE 3, P459-464, March 2019

Download started.


BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer


      • Women with high-grade serous ovarian cancer (HGSC) have a 20% risk of carrying a BRCA mutation.
      • Many women with HGSC are untested for BRCA mutations, and their first-degree relatives may be ineligible for BRCA testing.
      • BRCA testing for first-degree relatives of women with HGSC is cost-effective when BRCA status is unknown.
      • BRCA testing with subsequent risk-reducing surgery is more effective and less costly than surgery alone.



      Women with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or 2 mutation. Not all undergo genetic testing, and there is a large legacy group of untested patients. Their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity, or personal/family cancer history. We conducted a cost-effectiveness analysis to evaluate risk-reducing strategies for these FDR who are ineligible for testing.


      A Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: (1) no BRCA testing; (2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for mutation carriers; (3) universal RRBSO, without BRCA testing. Effectiveness was estimated in quality-adjusted life year (QALY) gains over a 50-year time horizon. Sensitivity analyses accounted for uncertainty around various parameters.


      Universal BRCA testing for female FDR of women with HGSC yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an incremental cost-effectiveness ratio of $7888 per QALY. Universal BRCA testing was more effective and less costly than universal RRBSO (19.20 QALYs vs. 18.52 QALYs, and $10,135 vs. $14,231, respectively). Results were stable over wide ranges of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 79.3% for universal RRBSO to be the most effective strategy.


      BRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when BRCA mutation status is unknown.


