Lancet
Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
Abstract
Background
Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook 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). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. 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.
Funding
Cancer Research UK, Medical Research Council.
Related Questions
Do you offer adjuvant bisphosphonates to high-risk premenopausal women on ovarian suppression for early-stage breast cancer who would want to consider pregnancy in the future?
ASCO guidelines from 1/2022 recommend a discussion of bisphosphonate therapy in post-menopausal women or women on ovarian suppression who are candidates for adjuvant therapy, but risks and benefits should be carefully weighed.In a large meta-analysis of adjuvant bisphosphonate therapy in early breas...
Do you give bisphosphonates after completing adjuvant anti-HER2 therapy and chemotherapy for HER2+ breast cancer to reduce the risk of recurrence?
Bisphosphonates and the RANK-ligand inhibitor, denosumab, are bone-modifying agents that are indicated to decrease the risk of bone fragility fractures in at-risk populations without cancer, and to decrease pain and complications related to metastatic bone disease. In the adjuvant setting for postme...
What chemotherapy regimen do you prefer for postmenopausal women with T1 ER positive tumors with 1 positive LN?
For T1N1M0 ER positive tumors, I first do a Mammaprint. In MINDACT, Mammaprint low risk ER + N+ (up to three nodes) tumors had no improvement in 5 year DDFS (still about 94-95%) with the addition of chemotherapy to endocrine therapy.If the woman had a high risk Mammaprint, I would give AC x 4 follow...
When do you add an adjuvant bone-modifying agent in patients with history of localized breast cancer?
In my opinion this is controversial question. The meta-analysis performed by EBCTG 2016 of over 11,000 post-menopausal women, and over 6000 premenopausal women, clearly shows a benefit for the postmenopausal subset. The absolute overall survival improvement was 3.3% (p=0.002) for postmenopausal wome...