Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer

Martin P Nilsson, Christof Winter, Ulf Kristoffersson, Martin Rehn, Christer Larsson, Lao H Saal, Niklas Loman, Martin P Nilsson, Christof Winter, Ulf Kristoffersson, Martin Rehn, Christer Larsson, Lao H Saal, Niklas Loman

Abstract

Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast cancer patients from the well-characterized, population-based, single-site All Breast Cancer in Malmö (ABiM) study. The patients were diagnosed with breast cancer during the years 2007 through 2009. Out of 20 mutation carriers identified, 13 fulfilled Swedish criteria at time of diagnosis. Thus, the efficacy of these criteria was 65%. Excluding three patients in whom a mutation was already known at time of diagnosis, only 3/17 had been identified in the clinical routine, corresponding to an effectiveness of 18%. Here we detail the reasons why mutation carriers in our cohort were not detected though routine health care. In conclusion, effectiveness of BRCA testing criteria was much lower than efficacy. Our results indicate that current testing criteria and procedures associated with BRCA1 and BRCA2 testing are insufficient. There is room for improvement of their efficacy, but even more so regarding effectiveness. Clinical BRCA testing routines need to be critically revised.

Keywords: BRCA1; BRCA2; Breast cancer; Effectiveness; Genetic testing; Testing criteria.

Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Declarations

The study was approved by the Regional Ethical Review Board in Lund.

