Abstract
BackgroundThe role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC.MethodsRCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled.ResultsThirteen trials met the inclusion criteria, evaluating a total of 15,762 patients. Meta-analysis of ten trials which reported OS revealed no statistically significant benefit in OS for BP (HR 0.89, 95% CI = 0.79 to 1.01). Meta-analysis of nine trials which reported the DFS revealed no benefit in DFS (HR 0.95 (0.81–1.12)). Meta-analysis upon menopausal status showed a statistically significant better DFS in the BP-treated patients (HR 0.81(0.69–0.95)). In meta-regression, chemotherapy was negatively associated with HR of survival.ConclusionsOur meta-analysis indicates a positive effect for adjuvant BP on survival only in postmenopausal patients. Meta-regression demonstrated a negative association between chemotherapy use BP effect on survival. Further large scale RCTs are warranted to unravel the specific subgroups that would benefit from the addition of BP in the adjuvant setting.
Highlights
Breast cancer is the most common malignancy among women, accounting for nearly 1 in 3 cancers diagnosed and the second leading cause of cancer death among women in the United States [1]
Breast cancer has a particular propensity for the bone; likewise, it has been previously demonstrated that the relationship between cancer cells and the bone microenvironment is mediated by a reciprocal interaction between cancer cells and normal bone cells [2,3,4]
Thirteen trials were designed to evaluate the effect of bisphosphonates on survival and fulfilled the inclusion criteria for published studies ([13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]; including safety reports) including two recently published abstracts of large scale randomized controlled trials [28,29]
Summary
Breast cancer is the most common malignancy among women, accounting for nearly 1 in 3 cancers diagnosed and the second leading cause of cancer death among women in the United States [1]. Breast cancer has a particular propensity for the bone; likewise, it has been previously demonstrated that the relationship between cancer cells and the bone microenvironment is mediated by a reciprocal interaction between cancer cells and normal bone cells [2,3,4] Due to their beneficial effects on bone turnover, bisphosphonates have been evaluated for the prevention and treatment of bone metastases in women with breast cancer [5,6,7,8]. Two large population-based cohort studies demonstrated a significant reduction in the incidence of breast cancer in women who were treated with BP for non-cancer indications for more than a year [9,10] Both preclinical and clinical evidence indicate that BP exhibit antimetastatic and anti-tumor properties, including the inhibition of angiogenesis, and a unique effect in the bony niche – inhibition of cancer cell invasion and adhesion and the induction of apoptosis [11,12]. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC
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