Advertisement

Predictability of BRCA1/2 mutation status in patients with ovarian cancer: How to select women for genetic testing in middle-income countries

      Highlights

      • Assessment of genetic risk is not widely available in middle-income countries.
      • It is crucial to select those patients who will benefit the most from genetic testing.
      • BOADICEA (threshold ≥10%) performed better than other algorithms in this population.
      • Using algorithms to select patients can reduce the number of tests by more than 70%.
      • However, a quarter of all mutation carriers would be missed.

      Abstract

      Objectives

      To evaluate the accuracy of algorithms for predicting BRCA1/2 germ-line mutation carrier probability, and to identify factors that could improve their performance among Brazilian women with ovarian cancer (OC).

      Study design

      In this cross-sectional study, we enrolled patients (unselected for family history of cancer) undergoing treatment or follow-up for OC in a single centre in Brazil. Clinical and demographic data, including family history of cancer, were obtained. Blood samples were collected for genetic testing.

      Main outcome measures

      The entire coding sequence of BRCA1 and BRCA2 was evaluated for mutations. Mutation carrier probability was calculated using BOADICEA, BRCAPRO, Myriad and the Manchester score. Sensitivity, specificity, positive and negative predictive values, and area under the receiver operating characteristic curves (AUC) were calculated for each algorithm. Logistic regression was used to detect additional factors associated with BRCA1/2 status, and these were added to the algorithms before recalculating the AUCs.

      Results

      BRCA1/2 mutations were identified in 19 of the 100 included patients. BOADICEA outperformed other algorithms (sensitivity, 73.7%; specificity, 87.7%; AUC, 0.87, with a threshold of a 10% risk of mutation). Later menarche was associated with the presence of a BRCA1/2 mutation. Although adding age at menarche resulted in a larger AUC for all models, this increase was significant only for the Myriad algorithm.

      Conclusion

      A BOADICEA risk evaluation of 10% or more most accurately predicted BRCA1/2 status, and the inclusion of age at menarche tended to improve the performance of all algorithms. Using these tools could reduce the number of tests, but at the expense of missing a significant proportion of mutation carriers.

      Abbreviations

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

      References

      1. MS/INCA/Estimativa de Câncer no Brasil, 2016. Available at: http://www.inca.gov.br/wcm/dncc/2015/por-sexo.asp. Accessed 17 December 2015.

        • Eccles D.M.
        • Balmana J.
        • Clune J.
        • et al.
        Selecting patients with ovarian cancer for germline BRCA mutation testing: findings from guidelines and a systematic literature review.
        Adv. Ther. 2016; 33: 129-150
        • Antoniou A.
        • Pharoah P.D.
        • Narod S.
        • 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; 72: 1117-1130
        • van der Kolk D.M.
        • de Bock G.H.
        • Leegte B.K.
        • et al.
        Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age.
        Breast Cancer Res. Treat. 2010; 124: 643-651
        • Cragun J.M.
        Screening for ovarian cancer.
        Cancer Control. 2011; 8: 16-21
        • Reitsma W.
        • de Bock G.H.
        • Oosterwijk J.C.
        • Bart J.
        • Hollema H.
        • Mourits M.J.
        Support of the ‘fallopian tube hypothesis' in a prospective series of risk-reducing salpingo-oophorectomy specimens.
        Eur. J. Cancer. 2013; 49: 132-141
        • 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; 101: 80-87
        • Ledermann J.A.
        • El-Khouly F.
        PARP inhibitors in ovarian cancer: clinical evidence for informed treatment decisions.
        Br. J. Cancer. 2015; 113: S10-S16
        • NCCN
        Guidelines Version 2.2015 Genetic/Familial High Risk Assessment: Breast and Ovarian.
        2015 (Accessed December/18, 2015. Available at:)
        • Maistro S.
        • Teixeira N.
        • Encinas G.
        • et al.
        Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil.
        BMC Cancer. 2016; 16: 934
        • Antoniou A.C.
        • Pharoah P.P.
        • Smith P.
        • Easton D.F.
        The BOADICEA model of genetic susceptibility to breast and ovarian cancer.
        Br. J. Cancer. 2004; 91: 1580-1590
        • Frank T.S.
        • Deffenbaugh A.M.
        • Reid J.E.
        • et al.
        Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10, 000 individuals.
        J. Clin. Oncol. 2002; 20: 1480-1490
        • Parmigiani G.
        • Berry D.
        • Aguilar O.
        Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2.
        Am. J. Hum. Genet. 1998; 2: 145-158
        • Evans D.G.
        • Eccles D.M.
        • Rahman N.
        • et al.
        A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO.
        J. Med. Genet. 2004; 41: 474-480
        • Teixeira N.
        • Folgueira M.A.
        • Maistro S.
        • Encinas G.
        • Bock G.H.
        • del M.
        • Diz P.
        Association of family risk and lifestyle/comorbidities in ovarian cancer patients.
        Rev. Assoc. Med. Bras. 2015; 61: 234-239
      2. © 2013 Centre for Cancer Genetic Epidemiology. BOADICEA risk estimation. Available at: https://pluto.srl.cam.ac.uk/cgi-bin/bd3/v3/bd.cgi. Accessed January, 2016.

