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Characteristics of women with ovarian carcinoma who have BRCA1 and BRCA2 mutations not identified by clinical testing

Published:February 19, 2014DOI:https://doi.org/10.1016/j.ygyno.2012.12.015

      Abstract

      Objectives

      Few studies have comprehensively tested all ovarian cancer patients for BRCA1 and BRCA2 (BRCA1/2) mutations. We sought to determine if clinically identified mutation carriers differed in clinical characteristics and outcomes from mutation carriers not identified during routine clinical care.

      Methods

      We included women with ovarian, tubal or peritoneal carcinoma. BROCA, an assay using targeted capture and massively parallel sequencing was used to identify mutations in BRCA1/2 and 19 other tumor suppressor genes. We identified subjects with BRCA1/2 mutations using BROCA that had not previously received standard genetic testing (BROCA, n=37) and compared them to subjects with BRCA1/2 mutations identified during routine clinical care (known, n=70), and to those wildtype for 21 genes using BROCA (wildtype, n=291).

      Results

      BROCA mutation carriers were older than known carriers, median age of 58 (range 41–77), vs. 51 (range 33-76, p=0.003, Mann–Whitney). 58/70 (82.9%) of known carriers had a strong family history, compared with 15/37 (40.5%) of BROCA carriers, p<0.0001, (Fisher's Exact). Median overall survival was significantly worse for BROCA mutation carriers compared to known mutation carriers, (45 vs. 93 months, p<0.0001, HR 3.47 (1.79–6.72), Log-rank test). The improved survival for BRCA1/2 mutation carriers (known and BROCA) compared with wildtype cases (69 vs. 44 months, p=0.0001, HR 0.58 (0.43–0.77), Log-rank test) was driven by known mutation carriers.

      Conclusions

      Older age, absence of a strong family history, and poor survival are all associated with decreased clinical identification of inherited BRCA1/2 mutations in women with ovarian cancer. Using age and family history to direct genetic testing will miss a significant percentage of mutation carriers. Testing should be initiated at the time of diagnosis to maximize identification of mutations and minimize survival bias.

      Highlights

      • Older age, lack of family history, and poor survival are associated with decreased clinical identification of BRCA1/2 mutations.
      • Testing should be initiated at time of diagnosis to maximize identification and minimize survival bias.

      Keywords

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      References

        • Pal T.
        • Permuth-Wey J.
        • Betts J.A.
        • Krischer J.P.
        • Fiorica J.
        • Arango H.
        • et al.
        BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.
        Cancer. 2005 Dec 15; 104: 2807-2816
        • Risch H.A.
        • McLaughlin J.R.
        • Cole D.E.
        • Rosen B.
        • Bradley L.
        • Kwan E.
        • et al.
        Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.
        Am J Hum Genet. 2001; 68: 700-710
        • Zhang S.
        • Royer R.
        • Li S.
        • McLaughlin J.R.
        • Rosen B.
        • Risch H.A.
        • et al.
        Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.
        Gynecol Oncol. 2011 May 1; 121: 353-357
        • King M.C.
        • Marks J.H.
        • Mandell J.B.
        • Group N.Y.B.C.S.
        Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
        Science. 2003 Oct 24; 302: 643-646
        • Lakhani S.R.
        • Manek S.
        • Penault-Llorca F.
        • Flanagan A.
        • Arnout L.
        • Merrett S.
        • et al.
        Pathology of ovarian cancers in BRCA1 and BRCA2 carriers.
        Clin Cancer Res. 2004 Apr 1; 10: 2473-2481
        • Shaw P.A.
        • McLaughlin J.R.
        • Zweemer R.P.
        • Narod S.A.
        • Risch H.
        • Verheijen R.H.
        • et al.
        Histopathologic features of genetically determined ovarian cancer.
        Int J Gynecol Pathol. 2002 Oct; 21: 407-411
        • Bolton K.L.
        • Chenevix-Trench G.
        • Goh C.
        • Sadetzki S.
        • Ramus S.J.
        • Karlan B.Y.
        • et al.
        Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.
        JAMA. 2012 Jan 25; 307: 382-390
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • Defazio 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: 2654-2663
        • Domchek S.M.
        • Friebel T.M.
        • Neuhausen S.L.
        • Wagner T.
        • Evans G.
        • Isaacs C.
        • et al.
        Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study.
        Lancet Oncol. 2006 Mar; 7: 223-229
        • Kauff N.D.
        • Domchek S.M.
        • Friebel T.M.
        • Robson M.E.
        • Lee J.
        • Garber J.E.
        • et al.
        Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study.
        J Clin Oncol. 2008 Mar 10; 26: 1331-1337
        • Rebbeck T.R.
        • Kauff N.D.
        • Domchek S.M.
        Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.
        J Natl Cancer Inst. 2009 Jan 21; 101: 80-87
        • Bryant H.E.
        • Schultz N.
        • Thomas H.D.
        • Parker K.M.
        • Flower D.
        • Lopez E.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
        Nature. 2005 Apr 14; 434: 913-917
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • Tutt A.N.
        • Johnson D.A.
        • Richardson T.B.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005 Apr 14; 434: 917-921
        • Boyd J.
        • Sonoda Y.
        • Federici M.G.
        • Bogomolniy F.
        • Rhei E.
        • Maresco D.L.
        • et al.
        Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.
        JAMA. 2000 May 3; 283: 2260-2265
        • Cass I.
        • Baldwin R.L.
        • Varkey T.
        • Moslehi R.
        • Narod S.A.
        • Karlan B.Y.
        Improved survival in women with BRCA-associated ovarian carcinoma.
        Cancer. 2003 May 1; 97: 2187-2195
        • Chetrit A.
        • Hirsh-Yechezkel G.
        • Ben-David Y.
        • Lubin F.
        • Friedman E.
        • Sadetzki S.
        Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer.
        J Clin Oncol. 2008 Jan 1; 26: 20-25
        • Hyman D.M.
        • Long K.C.
        • Tanner E.J.
        • Grisham R.N.
        • Arnold A.G.
        • Bhatia J.
        • et al.
        Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma.
        Gynecol Oncol. 2012 Aug; 126: 224-228
        • Rubin S.C.
        • Benjamin I.
        • Behbakht K.
        • Takahashi H.
        • Morgan M.A.
        • LiVolsi V.A.
        • et al.
        Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1.
        N Engl J Med. 1996; 335: 1413-1416
        • Tan D.S.
        • Rothermundt C.
        • Thomas K.
        • Bancroft E.
        • Eeles R.
        • Shanley S.
        • et al.
        "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations.
        J Clin Oncol. 2008 Dec 1; 26: 5530-5536
        • Yang D.
        • Khan S.
        • Sun Y.
        • Hess K.
        • Shmulevich I.
        • Sood A.K.
        • et al.
        Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer.
        JAMA. 2011 Oct 12; 306: 1557-1565
        • Walsh T.
        • Lee M.K.
        • Casadei S.
        • Thornton A.M.
        • Stray S.M.
        • Pennil C.
        • et al.
        Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing.
        Proc Natl Acad Sci U S A. 2010 Jul 13; 107: 12629-12633
        • Walsh T.
        • Casadei S.
        • Lee M.K.
        • Pennil C.C.
        • Nord A.S.
        • Thornton A.M.
        • 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 Nov 1; 108: 18032-18037
      1. Breast Cancer Information Core Databases.
        (Available from:)
        • Metcalfe K.A.
        • Fan I.
        • McLaughlin J.
        • Risch H.A.
        • Rosen B.
        • Murphy J.
        • et al.
        Uptake of clinical genetic testing for ovarian cancer in Ontario: a population-based study.
        Gynecol Oncol. 2009 Jan; 112: 68-72
        • 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: 235-240
      2. Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer.
        2012 ([Available from: nccn.org.])
        • Audeh M.W.
        • Carmichael J.
        • Penson R.T.
        • Friedlander M.
        • Powell B.
        • Bell-McGuinn K.M.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
        Lancet. 2010 Jul 24; 376: 245-251
        • Fong P.C.
        • Boss D.S.
        • Yap T.A.
        • Tutt A.
        • Wu P.
        • Mergui-Roelvink M.
        • et al.
        Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
        N Engl J Med. 2009 Jul 9; 361: 123-134