      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 to Gynecologic Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • de Fazio A.
        • Emmanuel C.
        • George J.
        • 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 Jul 20; 30 (PubMed PMID: 22711857. Pubmed Central PMCID: 3413277): 2654-2663
        • Schrader K.A.
        • Hurlburt J.
        • Kalloger S.E.
        • Hansford S.
        • Young S.
        • Huntsman D.G.
        • et al.
        Germline BRCA1 and BRCA2 mutations in ovarian cancer: utility of a histology-based referral strategy.
        Obstet. Gynecol. 2012 Aug; 120 (PubMed PMID: 22776961): 235-240
        • Agency BC
        Hereditary cancer program referral form 2015.
        (Available from)
        • Force USPST
        Final recommendation statement: BRCA-related cancer: risk assessment, genetic counseling, and genetic testing 2013.
        (Available from)
        • Antoniou A.
        • Pharoah P.D.
        • Narod S.
        • Risch H.A.
        • Eyfjord J.E.
        • Hopper J.L.
        • et al.
        Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.
        Am. J. Hum. Genet. 2003 May; 72 (PubMed PMID: 12677558. eng): 1117-1130
        • Chen S.
        • Parmigiani G.
        Meta-analysis of BRCA1 and BRCA2 penetrance.
        J. Clin. Oncol. 2007 Apr 10; 25 (PubMed PMID: 17416853. eng): 1329-1333
        • SEER
        Probability of developing cancer by cancer site, all ages, all races, female 2003–2005 ovary 2007.
        (Available from)
        • SEER
        Probability of developing cancer by cancer site, all ages, all races, female 2003–2005 breast 2007.
        (Available from)
        • Metcalfe K.A.
        • Ghadirian P.
        • Rosen B.
        • Foulkes W.
        • Kim-Sing C.
        • Eisen A.
        • et al.
        Variation in rates of uptake of preventive options by Canadian women carrying the BRCA1 or BRCA2 genetic mutation.
        Open Med. Chem. J.. 2007; 1 (PubMed PMID: 20101300. eng): e92-e98
        • CIHI
        Patient cost estimator 2017.
        (Available from)
        • Health BCMo
        BC ministry of health medical services commission payment schedule 2017 [updated July 1, 2017; cited 2017 July 7, 2017].
        (Available from)
        • Challberg J.
        • Ashcroft L.
        • Lalloo F.
        • Eckersley B.
        • Clayton R.
        • Hopwood P.
        • et al.
        Menopausal symptoms and bone health in women undertaking risk reducing bilateral salpingo-oophorectomy: significant bone health issues in those not taking HRT.
        Br. J. Cancer. 2011 Jun 28; 105 (PubMed PMID: 21654687. Pubmed Central PMCID: 3137416): 22-27
        • Domchek S.M.
        • Friebel T.M.
        • Singer C.F.
        • Evans D.G.
        • Lynch H.T.
        • Isaacs C.
        • et al.
        Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality.
        JAMA. 2010 Sep 1; 304 (PubMed PMID: 20810374. eng): 967-975
        • Madalinska J.B.
        • van Beurden M.
        • Bleiker E.M.
        • Valdimarsdottir H.B.
        • Hollenstein J.
        • Massuger L.F.
        • et al.
        The impact of hormone replacement therapy on menopausal symptoms in younger high-risk women after prophylactic salpingo-oophorectomy.
        J. Clin. Oncol. 2006 Aug 01; 24 (PubMed PMID: 16877724): 3576-3582
        • Canada S
        Table 053-0003 - Elements of the Life Table, Canada, Provinces and Territories, Annual, 2011–2013, Female.
        • Wright J.D.
        • Kostolias A.
        • Ananth C.V.
        • Burke W.M.
        • Tergas A.I.
        • Prendergast E.
        • et al.
        Comparative effectiveness of robotically assisted compared with laparoscopic adnexal surgery for benign gynecologic disease.
        Obstet. Gynecol. 2014 Nov; 124 (PubMed PMID: 25437715. Pubmed Central PMCID: 4251548): 886-896
        • Anderson K.
        • Jacobson J.S.
        • Heitjan D.F.
        • Zivin J.G.
        • Hershman D.
        • Neugut A.I.
        • et al.
        Cost-effectiveness of preventive strategies for women with a BRCA1 or a BRCA2 mutation.
        Ann. Intern. Med. 2006 Mar 21; 144 (PubMed PMID: 16549852. eng): 397-406
        • Fryback D.G.
        • Dasbach E.J.
        • Klein R.
        • Klein B.E.
        • Dorn N.
        • Peterson K.
        • et al.
