Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants

Abstract

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR-]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I-III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60-0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94-2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients' counseling on treatment, prevention, and surveillance strategies.

Conflict of interest statement

M.L. acted as a consultant for Roche, AstraZeneca, Lilly and Novartis, and received honoraria from Sandoz, Roche, Novartis, Takeda, Pfizer and Lilly outside the submitted work. O.C. acted as a consultant for AstraZeneca, and received travel grants from Ipsen outside the submitted work. C.R.J. acted as a consultant for Mylan medical, and received honoraria from Theramex and Bayer outside the submitted work. F.P. acted as a consultant for Astrazeneca, Daichii Sankyo, MSD, Novartis, Pierre Fabre, and Roche, received honoraria from Lilly, Novartis, Pfizer, Roche and Takeda, and received research grants from Astrazeneca, EISAI, and Roche outside the submitted work. K.P. acted as a consultant, received speaker honoraria and travel grants from Roche, Novartis, Pfizer, AstraZeneca, Lilly, Pierre Fabre, Egis, Amgen, Angelini and Teva outside the submitted work. J.A.P.F. acted as a consultant for Amgem, Astrazeneca, Clovis, and G.S.K., received honoraria from Roche, Astrazeneca, Novartis, Clovis, and G.S.K. and travel expenses by Roche, Astrazeneca, Pfizer, and G.S.K. outside the submitted work. C.V.G. acted as a consultant for Pfizer, Roche, Novartis, and Lilly, received honoraria from Myriad Genetics, Roche and Novartis, research funding from Roche and AstraZeneca, and travel expenses by Roche, MSD Oncology and Pfizer outside the submitted work. F.C. acted as a consultant for Lilly, BMS and Roche, received speaker honoraria from Merck Serono and BMS, research funding to his institution from AstraZeneca, and travel grants from Roche, Merck Serono, and BMS outside the submitted work. F.P.D. acted as a consultant for Roche, Pfizer, AstraZeneca, Lilly, Amgen, Novartis, Pierre Fabre, and Daiichi Sankyo, and received travel grants from Roche, Pfizer, Teva, and Amgen outside the submitted work. L.T. acted as a consultant for AstraZeneca, Lilly, Novartis, Pfizer, and Roche, received speaker honoraria from AstraZeneca, Merck Serono, Lilly, Novartis, Roche, research funding to his institution from Pfizer and Novartis, and travel grants from Roche, Merck Serono, and AstraZeneca, Novartis and Roche outside the submitted work. A.S. acted as a consultant for Novartis, Roche, Pfizer, and Lilly, received speaker honoraria from Roche, Pfizer, Medison, Lilly, and Novartis, research funding from Novartis, and travel grants from Medison and Roche outside the submitted work. A.R.F. received travel grants from Novartis and Roche outside the submitted work. A.D.M. received honoraria from ThermoFisher outside of the submitted work. J.B. acted as a consultant and received travel grants from Pfizer and Astra Zeneca outside the submitted work. L.D.M. acted as a consultant for Roche, Novartis, MSD, Pfizer, Ipsen, AstraZeneca, Genomic Health, Lilly, Seattle Genetics, Eisai, Pierre Fabre, and Daiichi Sankyo, received speaker honoraria from Roche, Novartis, Lilly and MSD, and travel grants from Roche, Pfizer and Celgene outside the submitted work. H.A.A. Jr acted as a consultant for Roche, received honoraria from Novartis outside the submitted work, and reported employment at Innate Pharma at the end of this study; this employment is not related in any sort to the subject of the current study. All the other authors declare no competing interests.

Figures

Fig. 1. Comparison between patients with germline BRCA1 and BRCA2 pathogenic variants.

a Epanechnikov Kernel-Smoothed annual hazards of recurrence overall; b Disease-free survival; c Distant recurrence-free interval; d Overall survival.

Fig. 2. Comparison between patients with germline BRCA1 and BRCA2 pathogenic variants and hormone receptor-positive disease.

a Epanechnikov Kernel-Smoothed annual hazards of recurrence overall; b Disease-free survival; c Distant recurrence-free interval; d Overall survival.

Fig. 3. Comparison between patients with germline BRCA1 and BRCA2 pathogenic variants and hormone receptor-negative disease.

a Epanechnikov Kernel-Smoothed annual hazards of recurrence overall; b Disease-free survival; c Distant recurrence-free interval; d Overall survival.

Fig. 4. Comparison between patients with hormone receptor-positive and negative disease.

a Epanechnikov Kernel-Smoothed annual hazards of recurrence overall; b Disease-free survival; c Distant recurrence-free interval; d Overall survival. HR+ hormone receptor-positive; HR− hormone receptor-negative.