Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!

  • Hikmat Abdel-Razeq | habdel-razeq@khcc.jo Department of Internal Medicine, King Hussein Cancer Center, School of Medicine, University of Jordan, Amman, Jordan.


Since the identification of BRCA1 and BRCA2 genes 3 decades ago, genetic testing and genetic counseling have become an integral part of routine clinical practice. The risk of breast cancer among carriers of germline pathogenic variants, like BRCA1 and BRCA2, is well established. Risk-reducing interventions, including bilateral mastectomies and salpingo-oophorectomies are both effective and have become more acceptable. Many researchers and professional societies view current guidelines as restrictive and may miss many at-risk women, and are calling to expand testing to include all patients with breast cancer, regardless of their personal or family history of cancer, while others are calling for wider adoption to even include all healthy women at age 30 or older. This review will address expanding testing in two directions; horizontally to include more patients, and even healthy women, and vertically to include more genes using next-generation sequencing-based multi-gene panel testing.



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Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. DOI: https://doi.org/10.3322/caac.21492

Drohan B, Roche CA, Cusack JC Jr, Hughes KS. Hereditary breast and ovarian cancer and other hereditary syndromes: using technology to identify carriers. Ann Surg Oncol 2012;19:1732-7. DOI: https://doi.org/10.1245/s10434-012-2257-y

Pharoah PDP, Antoniou A, Bobrow M, et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 2002;31:33-6. DOI: https://doi.org/10.1038/ng853

Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990; 250:1684-9. DOI: https://doi.org/10.1126/science.2270482

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) [cited 2021 Dec 23]. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2021. Available from: https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf

National Collaborating Centre for Cancer (UK) [cited 2021 Jan 10]. Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People With a family History of Breast Cancer. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK247567/

Yadav S, Couch FJ. Germline genetic testing for breast cancer risk: The past, present, and future. Am Soc Clin Oncol Educ Book 2019;39:61-74. DOI: https://doi.org/10.1200/EDBK_238987

Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med 2014;174:275-80. DOI: https://doi.org/10.1001/jamainternmed.2013.12048

Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014; 32:2001-9. DOI: https://doi.org/10.1200/JCO.2013.53.6607

Maxwell KN, Domchek SM. Cancer treatment according to BRCA1 and BRCA2 mutations. Nat Rev Clin Oncol 2012;9:520-8. DOI: https://doi.org/10.1038/nrclinonc.2012.123

Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967-75. DOI: https://doi.org/10.1001/jama.2010.1237

Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2004;22:1055-62. DOI: https://doi.org/10.1200/JCO.2004.04.188

Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616-22. DOI: https://doi.org/10.1056/NEJMoa012158

Moyer VA, U.S. Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;160:271-81. DOI: https://doi.org/10.7326/M13-2747

The American Society of Breast Surgeons. Consensus Guideline on Genetic Testing for Hereditary Breast Cancer (2019) [cited 2020 Dec 23]. Available from: https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf

King M-C, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA 2014; 312:1091-2. DOI: https://doi.org/10.1001/jama.2014.12483

Robson M, Im S-A, Senkus E, et al. Abstract PD4-03: OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. In: Poster Spotlight Session Abstracts. American Association for Cancer Research; 2020. DOI: https://doi.org/10.1158/1538-7445.SABCS19-PD4-03

Robson ME, Tung N, Conte P, et al. OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol 2019;30:558-66. DOI: https://doi.org/10.1093/annonc/mdz012

Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med 2018;379:753-63. DOI: https://doi.org/10.1056/NEJMoa1802905

Tung NM, Robson ME, Ventz S, et al. TBCRC 048: Phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 2020;38:4274-82. DOI: https://doi.org/10.1200/JCO.20.02151

Levy-Lahad E, Lahad A, King M-C. Precision medicine meets public health: population screening for BRCA1 and BRCA2. J Natl Cancer Inst 2015;107:420. DOI: https://doi.org/10.1093/jnci/dju420

Childers CP, Childers KK, Maggard-Gibbons M, Macinko J. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol 2017;35:3800-6. DOI: https://doi.org/10.1200/JCO.2017.73.6314

Manchanda R, Blyuss O, Gaba F, et al. Current detection rates and time-to-detection of all identifiable BRCA carriers in the Greater London population. J Med Genet 2018;55:538-45. DOI: https://doi.org/10.1136/jmedgenet-2017-105195

Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: Are genetic testing guidelines a tool or an obstacle? J Clin Oncol 2019;37:453-60. DOI: https://doi.org/10.1200/JCO.18.01631

Manchanda R, Burnell M, Gaba F, et al. Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term outcomes. BJOG 2020;127:364-75. DOI: https://doi.org/10.1111/1471-0528.15905

Manchanda R, Loggenberg K, Sanderson S, et al. Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial. J Natl Cancer Inst 2015;107:379. DOI: https://doi.org/10.1093/jnci/dju379

Manchanda R, Legood R, Burnell M, et al. Cost-effectiveness of population screening for BRCA mutations in Ashkenazi jewish women compared with family history-based testing. J Natl Cancer Inst 2015;107:380. DOI: https://doi.org/10.1093/jnci/dju380

UK NSC Criteria for appraising the viability, effectiveness and appropriateness of a screening programme: UK National screening committee [cited 2021 Jan 10]. Available from: https://www.gov.uk/government/publications/evidence-review-criteria-nationalscreening-programmes/criteria-for-appraising-the-viability-effectiveness-and-appropriateness-of-a-screeningprogramme

Khoury MJ, McCabe LL, McCabe ERB. Population screening in the age of genomic medicine. N Engl J Med 2003;348:50-8. DOI: https://doi.org/10.1056/NEJMra013182