        The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors.
        Med. Decis. Mak. 1993 Apr–Jun; 13 (PubMed PMID: 8483408. eng): 89-102
        • Grann V.R.
        • Jacobson J.S.
        • Sundararajan V.
        • Albert S.M.
        • Troxel A.B.
        • Neugut A.I.
        The quality of life associated with prophylactic treatments for women with BRCA1/2 mutations.
        Cancer J. Sci. Am. 1999 Sep–Oct; 5 (PubMed PMID: 10526669. eng): 283-292
        • Holland M.L.
        • Huston A.
        • Noyes K.
        Cost-effectiveness of testing for breast cancer susceptibility genes.
        Value Health. 2009 Mar-Apr; 12 (PubMed PMID: 18647256): 207-216
        • Lidgren M.
        • Wilking N.
        • Jonsson B.
        • Rehnberg C.
        Health related quality of life in different states of breast cancer.
        Qual. Life Res. 2007 Aug; 16 (PubMed PMID: 17468943. eng): 1073-1081
        • Tengs T.O.
        • Winer E.P.
        • Paddock S.
        • Aguilar-Chavez O.
        • Berry D.A.
        Testing for the BRCA1 and BRCA2 breast-ovarian cancer susceptibility genes: a decision analysis.
        Med. Decis. Mak. 1998 Oct–Dec; 18 (PubMed PMID: 10372578. eng): 365-375
        • Thoma A.
        • Khuthaila D.
        • Rockwell G.
        • Veltri K.
        Cost-utility analysis comparing free and pedicled TRAM flap for breast reconstruction.
        Microsurgery. 2003; 23 (PubMed PMID: 12942517. eng): 287-295
        • van Roosmalen M.S.
        • Verhoef L.C.
        • Stalmeier P.F.
        • Hoogerbrugge N.
        • van Daal W.A.
        Decision analysis of prophylactic surgery or screening for BRCA1 mutation carriers: a more prominent role for oophorectomy.
        J. Clin. Oncol. 2002 Apr 15; 20 (PubMed PMID: 11956270. eng): 2092-2100
        • Parker W.H.
        • Feskanich D.
        • Broder M.S.
        • Chang E.
        • Shoupe D.
        • Farquhar C.M.
        • et al.
        Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses' health study.
        Obstet. Gynecol. 2013 Apr; 121 (PubMed PMID: 23635669. Pubmed Central PMCID: 4254662): 709-716
        • Steiner CAA, Weiss AJTHA, Barrett MLMLB, Inc.
        • KRTHA Fingar
        • PHA Davis
        Trends in bilateral and unilateral mastectomies in hospital inpatient and ambulatory settings, 2005–2013.
        (Rockville, MD)2016 Feburary 2016 (Report No)
        • AHRQ
        Trends in Hysterectomies and Oophorectomies in Hospital Inpatient and Ambulatory Settings, 2005–2013.
        (Rockville, MD)2016
        • CMS
        Physician fee schedule search 2017.
        (Available from)
        • Canada S
        Total fertility rate, Canada, 1926 to 2011.
        (Available from)
        • Arts-de Jong M.
        • de Bock G.H.
        • van Asperen C.J.
        • Mourits M.J.
        • de Hullu J.A.
        • Kets C.M.
        Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: a systematic review.
        Eur. J. Cancer. 2016 Jul; 61 (PubMed PMID: 27209246): 137-145
        • Hoberg-Vetti H.
        • Bjorvatn C.
        • Fiane B.E.
        • Aas T.
        • Woie K.
        • Espelid H.
        • et al.
        BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study.
        Eur. J. Hum. Genet. 2016 Jun; 24 (PubMed PMID: 26350514. Pubmed Central PMCID: 4867439): 881-888
        • Petzel S.V.
        • Vogel R.I.
        • McNiel J.
        • Leininger A.
        • Argenta P.A.
        • Geller M.A.
        Improving referral for genetic risk assessment in ovarian cancer using an electronic medical record system.
        Int. J. Gynecol. Cancer. 2014 Jul; 24 (PubMed PMID: 24887442. Pubmed Central PMCID: 4596256): 1003-1009
        • Childers C.P.
        • Childers K.K.
        • Maggard-Gibbons M.
        • Macinko J.
        National estimates of genetic testing in women with a history of breast or ovarian cancer.
        J. Clin. Oncol. 2017 Dec 1; 35 (PubMed PMID: 28820644. Pubmed Central PMCID: 5707208): 3800-3806
        • Quirk J.T.
        • Natarajan N.
        Ovarian cancer incidence in the United States, 1992–1999.
        Gynecol. Oncol. 2005 May; 97 (PubMed PMID: 15863154): 519-523
        • Canadian Cancer Society PHAoC, Statistics Canada
        Canadian cancer statistics 2016.
        (Available from)
        • NCCN
