Use of adjuvant bisphosphonates to improve breast cancer outcomes

Evidence on the anti-tumour effects of adjuvant bisphosphonates has been conflicting. Early trials using adjuvant clodronate for 2 or 3 years in breast cancer patients failed to show a beneficial anti-tumour effect.13,14The study by Saartoet al.showed adjuvant clodronate to result in inferior 10-year disease-free survival (DFS) compared to control (45% vs 58%, p=0.01);13while the NSABP B-34 trial showed no DFS benefit from adjuvant oral clodronate at a median follow-up of 90 months although interestingly, clodronate appeared to benefit women 50 years in secondary end points such as recurrence-free interval (0.75, p=0.045), bone metastasis-free interval (0.62, p=0.027), and non-bone metastasis-free interval (0.63, p=0.014). 14Similarly, in the German Adjuvant Intergroup Node-positive (GAIN) trial, there was no reported difference in DFS between early breast cancer patients randomised to oral ibandronate at 50mg daily versus standard of care for 2 years.15

The ZO-FAST and Z-FAST studies, although not powered to study zoledronate as an adjuvant treatment, found conflicting results for their secondary endpoint of DFS, with the ZO-FAST study reporting a decrease in incidence of 5-year DFS events by 34% in the upfront compared to the delayed group (HR 0.66; 95% CI0.44-0.97; p=0.0375)11and the Z-FAST study showing similar disease recurrence and deaths between the two groups at 5 years of follow-up. 10

The AZURE study investigating the role of adjuvant zoledronate over 5 years versus standard care in stage II and III breast cancer patients found no significant difference in the primary endpoint of DFS at a median follow-up of 5 years.7,16Notably, both pre- and post-menopausal women were included. Of interest, a pre-specified subgroup analysis showed a possible invasive-DFS benefit (HR 0.77; 95% CI 0.63-0.96) in those who had undergone menopause >5 years earlier.16The hazard ratios for overall survival were 0.81 (95% CI 0.63-1.04) for this group compared to 1.04 (95% CI 0.86-1.25) for those who were less than 5 years since menopause.

However, an earlier ABCSG-12 study by Gnant et al.using adjuvant zoledronate every 6 months for 3 years in premenopausal women with HR-positive early breast cancer randomised to tamoxifen/goserelin or anastrozole/goserelin with or without zoledronate showed an absolute reduction of 3.2% and a relative reduction of 36% in the risk of disease progression (HR 0.64; p=0.01) but no significant reduction in the risk of death.17This benefit was maintained in a subsequent updated analysis at 62 months follow-up.8Only 5% of women in the ABCSG-12 study had prior chemotherapy, compared to about 95% in the AZURE study.

The recent EBCTCG meta-analyses examining the role of adjuvant bisphosphonates in early breast cancer, consisting of 18,766 women, mostly those in trials of 2-5 year of bisphosphonates, demonstrated that it produced highly significant reductions in recurrence (RR = 0.86; 95% CI, 0.78 to 0.94; 2P = 0.002), distant recurrence (0.82; 0.74 to 0.92; 2P = 0.0003), bone recurrence (0.72; 0.60 to 0.86, 2P = 0.0002) and breast cancer mortality (0.82; 0.73 to 0.93; 2P = 0.002) among postmenopausal (natural or induced) women when treatment began; the effect of which was not similarly seen in premenopausal women.6Only the preliminary results of the EBCTCG meta-analyses had been incorporated into the ESMO guidelines we reviewed.

The literature is still unclear with regards to the exact choice of bisphosphonates, the optimal dosing and duration of therapy.

Cost effectiveness Analysis

In a recent cost-effectiveness analysis study of adjuvant bisphosphonates in a simulated cohort of 100,000 postmenopausal women with non-metastatic breast cancer followed over 10 years using available clinical trials and meta-analysis data, alendronate at 70mg/week and ibandronate at 150mg/month were cost saving compared to no therapy, while zoledronic acid at 4mg/6 months had an ICER of USD $10,317/QALY gained.18High dose ibandronate at 50mg/day and high dose zoledronate (six doses in the first 6 months, eight doses in the next 24 months and five doses in the final 30 months) were not cost-effective at a willingness-to-pay threshold of $50,000/QALY gained.

Local data for cost effectiveness analysis is not available at present.

The SCAN Workgroup voted unanimously in support of the ESMO 2014 guidelines which state that adjuvant bisphosphonates reduce the frequency of bone metastases and improve survival in postmenopausal women(natural or induced) with breast cancer (I, A), but they do not improve disease outcomes in premenopausal women (I, A). The collective opinion from the members was in line with these recommendations that offering adjuvant bisphosphonates is justified in the postmenopausal but not premenopausal setting.

There are no unsystematic recommendations.

The workgroup acknowledges that local data regarding the use of adjuvant bisphosphonates to improve breast cancer outcomes is lacking.