Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

Lancet 23 July 2015

Background
Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis.
Collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer.

Methods
We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control.
Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]).
Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs).

Findings
We received data on 18?766 women (18?206 [97%] in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths.
Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004).
Among premenopausal women, treatment had no apparent effect on any outcome,
but among 11?767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002).

No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02).

Interpretation
Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began.

G Mohan.