Marjanka K Schmidt1,2, Alexandra J van den Broek1,2, Rob A E M Tollenaar3, Vincent T H B M Smit4, Pieter J Westenend5, Mariël Brinkhuis6, Wolter J W Oosterhuis7, Jelle Wesseling2,8, Maryska L Janssen-Heijnen9,10, Jan J Jobsen11, Agnes Jager12, Adri C Voogd9,13, Flora E van Leeuwen1, Laura J van 't Veer2. 1. Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Amsterdam, The Netherlands. 2. Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Amsterdam, The Netherlands. 3. Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands. 4. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 5. Laboratory for Pathology, Dordrecht, The Netherlands. 6. Laboratory for Pathology East-Netherlands, Hengelo, The Netherlands. 7. Department of Pathology (Josephine Nefkens Institute), Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 8. Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Amsterdam, The Netherlands. 9. Department of Research, Netherlands Comprehensive Cancer Organization, Utrecht, The Netherlands. 10. Department of Clinical Epidemiology, VieCuri Medical Centre, Venlo, The Netherlands. 11. Department of Radiotherapy, Medisch Spectrum Twente, Enschede, The Netherlands. 12. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 13. Department of Epidemiology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Abstract
Background: The primary aim of the study was to investigate prognosis and long-term survival in young breast cancer patients with a BRCA1 or BRCA2 germline mutation compared with noncarriers. The secondary aim was to investigate whether differences in survival originate from associations with tumor characteristics, second cancers, and/or treatment response. Methods: We established a cohort of invasive breast cancer patients diagnosed younger than age 50 years in 10 Dutch hospitals between 1970 and 2003. BRCA1/2 testing of most prevalent mutations was mainly done using DNA isolate from formalin-fixed paraffin-embedded nontumor tissue. Survival estimates were derived using Cox regression and competing risk models. Results: In 6478 breast cancer patients, we identified 3.2% BRCA1 and 1.2% BRCA2 mutation carriers. BRCA1 mutation carriers had a worse overall survival independent of clinico-pathological/treatment characteristics, compared with noncarriers (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 0.97 to 1.47), though only statistically significant in the first five years of follow-up (adjusted HR = 1.40, 95% CI = 1.07 to 1.84). A large part of the worse survival was explained by incidence of ovarian cancers. Breast cancer-specific, disease-free, and metastasis-free survival results were less pronounced and mostly statistically nonsignificant but in the same direction with those of overall survival. Overall survival was worse, although not statistically significantly, within the ER-negative or ER-positive, grade 3, and small tumor subgroups. The worse survival was most pronounced in non-chemotherapy-treated patients (adjusted HR = 1.54, 95% CI = 1.08 to 2.19). Power for BRCA2 mutation carriers was limited; only after five years' follow-up overall survival was worse (adjusted HR = 1.47, 95% CI = 1.00 to 2.17). Conclusions: BRCA1/2 mutation carriers diagnosed with breast cancer before age 50 years are prone to a worse survival, which is partly explained by differences in tumor characteristics, treatment response, and second ovarian cancers.
Background: The primary aim of the study was to investigate prognosis and long-term survival in young breast cancerpatients with a BRCA1 or BRCA2 germline mutation compared with noncarriers. The secondary aim was to investigate whether differences in survival originate from associations with tumor characteristics, second cancers, and/or treatment response. Methods: We established a cohort of invasive breast cancerpatients diagnosed younger than age 50 years in 10 Dutch hospitals between 1970 and 2003. BRCA1/2 testing of most prevalent mutations was mainly done using DNA isolate from formalin-fixed paraffin-embedded nontumor tissue. Survival estimates were derived using Cox regression and competing risk models. Results: In 6478 breast cancerpatients, we identified 3.2% BRCA1 and 1.2% BRCA2 mutation carriers. BRCA1 mutation carriers had a worse overall survival independent of clinico-pathological/treatment characteristics, compared with noncarriers (adjusted hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 0.97 to 1.47), though only statistically significant in the first five years of follow-up (adjusted HR = 1.40, 95% CI = 1.07 to 1.84). A large part of the worse survival was explained by incidence of ovarian cancers. Breast cancer-specific, disease-free, and metastasis-free survival results were less pronounced and mostly statistically nonsignificant but in the same direction with those of overall survival. Overall survival was worse, although not statistically significantly, within the ER-negative or ER-positive, grade 3, and small tumor subgroups. The worse survival was most pronounced in non-chemotherapy-treated patients (adjusted HR = 1.54, 95% CI = 1.08 to 2.19). Power for BRCA2 mutation carriers was limited; only after five years' follow-up overall survival was worse (adjusted HR = 1.47, 95% CI = 1.00 to 2.17). Conclusions: BRCA1/2 mutation carriers diagnosed with breast cancer before age 50 years are prone to a worse survival, which is partly explained by differences in tumor characteristics, treatment response, and second ovarian cancers.
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