Adjuvant Bisphosphonates for Resected Breast Cancer: Not Quite Yet

Abstract

The current enthusiasm for adjuvant bisphosphonates for resected breast cancer is a result of the published results of Austrian Breast and Colorectal Cancer Study Group trial12 (ABCSG-12) and the still unpublished meta-analysis of patient-level data from studies of adjuvant bisphosphonates as presented at the 2013 San Antonio Breast Cancer Symposium. Benefit from adjuvant bisphosphonates in the metaanalysis occurred only in women who were older than 55 years or who had entered menopause more than 5 years prior to study entry (the date of last menses was not available in all studies included). The ABCSG-12 trial revealed a reduction in breast cancer recurrence after treatment with zoledronic acid, but the population was very low risk (disease-free survival at 62 months was 88% or better), the absolute benefit was small, and the anti-cancer hormonal treatments were not those usually given in current practice. The primary authors of ABCSG-12 and the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) bisphosphonate meta-analysis have suggested that postmenopausal women older than 55 years and premenopausal women just after starting treatment with goserelin acetate have similarly low estrogen levels. Therefore, in this view, these studies confirm one another and support the conclusion that bisphosphonates prevent breast cancer metastases and the patient’s early death in a low-estrogen environment. In contrast, we think these reports involve 2 different populations that need to be considered separately. The meta-analysis observation of benefit in the older postmenopausal women may have led to a correct conclusion, but because of the large number of ways the data could have been segmented, the statistical validity of any conclusion is uncertain. The age-based analysis was essentially an unplanned subgroup analysis. No study in the meta-analysis had as its hypothesis that bisphosphonates would benefit only older women. The younger women in the ABCSG-12 trial received open-label therapy with 3 years of ovarian suppression with either tamoxifen or anastrazole, plus or minus zoledronic acid. Thus, they had a sudden and temporary pharmacologic menopause, and so were likely quite different from a population of older women who had experienced natural menopause. The addition of ovarian suppression to tamoxifen has yet to be proven superior to tamoxifen alone in preventing recurrence or metastases from resected breast cancer. Three years is not now considered the standard duration of ovarian suppression. In our view, ABCSG-12 did not include a “standard therapy” in any of its 4 arms.