References

    1. Revicki DA, Frank L. Pharmacoeconomic evaluation in the real world. Effectiveness versus efficacy studies. PharmacoEconomics. 1999;15(5):423–434. doi: 10.2165/00019053-199915050-00001.
    1. Singal AG, Higgins PD, Waljee AK. A primer on effectiveness and efficacy trials. Clin Transl Gastroenterol. 2014;5:e45. doi: 10.1038/ctg.2013.13.
    1. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t’veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson G, Schildkraut J, Blum JL, Rebbeck TR. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304(9):967–975. doi: 10.1001/jama.2010.1237.
    1. Heemskerk-Gerritsen BA, Rookus MA, Aalfs CM, Ausems MG, Collee JM, Jansen L, Kets CM, Keymeulen KB, Koppert LB, Meijers-Heijboer HE, Mooij TM, Tollenaar RA, Vasen HF, Hooning MJ, Seynaeve C. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer. 2015;136(3):668–677.
    1. Metcalfe K, Gershman S, Ghadirian P, Lynch HT, Snyder C, Tung N, Kim-Sing C, Eisen A, Foulkes WD, Rosen B, Sun P, Narod SA. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ. 2014;348:g226. doi: 10.1136/bmj.g226.
    1. Finch A, Wang M, Fine A, Atri L, Khalouei S, Pupavac M, Rosen B, Eisen A, Elser C, Charames G, Metcalfe K, Chang MC, Narod SA, Lerner-Ellis J. Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. Clin Genet. 2015
    1. Hoberg-Vetti H, Bjorvatn C, Fiane BE, Aas T, Woie K, Espelid H, Rusken T, Eikesdal HP, Listol W, Haavind MT, Knappskog PM, Haukanes BI, Steen VM, Hoogerbrugge N. BRCA1/2 testing in newly diagnosed breast and ovarian cancer patients without prior genetic counselling: the DNA-BONus study. EJHG. 2015
    1. Moller P, Hagen AI, Apold J, Maehle L, Clark N, Fiane B, Lovslett K, Hovig E, Vabo A. Genetic epidemiology of BRCA mutations–family history detects less than 50% of the mutation carriers. Eur J Cancer. 2007;43(11):1713–1717. doi: 10.1016/j.ejca.2007.04.023.
    1. van den Broek AJ, de Ruiter K, van’t Veer LJ, Tollenaar RA, van Leeuwen FE, Verhoef S, Schmidt MK. Evaluation of the Dutch BRCA1/2 clinical genetic center referral criteria in an unselected early breast cancer population. EJHG. 2015;23(5):588–595. doi: 10.1038/ejhg.2014.161.
    1. Anderson B, McLosky J, Wasilevich E, Lyon-Callo S, Duquette D, Copeland G. Barriers and facilitators for utilization of genetic counseling and risk assessment services in young female breast cancer survivors. J Cancer Epidemiol. 2012;2012:298745.
    1. Ayme A, Viassolo V, Rapiti E, Fioretta G, Schubert H, Bouchardy C, Chappuis PO, Benhamou S. Determinants of genetic counseling uptake and its impact on breast cancer outcome: a population-based study. Breast Cancer Res Treat. 2014;144(2):379–389. doi: 10.1007/s10549-014-2864-3.
    1. Bellcross CA, Leadbetter S, Alford SH, Peipins LA. Prevalence and healthcare actions of women in a large health system with a family history meeting the 2005 USPSTF recommendation for BRCA genetic counseling referral. Cancer Epidemiol Biomark Prev. 2013;22(4):728–735. doi: 10.1158/1055-9965.EPI-12-1280.
    1. Cragun D, Bonner D, Kim J, Akbari MR, Narod SA, Gomez-Fuego A, Garcia JD, Vadaparampil ST, Pal T. Factors associated with genetic counseling and BRCA testing in a population-based sample of young Black women with breast cancer. Breast Cancer Res Treat. 2015;151(1):169–176. doi: 10.1007/s10549-015-3374-7.
    1. Febbraro T, Robison K, Wilbur JS, Laprise J, Bregar A, Lopes V, Legare R, Stuckey A. Adherence patterns to National Comprehensive Cancer Network (NCCN) guidelines for referral to cancer genetic professionals. Gynecol Oncol. 2015;138(1):109–114. doi: 10.1016/j.ygyno.2015.04.029.
    1. Kehl KL, Shen C, Litton JK, Arun B, Giordano SH. Rates of BRCA1/2 mutation testing among young survivors of breast cancer. Breast Cancer Res Treat. 2016;155(1):165–173. doi: 10.1007/s10549-015-3658-y.
    1. Levy DE, Byfield SD, Comstock CB, Garber JE, Syngal S, Crown WH, Shields AE. Underutilization of BRCA1/2 testing to guide breast cancer treatment: black and Hispanic women particularly at risk. Genetics Med. 2011;13(4):349–355. doi: 10.1097/GIM.0b013e3182091ba4.
    1. McCarthy AM, Bristol M, Fredricks T, Wilkins L, Roelfsema I, Liao K, Shea JA, Groeneveld P, Domchek SM, Armstrong K. Are physician recommendations for BRCA1/2 testing in patients with breast cancer appropriate? A population-based study. Cancer. 2013;119(20):3596–3603. doi: 10.1002/cncr.28268.
    1. Meyer LA, Anderson ME, Lacour RA, Suri A, Daniels MS, Urbauer DL, Nogueras-Gonzalez GM, Schmeler KM, Gershenson DM, Lu KH. Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol. 2010;115(5):945–952. doi: 10.1097/AOG.0b013e3181da08d7.
    1. Stuckey A, Febbraro T, Laprise J, Wilbur JS, Lopes V, Robison K. Adherence patterns to National Comprehensive Cancer Network guidelines for referral of women with breast cancer to genetics professionals. Am J Clin Oncol. 2014
    1. Susswein LR, Skrzynia C, Lange LA, Booker JK, Graham ML, 3rd, Evans JP. Increased uptake of BRCA1/2 genetic testing among African American women with a recent diagnosis of breast cancer. J Clin Oncol. 2008;26(1):32–36. doi: 10.1200/JCO.2007.10.6377.
    1. Vig HS, McCarthy AM, Liao K, Demeter MB, Fredericks T, Armstrong K. Age at diagnosis may trump family history in driving BRCA testing in a population of breast cancer patients. Cancer Epidemiol Biomark Prev. 2013;22(10):1778–1785. doi: 10.1158/1055-9965.EPI-13-0426.
    1. Wood ME, Kadlubek P, Pham TH, Wollins DS, Lu KH, Weitzel JN, Neuss MN, Hughes KS. Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the American Society of Clinical Oncology Quality Oncology Practice Initiative. J Clin Oncol. 2014;32(8):824–829. doi: 10.1200/JCO.2013.51.4661.
    1. Schlich-Bakker KJ, ten Kroode HF, Warlam-Rodenhuis CC, van den Bout J, Ausems MG. Barriers to participating in genetic counseling and BRCA testing during primary treatment for breast cancer. Genet Med. 2007;9(11):766–777. doi: 10.1097/GIM.0b013e318159a318.
    1. Sie AS, Brunner HG, Hoogerbrugge N. Easy-to-use decision aids for improved cancer family history collection and use among oncology practices. J Clin Oncol. 2014;32(29):3343. doi: 10.1200/JCO.2014.56.2942.
    1. Trivers KF, Baldwin LM, Miller JW, Matthews B, Andrilla CH, Lishner DM, Goff BA. Reported referral for genetic counseling or BRCA 1/2 testing among United States physicians: a vignette-based study. Cancer. 2011;117(23):5334–5343. doi: 10.1002/cncr.26166.
    1. Van Riel E, Warlam-Rodenhuis CC, Verhoef S, Rutgers EJ, Ausems MG. BRCA testing of breast cancer patients: medical specialists’ referral patterns, knowledge and attitudes to genetic testing. Eur J Cancer Care. 2010;19(3):369–376. doi: 10.1111/j.1365-2354.2008.01065.x.
    1. Winter C, Nilsson MP, Olsson E, George AM, Chen Y, Kvist A, Torngren T, Vallon-Christersson J, Hegardt C, Hakkinen J, Jonsson G, Grabau D, Malmberg M, Kristoffersson U, Rehn M, Gruvberger-Saal SK, Larsson C, Borg A, Loman N, Saal LH. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests one third of mutations are somatic. Ann Oncol. 2016
    1. NCCN guidelines version 2.2016.
    1. Gadzicki D, Evans DG, Harris H, Julian-Reynier C, Nippert I, Schmidtke J, Tibben A, van Asperen CJ, Schlegelberger B. Genetic testing for familial/hereditary breast cancer-comparison of guidelines and recommendations from the UK, France, the Netherlands and Germany. J Community Genet. 2011;2(2):53–69. doi: 10.1007/s12687-011-0042-4.
    1. Ropka ME, Wenzel J, Phillips EK, Siadaty M, Philbrick JT. Uptake rates for breast cancer genetic testing: a systematic review. Cancer Epidemiol Biomark Prev. 2006;15(5):840–855. doi: 10.1158/1055-9965.EPI-05-0002.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren