The aromatase inhibitor letrozole (Femara) produces a significant survival benefit over tamoxifen when used as adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer, according to updated results of a major trial released in a plenary session at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).
The updated results are from an analysis using an established methodology known as Inverse Probability of Censoring Weighted (IPCW) analysis that was undertaken to gauge the true clinical benefit of letrozole versus tamoxifen in the Breast International Group (BIG) 1-98 study. An earlier report drawn from an intent-to-treat (ITT) analysis was presented at the 2008 SABCS meeting.
“Additional IPCW analysis accounting for the selective crossover indicates that the benefit of letrozole over tamoxifen is larger than that reflected by the ITT estimate,” Meredith Regan, ScD, with Harvard Medical School in Boston, said.
The phase 3 BIG 1-98 study enrolled postmenopausal women who had completed surgery for estrogen-sensitive breast cancer and who had no evidence of metastasis.
Patients were randomly assigned to one of four treatment regimens: tamoxifen only for five years; letrozole only for 5 years; tamoxifen for two years followed by letrozole for three years; or letrozole for two years followed by tamoxifen for three years. The combined monotherapy arms of the trial included 4,922 patients randomly assigned to either letrozole or tamoxifen treatment.
The trial demonstrated the superiority of letrozole over tamoxifen in improving disease-free survival and decreasing the risk of recurrence in postmenopausal women with hormone receptor-positive early breast cancer.
Dr. Regan said that the 2008 results from the ITT analysis and censored analyses were possibly influenced by the selective crossover that occurred when some patients receiving tamoxifen crossed over to letrozole, the more effective treatment, after disease-free survival results were initially presented in 2005. The term “selective crossover’ refers to a special case of non-adherence to a randomized treatment following the report of positive trial results and is common to many trials in which an early result ethically mandates a switch to better therapy, she added.
The IPCW analysis presented at this year’s meeting offers an estimate of the clinical benefit of letrozole that might have been seen had there not been selective crossover in the BIG 1-98 trial. The results showed that five years of letrozole treatment after surgery significantly improved disease-free survival by 15% (HR 0.85, p ˂ 0.05) and overall survival by 17% (HR 0.83, p ˂ 0.05).
Alan Coates, MD, at the University of Sydney in Sydney, Australia, commented that the conventional ITT analysis is weakened by selective crossover and added that what’s needed are “trusted” statistical methods like IPCW in order to optimally determine clinical decision-making. Dr. Coates is the Scientific Committee Co-Chairman of the International Breast Cancer Study Group, which coordinated the BIG 1-98 trial.
Novartis funded the 27-counry study.
Written by Jill Stein