The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers.
We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression.
About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26–0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07–3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26–4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11–3.59, P = 0.02).
The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
Subscribe to Journal
Get full journal access for 1 year
only $20.79 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jonasson, J. G., Stefansson, O. A., Johannsson, O. T., Sigurdsson, H., Agnarsson, B. A., Olafsdottir, G. H. et al. Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers. Br. J. Cancer 115, 776–783 (2016).
IMH, Soenderstrup, Laenkholm, A. V., Jensen, M. B., Eriksen, J. O., Gerdes, A. M., TVO, Hansen et al. Clinical and molecular characterization of BRCA-associated breast cancer: results from the DBCG. Acta Oncol. 57, 95–101 (2018).
Evans, D. G., Harkness, E. F., Howell, A., Wilson, M., Hurley, E., Holmen, M. M. et al. Intensive breast screening in BRCA2 mutation carriers is associated with reduced breast cancer specific and all cause mortality. Hered. Cancer Clin. Pract. 14, 8–15 (2016).
Nilsson, M. P., Hartman, L., Idvall, I., Kristoffersson, U., Johannsson, O. T. & Loman, N. Long-term prognosis of early-onset breast cancer in a population-based cohort with a known BRCA1/2 mutation status. Breast Cancer Res. Treat. 144, 133–142 (2014).
Nilsson, M. P., Hartman, L., Kristoffersson, U., Johannsson, O. T., Borg, A., Henriksson, K. et al. High risk of in-breast tumor recurrence after BRCA1/2-associated breast cancer. Breast Cancer Res. Treat. 147, 571–578 (2014).
Winter, C., Nilsson, M. P., Olsson, E., George, A. M., Chen, Y., Kvist, A. et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann. Oncol. 27, 1532–1538 (2016).
Nilsson, M. P., Törngren, T., Henriksson, K., Kristoffersson, U., Kvist, A., Silfverberg, B. et al. BRCAsearch: written pre-test information and BRCA1/2 germline mutation testing in unselected patients with newly diagnosed breast cancer. Breast Cancer Res. Treat. 168, 17–126 (2018).
Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L. et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313, 1347–1361 (2015).
Royston P. “PTREND: Stata module for trend analysis for proportions”, Statistical Software Components S426101, (Boston College Department of Economics, 2014).
Coviello, V. & Boggess, M. Cumulative incidence estimation in the presence of competing risks. Stata J. 4, 103–112 (2004).
Lambert, P. C. & Royston, P. Further development of flexible parametric models for survival analysis. Stata J. 9, 265–290 (2009).
BAM, Heemskerk-Gerritsen., Seynaeve, C., van Asperen, C. J., MGEM, Ausems., Collée, J. M. & van Doorn, H. C. et al. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J. Natl Cancer Inst. 107, 1–9 (2015).
Bentzon, N., Düring, M., Rasmussen, B. B., Mouridsen, H. & Kroman, N. Prognostic effect of estrogen receptor status across age in primary breast cancer. Int. J. Cancer 122, 1089–1094 (2008).
Foulkes, W. D., Metcalfe, K., Sun, P., Hanna, W. M., Lynch, H. T., Ghadirian, P. et al. Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin. Cancer Res. 10, 2029–2034 (2004).
Hahnen, E., Lederer, B., Hauke, J., Loibl, S., Kröber, S., Schneeweiss, A. et al. Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol. 3, 1378–1385 (2017).
Azzato, E. M., Greenberg, D., Shah, M., Blows, F., Driver, K. E., Caporaso, N. E. et al. Prevalent cases in observational studies of cancer survival: do they bias hazard ratio estimates? BJC 100, 1806–1811 (2009).
Schmidt M. K., van den Broek A. J., Tollenaar R. A., Smit VTH, Westenend P. J., Brinkhuis M., et al. Breast cancer survival of BRCA1/BRCA2 mutation carriers in a hospital-based cohort of young women. J. Natl Cancer Inst. 109, 1–10 (2017).
