Bisphosphonates in Women with Early Breast Cancer

EBM Focus - Volume 10, Issue 40

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Reference - Lancet 2015 Oct 3;386(10001):1353 (level 2 [mid-level] evidence)

  • In postmenopausal women with early breast cancer, bisphosphonates may reduce breast cancer mortality and bone recurrence
  • In premenopausal women with early breast cancer, bisphosphonates do not appear to reduce breast cancer mortality or bone recurrence
  • Overall, bisphosphonates may reduce risk of fracture

    For women with breast cancer, bisphosphonates are recommended for the treatment of metastatic disease with evidence of bone destruction (J Clin Oncol 2011 Mar 20;29(9):1221, NCCN website). However, the American Society of Clinical Oncology does not currently recommend bone-modifying agents in women without evidence of bone metastasis, even if other extraskeletal metastases are present. While previous randomized trials have suggested that bisphosphonates may reduce recurrence and increase survival women with early breast cancer (N Engl J Med 2011 Oct 13;365(15):1396, N Engl J Med 2009 Feb 12;360(7):679, Lancet Oncol 2012 Jul;13(7):734), two systematic reviews have found no significant association (Cochrane Database Syst Rev 2012 Feb 15;(2):CD003474, J Natl Compr Canc Netw 2010 Mar;8(3):279). To further investigate the impact of bisphosphonates on breast cancer outcomes, the Early Breast Cancer Trialists’ Collaborative Group performed an individual patient data meta-analysis including 18,766 women with early breast cancer from 26 randomized trials comparing adjuvant bisphosphonates vs. control. The mean treatment duration was 3.4 years and 97% of women were treated for 2-5 years.

    During the median follow-up of 5.6 years, 3,453 women experienced a first recurrence and 2,106 died. Estimated 10-year event rates for recurrence, distant recurrence, bone recurrence, and breast cancer-specific mortality were calculated. Overall, women taking bisphosphonates had a significantly lower risk of a bone recurrence and also had a small, but statistically significant, reduction in breast cancer-specific mortality. However, in subgroup analyses examining demographic, disease-related, and treatment-related factors, bisphosphonate response was influenced by age and menopausal status.

    For the analysis by menopausal status, there were 11,767 postmenopausal women and 6,171 premenopausal women. Comparing bisphosphonates vs. control in analyses of postmenopausal women, the 10-year breast cancer-specific mortality (14.7% vs. 18%, p = 0.002) and risk of bone recurrence (6.6% vs. 8.8%, p = 0.0002) were significantly lower with adjuvant bisphosphonate therapy. In premenopausal women, there were no significant differences in 10-year risk of breast cancer-specific mortality (20.6% vs. 20.7%) or bone recurrence (10.3% vs. 10.3%) comparing bisphosphonates vs. controls. Bisphosphonates were also associated with a reduced risk of fracture in an analysis of 13,341 women from studies reporting this outcome.

    The results of this meta-analysis contradict two previous systematic reviews finding no significant associations between bisphosphonate treatment and breast cancer recurrence or bone metastases (Cochrane Database Syst Rev 2012 Feb 15;(2):CD003474, J Natl Compr Canc Netw 2010 Mar;8(3):279). These systematic reviews were limited by their inclusion of both early and advance breast cancer patients and more importantly, they did not take into account menopausal status. The current meta-analysis, which used individual patient data rather than trial-level data, found menopausal status significantly influences the effect of bisphosphonates on women with early breast cancer, with positive effects in postmenopausal women only. These results are consistent with one prior systematic review finding no significant difference overall comparing bisphosphonates vs. placebo in women with early breast cancer, but a significant increase in survival in a subgroup analysis of menopausal women (PLoS One 2013;8(8):e70044). Altogether, these results suggest bisphosphonates may be an appropriate adjuvant treatment to help increase survival in postmenopausal women with early breast cancer.

    For more information, see the Bone-modifying agents in breast cancer topic in DynaMed Plus. DynaMed users click here.