Bibliografisk note

Funding Information:
Jose P. Leone has received research funding from Kazia Therapeutics and Merck. Bernard F. Cole reports personal fees from the Frontier Science and Technology Research Foundation. Meredith M. Regan reports research funding (to her institution) from Novartis, Pfizer, Ipsen, TerSera, Merck, Ferring, Pierre Fabre, Roche, AstraZeneca, Bayer, and Bristol‐Myers Squibb and consulting or advisory roles with Ipsen/Debiopharm (International Breast Cancer Study Group), Bristol‐Myers Squibb, and Tolmar Pharmaceuticals. Beat Thürlimann receives consultation fees from Amgen, AstraZeneca, Eli Lilly, Genomic Health, Roche, and Pfizer; reports personal fees from Novartis and grants from AstraZeneca; and holds stock in Novartis and Roche. Richard D. Gelber receives research funding (to his institution) from Novartis, Pfizer, Ipsen, Merck, Ferring, Roche, AstraZeneca, and Celgene. Bent Ejlertsen reports grants from NanoString Technologies, Venture Oncology, AstraZeneca, MSD, Novartis, Pfizer, Roche, and Samsung. Andrew Wardley reports personal fees from Roche, Amgen, MSD, Novartis, Pfizer, AstraZeneca, Athenex, the Gerson Lehmann Group, the Coleman Expert Network Group, Guidepoint Global, and Boehringer‐Ingelheim; personal fees and other from Lilly and Daiichi Sankyo; and other from Andrew Wardley, Ltd, the Manchester Cancer Academy, and the Outreach Research and Innovation Group, Ltd. He is also leading the National Cancer Research Institute Breast Group Initiative to develop the next de‐escalation trial for HER2‐positive breast cancer, is the chair of the National Cancer Research Institute Breast Research Group, and is a member of the National Health Service England Chemotherapy Clinical Reference Group. Angelo Di Leo reports personal fees from Amgen, AstraZeneca, Athenex, Bayer, Daiichi Sankyo, Eisai, Genentech, Genomic Health, Ipsen, Pierre Fabre, Puma Biotechnology, Roche, Seattle Genetics, and Sellas Life Sciences; personal fees and nonfinancial support from Celgene, Pfizer, and Lilly; and grants and personal fees from Novartis. Marco Colleoni reports personal fees from Novartis. Ines Vaz‐Luis has received honoraria from AstraZeneca, Novartis, Kephren, and Amgen. Nancy U. Lin has received research funding (to her institution) from Novartis, Merck, Pfizer, Genentech, and Seattle Genetics; has served on advisory boards for Daichii Sankyo, Puma, AstraZeneca, and Seattle Genetics; and has received royalties from UpToDate. The other authors made no disclosures.