        Genetic/familial high-risk assessment: breast and ovarian 2018 [updated July 11, 2018; cited 2018]. Version 1.2019.
        (Available from)
        • Jervis S.
        • Song H.
        • Lee A.
        • Dicks E.
        • Tyrer J.
        • Harrington P.
        • et al.
        Ovarian cancer familial relative risks by tumour subtypes and by known ovarian cancer genetic susceptibility variants.
        J. Med. Genet. 2014 Feb; 51 (PubMed PMID: 24277755): 108-113
        • Easton D.F.
        • Matthews F.E.
        • Ford D.
        • Swerdlow A.J.
        • Peto J.
        Cancer mortality in relatives of women with ovarian cancer: the OPCS Study. Office of Population Censuses and Surveys.
        Int. J. Cancer. 1996 Jan 26; 65 (PubMed PMID: 8575846): 284-294
        • Hemminki K.
        • Sundquist J.
        • Brandt A.
        Incidence and mortality in epithelial ovarian cancer by family history of any cancer.
        Cancer. 2011 Sep 01; 117 (PubMed PMID: 21365633): 3972-3980
        • Lorenzo Bermejo J.
        • Rawal R.
        • Hemminki K.
        Familial association of specific histologic types of ovarian malignancy with other malignancies.
        Cancer. 2004 Apr 01; 100 (PubMed PMID: 15042686): 1507-1514
        • Manchanda R.
        • Legood R.
        • Antoniou A.C.
        • Gordeev V.S.
        • Menon U.
        Specifying the ovarian cancer risk threshold of ‘premenopausal risk-reducing salpingo-oophorectomy’ for ovarian cancer prevention: a cost-effectiveness analysis.
        J. Med. Genet. 2016 Sep; 53 (PubMed PMID: 27354448): 591-599
        • Parker W.H.
        • Broder M.S.
        • Chang E.
        • Feskanich D.
        • Farquhar C.
        • Liu Z.
        • et al.
        Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study.
        Obstet. Gynecol. 2009 May; 113 (PubMed PMID: 19384117. eng): 1027-1037
        • Rocca W.A.
        • Grossardt B.R.
        • de Andrade M.
        • Malkasian G.D.
        • Melton 3rd., L.J.
        Survival patterns after oophorectomy in premenopausal women: a population-based cohort study.
        Lancet Oncol. 2006 Oct; 7 (PubMed PMID: 17012044): 821-828
        • Lecarpentier J.
        • Silvestri V.
        • Kuchenbaecker K.B.
        • Barrowdale D.
        • Dennis J.
        • McGuffog L.
        • et al.
        Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores.
        J. Clin. Oncol. 2017 Jul 10; 35 (PubMed PMID: 28448241. Pubmed Central PMCID: 5501359): 2240-2250
        • Kwon J.S.
        • Pansegrau G.
        • Nourmoussavi M.
        • Hammond G.
        • Carey M.S.
        Long-term consequences of ovarian ablation for premenopausal breast cancer.
        Breast Cancer Res. Treat. 2016 Jun; 157 (PubMed PMID: 27236562): 565-573
        • Canada S
        Life expectancy - statistics Canada 2018.
        (Available from)
        • Prevention CfDCa
        Life expectancy 2018.
        (Available from)
        • Johansen N.
        • Liavaag A.H.
        • Iversen O.E.
        • Dorum A.
        • Braaten T.
        • Michelsen T.M.
        Use of hormone replacement therapy after risk-reducing salpingo-oophorectomy.
        Acta Obstet. Gynecol. Scand. 2017 May; 96 (PubMed PMID: 28236297): 547-555
        • Metcalfe K.A.
        • Birenbaum-Carmeli D.
        • Lubinski J.
        • Gronwald J.
        • Lynch H.
        • Moller P.
        • et al.
        International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers.
        Int. J. Cancer. 2008 May 1; 122 (PubMed PMID: 18196574. eng): 2017-2022
        • Program BCAHC
        Risk-Reducing Surgery in BRCA Mutation Carriers.
        • Tengs T.O.
        • Wallace A.
        One thousand health-related quality-of-life estimates.
        Med. Care. 2000 Jun; 38 (PubMed PMID: 10843310. eng): 583-637
        • Grann V.R.
        • Jacobson J.S.
        • Thomason D.
        • Hershman D.
        • Heitjan D.F.
        • Neugut A.I.
        Effect of prevention strategies on survival and quality-adjusted survival of women with BRCA1/2 mutations: an updated decision analysis.
        J. Clin. Oncol. 2002 May 15; 20 (PubMed PMID: 12011131. eng): 2520-2529
        • BCCA
        British Columbia Cancer Agency Hereditary Cancer Program: High Risk Clinic Statistics.
        • Compass P.
        Pharmacy compass - pacific blue cross 2017.
        (Available from)