Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study
Delal Akdeniz,
Mark van Barele,
Bernadette A.M. Heemskerk-Gerritsen,
Ewout W. Steyerberg,
Michael Hauptmann,
Irma van de Beek,
Klaartje van Engelen,
Marijke R. Wevers,
Encarnacion B. Gómez García,
Margreet G.E.M. Ausems,
Lieke P.V. Berger,
Christi J. van Asperen,
Muriel A. Adank,
Margriet J. Collée,
Denise J. Stommel-Jenner,
Agnes Jager,
Marjanka K. Schmidt,
Maartje J. Hooning
Affiliations
Delal Akdeniz
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Mark van Barele
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Bernadette A.M. Heemskerk-Gerritsen
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Ewout W. Steyerberg
Department of Public Health, Erasmus MC, Rotterdam, the Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands
Michael Hauptmann
Institute of Biostatistics and Registry Research, Brandenburg Medical School Theodor Fontane, Neuroppin, Germany
Irma van de Beek
Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Klaartje van Engelen
Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Marijke R. Wevers
Department for Clinical Genetics, Radboud University Medical Centre, Nijmegen, Netherlands
Encarnacion B. Gómez García
Department of Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
Margreet G.E.M. Ausems
Division of Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, Netherlands
Lieke P.V. Berger
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
Christi J. van Asperen
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands
Muriel A. Adank
Family Cancer Clinic, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
Margriet J. Collée
Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, the Netherlands
Denise J. Stommel-Jenner
Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands
Agnes Jager
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
Marjanka K. Schmidt
Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
Maartje J. Hooning
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Corresponding author. Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 5201, 3008, AE, Rotterdam, the Netherlands.
Aim: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methods: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. Results: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). Conclusion: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.