Funding Information:
The Breast International Group 1-98 trial was financed by Novartis and coordinated by the International Breast Cancer Study Group. Other support for the International Breast Cancer Study Group was provided by the Swedish Cancer Society, the Swedish Research Council, the Cancer Council Australia, the Australia New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, Cancer Research Switzerland, Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland. Jose P. Leone has received research funding from Kazia Therapeutics and Merck. Bernard F. Cole reports personal fees from the Frontier Science and Technology Research Foundation. Meredith M. Regan reports research funding (to her institution) from Novartis, Pfizer, Ipsen, TerSera, Merck, Ferring, Pierre Fabre, Roche, AstraZeneca, Bayer, and Bristol-Myers Squibb and consulting or advisory roles with Ipsen/Debiopharm (International Breast Cancer Study Group), Bristol-Myers Squibb, and Tolmar Pharmaceuticals. Beat Th?rlimann receives consultation fees from Amgen, AstraZeneca, Eli Lilly, Genomic Health, Roche, and Pfizer; reports personal fees from Novartis and grants from AstraZeneca; and holds stock in Novartis and Roche. Richard D. Gelber receives research funding (to his institution) from Novartis, Pfizer, Ipsen, Merck, Ferring, Roche, AstraZeneca, and Celgene. Bent Ejlertsen reports grants from NanoString Technologies, Venture Oncology, AstraZeneca, MSD, Novartis, Pfizer, Roche, and Samsung. Andrew Wardley reports personal fees from Roche, Amgen, MSD, Novartis, Pfizer, AstraZeneca, Athenex, the Gerson Lehmann Group, the Coleman Expert Network Group, Guidepoint Global, and Boehringer-Ingelheim; personal fees and other from Lilly and Daiichi Sankyo; and other from Andrew Wardley, Ltd, the Manchester Cancer Academy, and the Outreach Research and Innovation Group, Ltd. He is also leading the National Cancer Research Institute Breast Group Initiative to develop the next de-escalation trial for HER2-positive breast cancer, is the chair of the National Cancer Research Institute Breast Research Group, and is a member of the National Health Service England Chemotherapy Clinical Reference Group. Angelo Di Leo reports personal fees from Amgen, AstraZeneca, Athenex, Bayer, Daiichi Sankyo, Eisai, Genentech, Genomic Health, Ipsen, Pierre Fabre, Puma Biotechnology, Roche, Seattle Genetics, and Sellas Life Sciences; personal fees and nonfinancial support from Celgene, Pfizer, and Lilly; and grants and personal fees from Novartis. Marco Colleoni reports personal fees from Novartis. Ines Vaz-Luis has received honoraria from AstraZeneca, Novartis, Kephren, and Amgen. Nancy U. Lin has received research funding (to her institution) from Novartis, Merck, Pfizer, Genentech, and Seattle Genetics; has served on advisory boards for Daichii Sankyo, Puma, AstraZeneca, and Seattle Genetics; and has received royalties from UpToDate. The other authors made no disclosures. The BIG 1-98 design, schema, eligibility criteria, and study measures have been reported previously.3,5,7 Briefly, this was a double-blinded, phase 3, randomized clinical trial that enrolled postmenopausal women with early-stage hormone receptor?positive breast cancer. Between 1998 and 2000, patients were randomized to single-agent letrozole (Femara; Novartis, Basel, Switzerland) at 2.5 mg orally daily or tamoxifen at 20 mg orally daily for 5 years of treatment. Between 1999 and 2003, subjects were randomized to 1 of 4 arms: single-agent letrozole or tamoxifen for a total of 5 years or their sequences, which consisted of 2 years of letrozole followed by 3 years of tamoxifen or 2 years of tamoxifen followed by 3 years of letrozole. A total of 8010 participants were included in the intention-to-treat population. Figure 1 shows the disposition of the patients in the study. The BIG 1-98 design, schema, eligibility criteria, and study measures have been reported previously.3,5,7 Briefly, this was a double-blinded, phase 3, randomized clinical trial that enrolled postmenopausal women with early-stage hormone receptor?positive breast cancer. Between 1998 and 2000, patients were randomized to single-agent letrozole (Femara; Novartis, Basel, Switzerland) at 2.5 mg orally daily or tamoxifen at 20 mg orally daily for 5 years of treatment. Between 1999 and 2003, subjects were randomized to 1 of 4 arms: single-agent letrozole or tamoxifen for a total of 5 years or their sequences, which consisted of 2 years of letrozole followed by 3 years of tamoxifen or 2 years of tamoxifen followed by 3 years of letrozole. A total of 8010 participants were included in the intention-to-treat population. Figure 1 shows the disposition of the patients in the study. A statistical analysis was performed on the subset of randomized and eligible patients who experienced a DR as their first event during the median follow-up period of 8.1 years. Analyses were conducted according to the per-protocol treatment assignment. Summaries of the following baseline characteristics (at the time of randomization) were obtained: age (<65 vs ?65 years), body mass index (<18.8, 18.5 to <25, 25 to <30, or ?30 kg/m2), tumor size (?2 vs >2 cm), tumor grade, nodal status (negative, 1-3 positive nodes, or 4 or more positive nodes), estrogen receptor and progesterone receptor (PR) status, type of surgery (breast-conserving, mastectomy, or other), radiotherapy status, and chemotherapy status. We also summarized the following outcomes at the time of DR: cessation of randomized endocrine therapy within 30 days of DR and DFS interval (ie, months from randomization to DR). For categorical variables, we determined frequency counts and percentages within each treatment arm. These were compared with the Pearson chi-square test. For the DFS interval, we determined treatment group?specific medians and interquartile ranges (IQRs). These were compared with the Kruskal-Wallis test. The primary analysis endpoint was survival after DR, which was defined as the time interval between the date on which a proven DR was first suspected and death from any cause. Patients remaining alive were censored at the date on which they were last known to be alive. The distribution of post-DR survival was estimated with the Kaplan-Meier method. A comparison of the randomized treatment arms was performed with the log-rank test. We performed a multivariate analysis of post-DR survival by using proportional hazards regression to compare the treatment arms after adjustments for the baseline factors and DFS interval. The baseline adjustment factors consisted off all baseline variables listed previously. The fitted proportional hazards regression models were used to determine hazard ratios (HRs) and 95% confidence intervals (CIs).

Funding Information:
The Breast International Group 1‐98 trial was financed by Novartis and coordinated by the International Breast Cancer Study Group. Other support for the International Breast Cancer Study Group was provided by the Swedish Cancer Society, the Swedish Research Council, the Cancer Council Australia, the Australia New Zealand Breast Cancer Trials Group, the Frontier Science and Technology Research Foundation, the Swiss Group for Clinical Cancer Research, Cancer Research Switzerland, Oncosuisse, and the Foundation for Clinical Cancer Research of Eastern Switzerland.

Publisher Copyright:
© 2020 American Cancer Society