REVIEW OF BRCA1 AND BRCA2 MUTATION SCREENING STRATEGIES FOR REDUCING CANCER BURDEN IN HIGH-RISK FAMILIES
Keywords:
BRCA1, BRCA2, Genetic Testing, Hereditary Breast and Ovarian Cancer Syndrome, Cancer Prevention, High-Risk FamiliesAbstract
Background: Pathogenic variants in the BRCA1 and BRCA2 genes significantly elevate the lifetime risk of breast, ovarian, and other cancers, creating a substantial burden for high-risk families. Identifying carriers is paramount for implementing evidence-based risk-reduction strategies, yet the optimal approach to population screening remains a subject of refinement. This narrative review synthesizes the current landscape of BRCA screening methodologies and their impact on cancer outcomes.
Objective: This review aims to summarize and critically evaluate existing literature on various BRCA1 and BRCA2 mutation screening strategies, with a focus on their effectiveness in identifying carriers in high-risk families and their subsequent role in reducing familial cancer incidence.
Main Discussion Points: The discussion is structured around key thematic developments. It begins with the established model of family history-based screening and clinical prediction tools, acknowledging their utility and significant limitations. The review then explores the shift towards broader paradigms, including the mainstreaming of genetic testing into oncology care and the emerging evidence for population-based screening in specific founder populations. A critical analysis is presented on how a positive genetic test result translates into clinical action, encompassing risk-reducing surgeries and targeted therapies, and ultimately impacts cancer burden. The synthesis also addresses unresolved challenges, such as variants of uncertain significance and disparities in access to genetic services.
Conclusion: The evidence supports a move beyond reliance on family history alone towards more inclusive and proactive screening models to identify a greater proportion of BRCA carriers. While the clinical utility of genetic testing is well-established for guiding risk management and therapy, future efforts must focus on improving the implementation, accessibility, and equity of these strategies to maximize their public health benefit in diverse populations.
References
1. Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017 Jun 20;317(23):2402–16.
2. Nelson HD, Pappas M, Cantor A, Haney E, Holmes R. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: updated evidence report and systematic review for the US Preventive Services Task Force. Jama. 2019 Aug 20;322(7):666-85.
3. Manickam K, Buchanan AH, Schwartz MLB, Hallquist MLG, Williams JL, Rahm AK, et al. Exome Sequencing-Based Screening for BRCA1/2 Expected Pathogenic Variants Among Adult Biobank Participants. JAMA Netw Open. 2018 Sep 7;1(5):e182140.
4. 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 Sep 1;304(9):967–75.
5. Heemskerk-Gerritsen BAM, Seynaeve C, van Asperen CJ, Ausems MGEM, Collee JM, van Doorn HC, et al. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015 Jun 18;107(5).
6. Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun 24;384(25):2394–405.
7. Sun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, et al. A cost-effectiveness analysis of multigene testing for all patients with breast cancer. JAMA Oncol. 2019 Dec 1;5(12):1718–30.
8. Metcalfe KA, Poll A, Royer R, Llacuachaqui M, Tulman A, Sun P, Narod SA. Screening for founder mutations in BRCA1 and BRCA2 in unselected Jewish women. Journal of Clinical Oncology. 2010 Jan 20;28(3):387-91.
9. Kurian AW, Ward KC, Howlader N, Deapen D, Hamilton AS, Mariotto A, et al. Genetic Testing and Results in a Population-Based Cohort of Breast Cancer Patients and Ovarian Cancer Patients. J Clin Oncol. 2019 May 1;37(15):1305–15.
10. Miller RE, Leary A, Scott CL, Serra V, Lord CJ, Bowtell D, et al. ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. Ann Oncol. 2020 Dec;31(12):1606–22.
11. Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021 Jan 6;19(1):77–102.
12. Lee K, Seifert BA, Shimelis H, Ghosh R, Crowley SB, Couch FJ, et al. Clinical validity assessment of genes for BRCA-associated breast and ovarian cancer: A systematic review. J Clin Oncol. 2021 May 20;39(15_suppl):10520.
13. Kentwell M, Dow E, Antill Y, Wrede CD, McNally O, Higgs E, et al. Mainstreaming cancer genetics: A model integrating germline BRCA testing into routine ovarian cancer clinics. Gynecol Oncol. 2017 Apr;145(1):130–6.
14. George A, Riddell D, Seal S, Talukdar S, Mahamdallie S, Ruark E, et al. Implementing rapid, robust, cost-effective, patient-centred, routine genetic testing in ovarian cancer patients. Sci Rep. 2016 Jul 22;6:29506.
15. Heemskerk-Gerritsen BAM, Seynaeve C, van Asperen CJ, Ausems MGEM, Collee JM, van Doorn HC, et al. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst. 2015 Jun 18;107(5).
16. Rizvi Z, Sharma KC, Kunder V, Abreu A, Abreu AJ. Barriers of care to ovarian cancer: a scoping review. Cureus. 2023 Jun 12;15(6).
17. 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 Dec 1;35(34):3800-3806.
18. Roberts MC, Dotson WD, DeVore CS, Bednar EM, Bowen DJ, Ganiats TG, et al. Delivery Of Cascade Screening For Hereditary Conditions: A Scoping Review Of The Literature. Health Aff (Millwood). 2018 May;37(5):801-808.
19. Hauke J, Horvath J, Groß E, Gehrig A, Honisch E, Hackmann K, et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med. 2018 May;7(5):1349-1358.
20. Xu C, Zhuang J, Shen J, Sun H, Cai J, Wei X. Cost-utility analysis of olaparib assisted targeted therapy for BRCA mutation HER2-negative early breast cancer in China and in the United States. Cost Effectiveness and Resource Allocation. 2025 Apr 13;23(1):16.
21. Roberts MC, Mensah GA, Khoury MJ. Leveraging implementation science to address health disparities in genomic medicine: examples from the field. Ethnicity & disease. 2019 Feb 21;29(Suppl 1):187.
22. Manchanda R, Burnell M, Gaba F, Desai R, Wardle J, Gessler S, Side L, Sanderson S, Loggenberg K, Brady AF, Dorkins H. Randomised trial of population‐based BRCA testing in Ashkenazi Jews: long‐term outcomes. BJOG: An International Journal of Obstetrics & Gynaecology. 2020 Feb;127(3):364-75.
23. Blazer KR, Christie C, Uman G, Weitzel JN. Impact of web-based case conferencing on cancer genetics training outcomes for community-based clinicians. Journal of Cancer Education. 2012 Jun;27(2):217-25.
24. Flaum N, Morgan RD, Burghel GJ, Bulman M, Clamp AR, Hasan J, Mitchell CL, Badea D, Moon S, Hogg M, Hadjiyiannakis D. Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England. European Journal of Human Genetics. 2020 Nov;28(11):1541-7.
