Germline BRCA testing in Denmark following invasive breast cancer: Progress since 2000
DOI:
https://doi.org/10.2340/1651-226X.2025.42418Keywords:
Genetic testing, hereditary breast cancer, pathogenic germline variants, Danish Breast Cancer GroupAbstract
Background and purpose: Despite advancements in genetic testing and expanded eligibility criteria, underutilisation of germline testing for pathogenic variants in BRCA1 and BRCA2 (BRCA) remains evident among breast cancer (BC) patients. This observational cohort study presents real-world data on BRCA testing within the context of clinical practice challenges, including incomplete family history and under-referral.
Material and methods: From the Danish Breast Cancer Group (DBCG) clinical database, we included 65,117 females with unilateral stage I–III BC diagnosed in 2000–2017, of whom 9,125 (14%) were BRCA tested. Test results spanned from 1999 to 2021. We evaluated test rates overall and in three diagnosis periods. In logistic regression models, we examined the correlation between a BRCA test and patients’ age, residency region, receptor status, and diagnosis period.
Results: Test rates rose most significantly among patients aged under 40 years, increasing from 47% (2000–2005) to 88% (2012–2017), albeit with regional discrepancies. Test timing shifted in recent years, with most results within 6 months of BC diagnosis, primarily among the youngest patients. BRCA test rates were higher for oestrogen receptor-negative/human epidermal growth factor receptor 2-negative BC (25% in 2000–2005 vs. 38% in 2012–2017), and these findings were confirmed in multivariate regression models.
Interpretation: Our results indicate a critical need for an intensified focus on BRCA testing among BC patients older than 40, where a mainstreamed testing approach might overcome delayed or missed testing. Current DBCG guidelines recommend BRCA testing of all BC patients younger than 50 years, while a general recommendation for older patients is still missing.
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References
Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer. 2018;119(2):141–52.
https://doi.org/10.1038/s41416-018-0127-5 DOI: https://doi.org/10.1038/s41416-018-0127-5
Breast Cancer Risk Genes – Association analysis in more than 113,000 women. N Engl J Med. Massachusetts Medical Society; 2021;384(5):428–39.
https://doi.org/10.1056/NEJMoa1913948 DOI: https://doi.org/10.1056/NEJMoa1913948
Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440–51.
https://doi.org/10.1056/NEJMoa2005936 DOI: https://doi.org/10.1056/NEJMoa2005936
Marmolejo DH, Wong MYZ, Bajalica-Lagercrantz S, Tischkowitz M, Balmaña J, Patócs AB, et al. Overview of hereditary breast and ovarian cancer (HBOC) guide-lines across Europe. Eur J Med Genet. 2021;64(12):104350.
https://doi.org/10.1016/j.ejmg.2021.104350 DOI: https://doi.org/10.1016/j.ejmg.2021.104350
Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips K-A, Mooij TM, Roos-Blom M-J, et al. Risks of breast, ovarian, and contralateral breast cancer for brca1 and brca2 mutation carriers. JAMA. 2017;317(23):2402–16.
https://doi.org/10.1001/jama.2017.7112 DOI: https://doi.org/10.1001/jama.2017.7112
Metcalfe KA, Eisen A, Poll A, Candib A, McCready D, Cil T, et al. Frequency of Contralateral prophylactic mastectomy in breast cancer patients with a negative BRCA1 and BRCA2 rapid genetic test result. Ann Surg Oncol. 2021;28(9):4967–73.
https://doi.org/10.1245/s10434-021-09855-6 DOI: https://doi.org/10.1245/s10434-021-09855-6
DMCG.dk [Internet]. DBCG guidelines for Hereditary Breast Cancer, Dec 2022. Available from: https://www.dmcg.dk/siteassets/kliniske-retningslinjer---skabeloner-og-vejledninger/kliniske-retningslinjer-opdelt-pa-dmcg/dbcg/dbcg_arvelig-cancer-mamma_v.2.0_admgodk_02012023.pdf
Bedrosian I, Somerfield MR, Achatz MI, Boughey JC, Curigliano G, Friedman S, et al. Germline testing in patients with breast cancer: ASCO–Society of Surgical Oncology Guideline. J Clin Oncol. 2024;42(5):584–604.