      3. K. Hughes Hughes, Risk Apps Express Entry. Available at: http://66.118.159.147/HRAExpressEntry/(S(ydr4eggiiob13dr041n54qdc))/default.aspx. Accessed April, 2016.

        • Dutil J.
        • Golubeva V.A.
        • Pacheco-Torres A.L.
        • Diaz-Zabala H.J.
        • Matta J.L.
        • Monteiro A.N.
        The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective, Breast Cancer Res.
        Treat. 2015; 154: 441-453
        • Antoniou A.C.
        • Hardy R.
        • Walker L.
        • et al.
        Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics.
        J. Med. Genet. 2008; 45: 425-431
        • Panchal S.M.
        • Ennis M.
        • Canon S.
        • Bordeleau L.J.
        Selecting a BRCA risk assessment model for use in a familial cancer clinic.
        BMC Med. Genet. 2008; 9: 116
        • Thirthagiri E.
        • Lee S.Y.
        • Kang P.
        • et al.
        Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer.
        Breast Cancer Res. 2008; 10: R59
        • Weitzel J.N.
        • Lagos V.I.
        • Cullinane C.A.
        • et al.
        Limited family structure and BRCA gene mutation status in single cases of breast cancer.
        JAMA. 2007; 97: 2587-2595
        • 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
        • Riahi A.
        • Gourabi M.E.
        • Chabouni-Bouhamed H.
        Dissimilarity between sporadic, non-BRCA1/2 families and hereditary breast cancer, linked to BRCA genes, in the Tunisian population.
        Breast Cancer. 2015; 23: 807-812
        • Tea M.K.
        • Weghofer A.
        • Wagner K.
        • Singer C.F.
        Association of BRCA1/2 mutations with FMR1 genotypes: effects on menarcheal and menopausal age.
        Maturitas. 2013; 5: 148-151
        • Bayraktar S.
        • Amendola L.
        • Gutierrez-Barrera A.M.
        • et al.
        Clinicopathologic characteristics of breast cancer in BRCA-carriers and non-carriers in women 35 years of age or less.
        Breast. 2014; 3: 770-774
        • Dvornyk V.
        • Waqar-ul-Haq
        Genetics of age at menarche: a systematic review.
        Hum. Reprod. Update. 2012; 18: 198-210
        • Boyd J.
        • Sonoda Y.
        • Federici M.G.
        • et al.
        Clinicopathologic features of BRCA-linked and sporadic ovarian cancer.
        JAMA. 2000; 83: 2260-2265
        • Horovitz D.D.
        • de Faria Ferraz V.E.
        • Dain S.
        • Marques-de-Faria A.P.
        Genetic services and testing in Brazil.
        J. Commun. Genet. 2013; 4: 355-375
        • Schlatter R.P.
        • Matte U.
        • Polanczyk C.A.
        • Koehler-Santos P.
        • Ashton-Prolla P.
        Costs of genetic testing: supporting Brazilian Public Policies for the incorporating of molecular diagnostic technologies.
        Genet. Mol. Biol. 2015; 38: 332-337