Copson, E. R., Maishman, T. C., Tapper, W. J., Cutress, R. I., Greville-Heygate, S., Altman, D. G. et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 19, 169–180 (2018).
Metcalfe, K., Lynch, H. T., Foulkes, W. D., Tung, N., Olopade, O. I., Eisen, A. et al. Oestrogen receptor status and survival in women with BRCA2-associated breast cancer. BJC 120, 398–403 (2019).
Vocka, M., Zimovjanova, M., Bielcikova, Z., Tesarova, P., Petruzelka, L., Mateju, M. et al. Estrogen receptor status oppositely modifies breast cancer prognosis in BRCA1/BRCA2 mutation carriers versus non-carriers. Cancers (Basel). 11, 738 (2019).
Liu, Y.-R., Jiang, Y.-Z., Yu, K.-D. & Shao, Z.-M. Different patterns in the prognostic value of age for breast cancer-specific mortality depending on hormone receptor status: a SEER population-based analysis. Ann. Surg. Oncol. 22, 1102–1110 (2015).
Sopik, V., Sun, P. & Narod, S. A. The prognostic effect of estrogen receptor status differs for younger versus older breast cancer patients. Breast Cancer Res. Treat. 165, 391–402 (2017).
Johansson, A. L. V., Trewin, C. B., Hjerkind, K. V., Ellingjord-Dale, M., Johannesen, T. B. & Ursin, G. Breast cancer-specific survival by clinical subtype after 7 years follow-up of young and elderly women in a nationwide cohort. Int. J. Cancer 144, 1251–1261 (2019).
Tryggvadottir, L., Olafsdottir, E. J., Olafsdottir, G. H., Sigurdsson, H., Johannsson, O. T., Bjorgvinsson, E. et al. Tumour diploidy and survival in breast cancer patients with BRCA2 mutations. Breast Cancer Res. Treat. 140, 375–384 (2013).
Rakha, E. A., Reis-Filho, J. S., Baehner, F., Dabbs, D. J., Decker, T., Eusebi, V. et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 12, 207–218 (2010).
Sotiriou, C., Wirapati, P., Loi, S., Harris, A., Fox, S. Smeds, J. et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J. Natl Cancer Inst. 98, 262–272 (2006).
Maxwell, K. N., Wubbenhorst, B., Wenz, B. M., De Sloover, D., Pluta, J., Emery, L. et al. BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nat. Commun. 8, 319 (2017).
We thank the Nordic women who participated in the studies. All colleagues are thanked for their contribution of BRCA2 data.
Ethics approval and consent to participate
The study was approved by The Danish Data Protection Agency (2009-41-3611) and the Danish Ethical Committee (registration number 33483), The National Bioethics Committee of Iceland (VSN-13-133-V5), The Norwegian Data Inspectorate (ref. 2001/2988-2) and Ethical Review Board (ref. S-02030) and (ref. 2015/2382) and The Regional Ethical Review Board in Lund. All Norwegian and Swedish patients consented to the study. The Danish Ethical Committee gave a waiver concerning consent to this study, and genetic testing is part of routine diagnostics in Denmark. In Iceland, genetic testing for the majority of patients (historical cohort) was done using paraffin- embedded tumour specimens from pathology archives, based on permission from the National Bioethics Committee of Iceland. The remaining Icelandic patients consented to the study.
Consent to publish
Our paper does not contain any individual person’s data in any form.
The datasets generated and/or analysed during the current study are not publicly available, due to protection of the privacy of BRCA2 mutation carrier patients, but are available from the corresponding author on reasonable request.
Steven A. Narod is an Editorial board member to British Journal of Cancer.
The study was funded by the Nordic Cancer Union and the Icelandic Cancer Society. S.A.N. is supported by the Peter Gilgan Centre for Cancer in Women.
Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Olafsdottir, E.J., Borg, A., Jensen, MB. et al. Breast cancer survival in Nordic BRCA2 mutation carriers—unconventional association with oestrogen receptor status. Br J Cancer 123, 1608–1615 (2020). https://doi.org/10.1038/s41416-020-01056-4