https://doi.org/10.1200/JCO.23.02225 DOI: https://doi.org/10.1200/JCO.23.02225
Loibl S, André F, Bachelot T, Barrios CH, Bergh J, Burstein HJ, et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up☆. Ann Oncol. 2024;35(2):159–82.
https://doi.org/10.1016/j.annonc.2023.11.016 DOI: https://doi.org/10.1016/j.annonc.2023.11.016
Curigliano G, Burstein HJ, Gnant M, Loibl S, Cameron D, Regan MM, et al. Understanding breast cancer complexity to improve patient outcomes: The St Gallen International Consensus Conference for the Primary Therapy of Individuals with Early Breast Cancer 2023. Ann Oncol. 2023;34(11):970–86. DOI: https://doi.org/10.1016/j.annonc.2024.11.001
https://doi.org/10.1016/j.annonc.2023.08.017 DOI: https://doi.org/10.1016/j.annonc.2023.08.017
Grindedal EM, Jørgensen K, Olsson P, Gravdehaug B, Lurås H, Schlichting E, et al. Mainstreamed genetic testing of breast cancer patients in two hospitals in South Eastern Norway. Fam Cancer. 2020;19(2):133–42.
https://doi.org/10.1007/s10689-020-00160-x DOI: https://doi.org/10.1007/s10689-020-00160-x
Grindedal EM, Heramb C, Karsrud I, Ariansen SL, Mæhle L, Undlien DE, et al. Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. BMC Cancer. 2017;17(1):438.
https://doi.org/10.1186/s12885-017-3422-2 DOI: https://doi.org/10.1186/s12885-017-3422-2
Beitsch PD, Whitworth PW, Hughes K, Patel R, Rosen B, Compagnoni G, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37(6):453–60.
https://doi.org/10.1200/JCO.18.01631 DOI: https://doi.org/10.1200/JCO.18.01631
Meshkani Z, Aboutorabi A, Moradi N, Langarizadeh M, Motlagh AG. Population or family history based BRCA gene tests of breast cancer? A systematic review of economic evaluations. Hered Cancer Clin Pract. 2021;19(1):35.
https://doi.org/10.1186/s13053-021-00191-0 DOI: https://doi.org/10.1186/s13053-021-00191-0
Rajagopal PS, Catenacci DVT, Olopade OI. The time for mainstreaming germline testing for patients with breast cancer is now. J Clin Oncol. 2019;37(24):2177–8.
https://doi.org/10.1200/JCO.19.00160 DOI: https://doi.org/10.1200/JCO.19.00160
Nilsson MP, Winter C, Kristoffersson U, Rehn M, Larsson C, Saal LH, et al. Efficacy versus effectiveness of clinical genetic testing criteria for BRCA1 and BRCA2 hereditary mutations in incident breast cancer. Fam Cancer. 2017;16(2):187–93.
https://doi.org/10.1007/s10689-016-9953-x DOI: https://doi.org/10.1007/s10689-016-9953-x
Li J, Wen WX, Eklund M, Kvist A, Eriksson M, Christensen HN, et al. Prevalence of BRCA1 and BRCA2 pathogenic variants in a large, unselected breast cancer cohort. Int J Cancer. 2019;144(5):1195–204.
https://doi.org/10.1002/ijc.31841 DOI: https://doi.org/10.1002/ijc.31841
Kurian AW, Ward KC, Abrahamse P, Bondarenko I, Hamilton AS, Deapen D, et al. Time trends in receipt of germline genetic testing and results for women diag-nosed with breast cancer or ovarian cancer, 2012-2019. J Clin Oncol Off J Am Soc Clin Oncol. 2021;39(15):1631–40.
https://doi.org/10.1200/JCO.20.02785 DOI: https://doi.org/10.1200/JCO.20.02785
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(34):3800–6.
https://doi.org/10.1200/JCO.2017.73.6314 DOI: https://doi.org/10.1200/JCO.2017.73.6314
Christiansen P, Ejlertsen B, Jensen M-B, Mouridsen H. Danish Breast Cancer Cooperative Group. Clin Epidemiol. 2016;8:445–9.
https://doi.org/10.2147/CLEP.S99457 DOI: https://doi.org/10.2147/CLEP.S99457
Bjerregaard B, Larsen OB. The Danish Pathology Register. Scand J Public Health. 2011;39(7_suppl):72–4.
