Clinical and Translational Oncology

, Volume 18, Issue 10, pp 981–987 | Cite as

Germline BRCA testing is moving from cancer risk assessment to a predictive biomarker for targeting cancer therapeutics

  • L. Moreno
  • C. Linossi
  • I. Esteban
  • N. Gadea
  • E. Carrasco
  • S. Bonache
  • S. Gutiérrez-Enríquez
  • C. Cruz
  • O. Díez
  • J. Balmaña
Research Article

Abstract

Purpose

Originally, BRCA testing was used for risk assessment and prevention strategies for breast and ovarian cancer. Nowadays, BRCA status may influence therapeutic decision making at cancer diagnosis. Our objective was to analyze whether the medical advances have changed the burden and pattern of referral, and the pathogenic mutation detection rate.

Methods

We included 969 probands from our hereditary cancer registry who undertook a full BRCA analysis between 2006 and 2014. Chi-square tests were used to compare categorical variables.

Results

The number of genetic tests have raised from 28 to 170, representing a sixfold increase. In 2006, we tested 1.6 relatives/proband while this proportion was four in 2014. Overall, 20 % harbored a deleterious mutation and 11 % had a variant of unknown significance (VUS). There has been a downward trend in the detection rate of VUS. Testing patients with breast cancer during neoadjuvancy has raised from 4 to 25 % (p = 0.002), while testing them during remission has decreased from 79 to 29 % (p < 0.001). The proportion of patients assessed during the first 6 months after their cancer diagnosis has increased from 3 to 34 % (p = 0.001). Risk reducing mastectomy and salpingoophorectomy have raised from 0 to 24 %, and from 36 to 65 %, respectively.

Conclusions

BRCA testing has experienced a sixfold increase, the number of relatives being tested has doubled, and the test is being performed at earlier phases of the disease. It is necessary to adequate the health resources to preserve the BRCA genetic counseling quality while incorporating BRCA testing for therapeutic decision making.

Keywords

BRCA Genetic testing Genetic counseling Risk assessment Therapeutic decision making 

References

  1. 1.
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66–71.CrossRefPubMedGoogle Scholar
  2. 2.
    Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996;12(3):333–7. doi:10.1038/ng0396-333.CrossRefPubMedGoogle Scholar
  3. 3.
    Ford D, Easton FD, Stratton M, Narod SA, Goldgar DE, Devilee P, et al. Genetic heterogeneity and penetrance analysis of the BRCA genes in breast cancer families. Am J Hum Genet. 1998;62:14.CrossRefGoogle Scholar
  4. 4.
    Eccles DM, Evans DG, Mackay J. Guidelines for a genetic risk based approach to advising women with a family history of breast cancer. J Med Genet. 2000;37:7.CrossRefGoogle Scholar
  5. 5.
    American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003;21(12):2397–406. doi:10.1200/JCO.2003.03.189.CrossRefGoogle Scholar
  6. 6.
    Berliner JL, Fay AM. Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2007;16(3):19.CrossRefGoogle Scholar
  7. 7.
    Bradbury AR, Olopade O. Genetic susceptibility to breast cancer. Rev Endocr Metab Disord. 2007;8(3):12.CrossRefGoogle Scholar
  8. 8.
    Warner E, Plewes DB, Hill KA, Causer PA, Zubovits JT, Jong RA, et al. Surveillance of BRCA mutation carriers with MRI, ultrasound, mammography and clinical breast examination. JAMA. 2004;292(11):9.CrossRefGoogle Scholar
  9. 9.
    Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van ‘t Veer L, Garber JE, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055–62. doi:10.1200/JCO.2004.04.188.CrossRefPubMedGoogle Scholar
  10. 10.
    National Comprehensive Cancer Network (US). NCCN clinical practice guidelines in oncology. Genetic/Familial high-risk assessment: Breast and Ovarian, V.2.2015. Washington (DC): NCCN; 2015.Google Scholar
  11. 11.
    Balmana J, Diez O, Rubio IT, Cardoso F, Group EGW. BRCA in breast cancer: ESMO clinical practice guidelines. Ann Oncol. 2011;22(Suppl 6):31–4. doi:10.1093/annonc/mdr373.Google Scholar
  12. 12.
    Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, et al. Risk reducing salpingo-oophorectomy for women with BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346(21):7.CrossRefGoogle Scholar
  13. 13.
    Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–75. doi:10.1001/jama.2010.1237.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Telli ML, Jensen KC, Vinayak S, Kurian AW, Lipson JA, Flaherty PJ, et al. Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol. 2015;33(17):1895–901. doi:10.1200/JCO.2014.57.0085.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, et al. TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol. 2015;33(17):1902–9. doi:10.1200/JCO.2014.57.6660.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105(11):812–22. doi:10.1093/jnci/djt095.CrossRefPubMedGoogle Scholar
  17. 17.
    Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, et al. Population-Based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol. 2010;28(14):6.CrossRefGoogle Scholar
  18. 18.
    Schwartz MD, Lerman C, Brogan B, Peshkin BN, Halbert CH, DeMarco T, et al. Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol. 2004;22(10):1823–9. doi:10.1200/JCO.2004.04.086.CrossRefPubMedGoogle Scholar
  19. 19.
    Fong PC, Boss DS, Yap TA, 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;361(2):12.CrossRefGoogle Scholar
  20. 20.
    Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, 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;376(9737):245–51. doi:10.1016/S0140-6736(10)60893-8.CrossRefPubMedGoogle Scholar
  21. 21.
    Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):9. doi:10.1016/S1470-2045(14)70228-1.CrossRefGoogle Scholar
  22. 22.
    Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2014;. doi:10.1200/JCO.2014.56.2728.Google Scholar
  23. 23.
    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;30(21):2654–63. doi:10.1200/JCO.2011.39.8545.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lancaster JM, Powell CB, Chen LM, Richardson DL. Committee SGOCP. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2015;136(1):3–7. doi:10.1016/j.ygyno.2014.09.009.CrossRefPubMedGoogle Scholar
  25. 25.
    Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304–11. doi:10.1200/JCO.2014.57.1414.CrossRefPubMedGoogle Scholar
  26. 26.
    Hartman AR, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, et al. Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer. 2012;118(11):2787–95. doi:10.1002/cncr.26576.CrossRefPubMedGoogle Scholar
  27. 27.
    Evans DG, Barwell J, Eccles D, Collins A, Izatt L, Jacobs C, et al. The Angelina Jolie Effect: how high celebrity profile can have major impact provision of cancer related services. Breast Cancer Res. 2014;16:6.CrossRefGoogle Scholar
  28. 28.
    Bellcross CA. The changing landscape of genetic testing for hereditary breast and ovarian cancer. Curr Probl Cancer. 2014;38(6):209–15. doi:10.1016/j.currproblcancer.2014.10.001.CrossRefPubMedGoogle Scholar
  29. 29.
    Diez O, Gutierrez-Enriquez S, Masas M, Tenes A, Yague C, Arcusa A, et al. Identification of a new complex deleterious mutation in exon 18 of the BRCA2 gene in a hereditary male/female breast cancer family. Breast Cancer Res Treat. 2010;123(2):587–90. doi:10.1007/s10549-010-0830-2.CrossRefPubMedGoogle Scholar
  30. 30.
    Spurdle AB, Healey S, Devereau A, Hogervorst FB, Monteiro AN, Nathanson KL, et al. ENIGMA–evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat. 2012;33(1):2–7. doi:10.1002/humu.21628.CrossRefPubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2015

Authors and Affiliations

  • L. Moreno
    • 1
  • C. Linossi
    • 1
  • I. Esteban
    • 1
  • N. Gadea
    • 1
  • E. Carrasco
    • 1
  • S. Bonache
    • 2
  • S. Gutiérrez-Enríquez
    • 2
  • C. Cruz
    • 1
  • O. Díez
    • 2
    • 3
  • J. Balmaña
    • 1
  1. 1.High Risk and Cancer Prevention Unit, Medical Oncology DepartmentUniversity Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, and Vall d’Hebron Institute of Oncology (VHIO)BarcelonaSpain
  2. 2.Oncogenetics GroupVall d’Hebron Institute of Oncology (VHIO) and Universitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Clinical and Molecular Genetics AreaUniversity Hospital Vall d’HebronBarcelonaSpain

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