@article{fe8c150bf27546fcb25054b45e8b4c00,
title = "Identifying oncogenic drivers associated with increased risk of late distant recurrence in postmenopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study",
abstract = "Background: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. Patients and methods: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as ≥5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. Results: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20–0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30–9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51–19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. Conclusions: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.",
keywords = "breast, cancer, hormone, late, prognosis, recurrence",
author = "Luen, {S. J.} and R. Asher and Lee, {C. K.} and P. Savas and R. Kammler and P. Dell'Orto and Biasi, {O. M.} and D. Demanse and W. Hackl and B. Thuerlimann and G. Viale and {Di Leo}, A. and M. Colleoni and Regan, {M. M.} and S. Loi",
note = "Funding Information: We are indebted to the women, physicians, nurses, and data managers who participated in the BIG 1-98 clinical trial and the many pathologists who submitted tumor blocks; to the BIG Collaborative Group, BIG secretariat, and BIG 1-98 Steering Committee; to the IBCSG for the design of the trial, coordination, data management, medical review, and statistical support; to the IBCSG Central Pathology Office for tumor block collection and processing; to Maria Olivia Biasi for DNA extraction; to the Swiss Group for Clinical Cancer Research (SAKK) and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK) for their support of BIG 1-98. SL is supported by the Breast Cancer Research Foundation of Australia, the John Colebatch Cancer Council Victoria Clinical fellowship, and the National Breast Cancer Foundation (NBCF). This work was supported in part by Novartis (partial funding of tissue block collection and full funding of next generation sequencing at Foundation Medicine) and Susan G. Komen for the Cure Promise Grant (nucleic acid extraction [grant number KG080081 to GV, OP, MMR]). The BIG 1-98 trial was supported by Novartis. The IBCSG, which coordinated the BIG 1-98 trial, was also supported by The Swedish Cancer Society, The Swedish Research Council, The Cancer Council Australia, Australia and New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland. CL declares honoraria (outside of this submitted study) from AstraZeneca, Novartis, Pfizer, Roche, Boehringer Ingelheim; consulting or advisory role with AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim; research funding to his institution from AstraZeneca; travel funding from AstraZeneca, and Boehringer Ingelheim. PS has acted as an uncompensated consultant for Roche-Genentech. BT declares stocks for Novartis and Roche; has acted as a consultant for Roche. GV has received honoraria (outside of this submitted study) from MSD Oncology, Roche, Pfizer, Novartis, Bayer, Daiichi Sankyo, and Dako Agilent. MR declares institutional research funding and/or provision of drug supply for clinical trials from Novartis, Pfizer, Ipsen, AstraZeneca, Pierre Fabre, Roche, TerSera; institutional research funding from Novartis, Bayer, and Bristol-Myers Squibb (BMS); institutional advisory role from Ipsen; advisory role, travel support, and honoraria from BMS. SL has no conflicts related to the current manuscript; receives research funding to her institution from Novartis, BMS, Merck, Roche-Genentech, Puma Biotechnology, and Pfizer; consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, and Roche-Genentech. All remaining authors have declared no conflicts of interest. Funding Information: This work was supported in part by Novartis (partial funding of tissue block collection and full funding of next generation sequencing at Foundation Medicine) and Susan G. Komen for the Cure Promise Grant (nucleic acid extraction [grant number KG080081 to GV, OP, MMR]). The BIG 1-98 trial was supported by Novartis. The IBCSG, which coordinated the BIG 1-98 trial, was also supported by The Swedish Cancer Society , The Swedish Research Council , The Cancer Council Australia , Australia and New Zealand Breast Cancer Trials Group, Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland/Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland. Funding Information: We are indebted to the women, physicians, nurses, and data managers who participated in the BIG 1-98 clinical trial and the many pathologists who submitted tumor blocks; to the BIG Collaborative Group, BIG secretariat, and BIG 1-98 Steering Committee; to the IBCSG for the design of the trial, coordination, data management, medical review, and statistical support; to the IBCSG Central Pathology Office for tumor block collection and processing; to Maria Olivia Biasi for DNA extraction; to the Swiss Group for Clinical Cancer Research (SAKK) and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK) for their support of BIG 1-98. SL is supported by the Breast Cancer Research Foundation of Australia, the John Colebatch Cancer Council Victoria Clinical fellowship, and the National Breast Cancer Foundation (NBCF). Funding Information: CL declares honoraria (outside of this submitted study) from AstraZeneca, Novartis, Pfizer, Roche, Boehringer Ingelheim; consulting or advisory role with AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim; research funding to his institution from AstraZeneca; travel funding from AstraZeneca, and Boehringer Ingelheim. PS has acted as an uncompensated consultant for Roche-Genentech. BT declares stocks for Novartis and Roche; has acted as a consultant for Roche. GV has received honoraria (outside of this submitted study) from MSD Oncology, Roche, Pfizer, Novartis, Bayer, Daiichi Sankyo, and Dako Agilent. MR declares institutional research funding and/or provision of drug supply for clinical trials from Novartis, Pfizer, Ipsen, AstraZeneca, Pierre Fabre, Roche, TerSera; institutional research funding from Novartis, Bayer, and Bristol-Myers Squibb (BMS); institutional advisory role from Ipsen; advisory role, travel support, and honoraria from BMS. SL has no conflicts related to the current manuscript; receives research funding to her institution from Novartis, BMS, Merck, Roche-Genentech, Puma Biotechnology, and Pfizer; consultant (not compensated) for Seattle Genetics, Pfizer, Novartis, BMS, Merck, and Roche-Genentech. All remaining authors have declared no conflicts of interest. Publisher Copyright: {\textcopyright} 2020 European Society for Medical Oncology Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = oct,
doi = "10.1016/j.annonc.2020.06.024",
language = "English",
volume = "31",
pages = "1359--1365",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "NLM (Medline)",
number = "10",
}