Akbari MR, Gojska N, Narod SA. Coming of age in Canada: a study of population-based genetic testing for breast and ovarian cancer. Curr Oncol 2017;24:282-3. DOI: https://doi.org/10.3747/co.24.3828

Evans O, Gaba F, Manchanda R. Population-based genetic testing for Women’s cancer prevention. Best Pract Res Clin Obstet Gynaecol 2020;65:139-53. DOI: https://doi.org/10.1016/j.bpobgyn.2020.02.007

Parker WH, Feskanich D, Broder MS, et al. Long-term mortality associated with oophorectomy compared with ovarian conservation in the nurses’ health study. Obstet Gynecol Surv 2013;68:561-3. DOI: https://doi.org/10.1097/01.ogx.0000433842.26579.00

Wentzensen N, Wacholder S. From differences in means between cases and controls to risk stratification: A business plan for biomarker development. Cancer Discov 2013;3:148-57. DOI: https://doi.org/10.1158/2159-8290.CD-12-0196

LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2000 patients. Genet Med 2014;16:830-7. DOI: https://doi.org/10.1038/gim.2014.40

Maxwell KN, Wubbenhorst B, D’Andrea K, et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med 2015;17:630-8. DOI: https://doi.org/10.1038/gim.2014.176

Lincoln SE, Kobayashi Y, Anderson MJ, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn 2015;17:533-44. DOI: https://doi.org/10.1016/j.jmoldx.2015.04.009

O’Leary E, Iacoboni D, Holle J, et al. Expanded gene panel use for women with breast cancer: Identification and intervention beyond breast cancer risk. Ann Surg Oncol 2017;24:3060-6. DOI: https://doi.org/10.1245/s10434-017-5963-7

Manchanda R, Sun L, Patel S, et al. Economic evaluation of population-based BRCA1/BRCA2 mutation testing across multiple countries and health systems. Cancers (Basel) 2020;12:1929. DOI: https://doi.org/10.3390/cancers12071929

Sun L, Brentnall A, Patel S, et al. A Cost-effectiveness analysis of multigene testing for all patients with breast cancer. JAMA Oncol 2019;5:1718-30. DOI: https://doi.org/10.1001/jamaoncol.2019.3323

Manchanda R, Patel S, Gordeev VS, et al. Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women. J Natl Cancer Inst 2018;110:714-25. DOI: https://doi.org/10.1093/jnci/djx265

Abdel-Razeq H, Abujamous L, Jadaan D. Patterns and prevalence of germline BRCA1 and BRCA2 mutations among high-risk breast cancer patients in Jordan: A study of 500 patients. J Oncol 2020;2020:8362179. DOI: https://doi.org/10.1155/2020/8362179

Yurgelun MB, Hiller E, Garber JE. Population-wide screening for germline BRCA1 and BRCA2 mutations: too much of a good thing? J Clin Oncol 2015;33:3092e5. DOI: https://doi.org/10.1200/JCO.2015.60.8596

Hall MJ, Olopade OI. Disparities in genetic testing: thinking outside the BRCA box. J Clin Oncol 2006;24:2197-203. DOI: https://doi.org/10.1200/JCO.2006.05.5889

Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol 2020;30:e206252.

Cragun D, Kinney AY, Pal T. Care delivery considerations for widespread and equitable implementation of inherited cancer predisposition testing. Expert Rev Mol Diagn 2017;17:57-70. DOI: https://doi.org/10.1080/14737159.2017.1267567

Landsbergen K, Verhaak C, Kraaimaat F, Hoogerbrugge N. Genetic uptake in BRCA-mutationfamilies is related to emotional and behavioral communication characteristics of index patients. Fam Cancer 2005;4:115-9. DOI: https://doi.org/10.1007/s10689-004-7991-2

Finlay E, Stopfer JE, Burlingame E, et al. Factors determining dissemination of results and uptake of genetic testing in families with known BRCA1/2 mutations. Genet Test 2008;12:81-91. DOI: https://doi.org/10.1089/gte.2007.0037

Chopra I, Kelly KM. Cancer risk information sharing: The experience of individuals receiving genetic counseling for BRCA1/2 mutations. J Health Commun 2017;22:143-52. DOI: https://doi.org/10.1080/10810730.2016.1258743

Elrick A, Ashida S, Ivanovich J, et al. Psychosocial and clinical factors associated with family communication of cancer genetic test results among women diagnosed with breast cancer at a young age. J Genet Couns 2017;26:173-81. DOI: https://doi.org/10.1007/s10897-016-9995-0

Lipton JH, Zargar M, Warner E, et al. Cost effectiveness of in vitro fertilisation and preimplantation genetic testing to prevent transmission of BRCA1/2 mutations. Hum Reprod 2020;35:434-45. DOI: https://doi.org/10.1093/humrep/dez203

Vuković P, Peccatori FA, Massarotti C, et al. Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants. Crit Rev Oncol Hematol 2021;157:103201. DOI: https://doi.org/10.1016/j.critrevonc.2020.103201

Derks-Smeets IAP, Gietel-Habets JJG, Tibben A, et al. Decision-making on preimplantation genetic diagnosis and prenatal diagnosis: a challenge for couples with hereditary breast and ovarian cancer. Hum Reprod 2014;29:1103-12. DOI: https://doi.org/10.1093/humrep/deu034

Breast cancer, hereditary breast cancer, BRCA, next-generation sequencing.
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How to Cite
Abdel-Razeq, H. (2021). Expanding the search for germline pathogenic variants for breast cancer. How far should we go and how high should we jump? The missed opportunity!. Oncology Reviews, 15(1). https://doi.org/10.4081/oncol.2021.544