https://doi.org/10.1177/1403494810393563 DOI: https://doi.org/10.1177/1403494810393563
Schmidt M, Schmidt SAJ, Sandegaard JL, Ehrenstein V, Pedersen L, Sørensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–90.
https://doi.org/10.2147/CLEP.S91125 DOI: https://doi.org/10.2147/CLEP.S91125
Gjerstorff ML. The Danish Cancer Registry. Scand J Public Health. 2011;39(7 Suppl):42–5.
https://doi.org/10.1177/1403494810393562 DOI: https://doi.org/10.1177/1403494810393562
Cuschieri S. The STROBE guidelines. Saudi J Anaesth. 2019;13(Suppl 1):S31–4.
https://doi.org/10.4103/sja.SJA_543_18 DOI: https://doi.org/10.4103/sja.SJA_543_18
Pedersen IS, Schmidt AY, Bertelsen B, Ernst A, Andersen CLT, Kruse T, et al. A Danish national effort of BRCA1/2 variant classification. Acta Oncol. 2018;57(1):159–62.
https://doi.org/10.1080/0284186X.2017.1400693 DOI: https://doi.org/10.1080/0284186X.2017.1400693
Laugesen K, Ludvigsson JF, Schmidt M, Gissler M, Valdimarsdottir UA, Lunde A, et al. Nordic Health Registry-based research: a review of health care systems and key registries. Clin Epidemiol. 2021;13:533–54.
https://doi.org/10.2147/CLEP.S314959 DOI: https://doi.org/10.2147/CLEP.S314959
Hooker GW, Clemens KR, Quillin J, Vogel Postula KJ, Summerour P, Nagy R, et al. Cancer genetic counseling and testing in an era of rapid change. J Genet Couns. 2017;26(6):1244–53.
https://doi.org/10.1007/s10897-017-0099-2 DOI: https://doi.org/10.1007/s10897-017-0099-2
Gronwald J, Cybulski C, Huzarski T, Jakubowska A, Debniak T, Lener M, et al. Genetic testing for hereditary breast cancer in Poland: 1998–2022. Hered Cancer Clin Pract. 2023;21:9.
https://doi.org/10.1186/s13053-023-00252-6 DOI: https://doi.org/10.1186/s13053-023-00252-6
Thomassen M, Hansen TVO, Borg Å, Theilmann Lianee H, Wikman F, Søkilde Pedersen I, et al. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. Acta Oncol. 2008;47(4):772–7.
https://doi.org/10.1080/02841860802004974 DOI: https://doi.org/10.1080/02841860802004974
DBCG.dk [Internet]. DBCG guidelines for Hereditary Breast Cancer, Sept 2016. Available from: https://dbcg.dk/PDF%20Filer/Kapitel_19_HBOC_23.09.2016.pdf
Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev. 2012;21(1):134–47. DOI: https://doi.org/10.1016/j.yobg.2012.05.049
https://doi.org/10.1158/1055-9965.EPI-11-0775 DOI: https://doi.org/10.1158/1055-9965.EPI-11-0775
Tomasello G, Gambini D, Petrelli F, Azzollini J, Arcanà C, Ghidini M, et al. Characterization of the HER2 status in BRCA-mutated breast cancer: a single institu-tional series and systematic review with pooled analysis. ESMO Open. 2022;7(4):100531.
https://doi.org/10.1016/j.esmoop.2022.100531 DOI: https://doi.org/10.1016/j.esmoop.2022.100531
Viansone A, Pellegrino B, Omarini C, Pistelli M, Boggiani D, Sikokis A, et al. Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer. Breast. 2022;65:145–50.
https://doi.org/10.1016/j.breast.2022.07.012 DOI: https://doi.org/10.1016/j.breast.2022.07.012
Geyer CE, Garber JE, Gelber RD, Yothers G, Taboada M, Ross L, et al. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022;33(12):1250–68.
https://doi.org/10.1016/j.annonc.2022.09.159 DOI: https://doi.org/10.1016/j.annonc.2022.09.159
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Copyright (c) 2025 Aleksandar M. Kostov, Maj-Britt Jensen, Bent Ejlertsen, Mads Thomassen, Maria Rossing, Inge S. Pedersen, Annabeth H. Petersen, Lise Lotte Christensen, Karin A.W. Wadt, Anne-Vibeke Lænkholm
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