Abstract
548 Background: The role of bisphosphonates (BP) in the adjuvant setting in breast cancer has been evaluated in several studies, yielding inconsistent evidence. We performed a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluate the effects of BP treatment on survival in patients with early breast cancer in the adjuvant setting. Methods: RCTs that compared BP therapy in addition to the standard adjuvant therapy (cytotoxic or hormonal) with standard adjuvant therapy only were identified by searching the Cochrane Library, LILACS, MEDLINE databases and conference proceedings (12.2011). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled. All statistical tests were two-sided. Results: Thirteen trials met the inclusion criteria., among which are the two recently published abstracts of large scale RCTs (NSABP-B34, GAIN) evaluating a total of 15,762 patients. Ten trials reported the OS outcome. Meta-analysis revealed no statistically significant benefit for BP (HR 0.89, 95% CI = 0.79 to 1.01). Nine trials reported the DFS outcome. Meta-analysis revealed no statistically significant better DFS for the intervention (HR 0.95 (0.80-1.11)). Six trials reported DFS stratified upon menopausal status. Postmenopausal patients who were treated with BP therapy had statistically significant better DFS than the control group (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of OS (coefficient, -0.23; standard error, 0.144). BP therapy resulted in less fractures in the intervention arm, but higher incidence of osteonecrosis of the jaw and pyrexia. Conclusions: Our meta-analysis indicates a positive effect for adjuvant BP on survival outcomes only in postmenopausal patients with breast cancer. Meta-regression appraised the effect of confounders such as chemotherapy, showed a negative association between chemotherapy use and the effect of bisphosphonates on survival. Further large scale RCTs are warranted to unravel the specific subgroups and adjuvant treatments 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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