SABCS 2013 - CARE Breast Cancer Faculty Update - Biophosphonates

No Bones About It: Adjuvant Biophosphonate Meta-Analysis – Overall Survival Benefit in Postmenopausal Patients

SABCS 2013 audience members were treated to an excellent Thursday morning plenary overview of adjuvant bisphosphonate therapy in breast cancer1 by Dr. Michael Gnant followed by the long awaited EBCTCG adjuvant bisphosphonate meta-analysis2 presented by Dr. Robert Coleman in the afternoon.

SABCS 2013 S4-07: Effects of BP Treatment on Recurrence and Cause-Specific Mortality in Women With Early Breast Cancer: A Meta-Analysis of Individual Patient Data From Randomised Trials. R. Coleman et al.

Background: Disseminated tumour cells can remain dormant in the bone marrow for years prior to subsequent activation and the development of overt metastases. Bisphosphonates (BP) have profound effects on bone physiology and could potentially modify the metastatic disease process. Variable outcomes in terms of disease recurrence have been reported, with efficacy apparently influenced by menopausal status.

Methods: We sought individual patient data for meta-analysis from 41 randomised trials that compared BP to no BP (placebo or open control). Primary outcomes were time to recurrence, time to first distant recurrence and breast cancer mortality. Predefined subgroup comparisons were of type of BP (amino-/non-amino), duration and schedule of BP treatment, menopausal status, age, ER status, concomitant chemotherapy and site of distant recurrence (bone/other).

Results: Data on 17,751 women (75% of 23,573 randomised in relevant trials) have so far been received, with around 3,300 breast cancer recurrences and 2,500 deaths. Effects on breast cancer mortality, recurrence and bone metastases for 17,016 women in the locked database and for 10,540 who were postmenopausal are shown below.

In this individual patient level meta-analysis from the EBCTCG bisphosphonate working group, adjuvant bisphosphonate therapy was shown to have a beneficial effect on breast cancer mortality and bone recurrence.

The beneficial effects were restricted to the postmenopausal cohort, with an approximate 3%, 10-year improvement in breast cancer mortality, breast cancer recurrence and distant recurrence. Distant recurrence was essentially confined to reductions in bone only, and not in other distant sites. The effects observed were irrespective of bisphosphonate type, schedule, ER status, nodal involvement or use of concomitant adjuvant chemotherapy. No improvements in bone or other recurrence were observed for pre-menopausal women. As expected, adjuvant bisphosphonates also reduced the rates of bone fractures overall (RR 0.83, 2 p = 0.009).

The benefits reported in this adjuvant bisphosphonate meta-analysis are robust, is in the order of other adjuvant systemic therapy benefit (e.g., DFS benefit of AIs) and the results have the potential to be practice changing. At minimum, the results are worthy of a discussion with each of our adjuvant postmenopausal breast cancer patients (most of whom will already be at risk for bone loss due to age alone and/or adjuvant AI therapy) and at reasonable risk to obtain a clinically meaningful absolute benefit.

The question of which bisphosphonate and schedule to choose is left up to the treating oncologist and their patient to decide. Drug side effect profile, out of pocket cost and patient convenience need to be kept in mind. Maximum duration of adjuvant bisphosphonate therapy in the trials was 5 years.

At this time, the benefits observed in this meta-analysis cannot be extended to other non-oncologic, osteoporosis indicated bisphosphonates (e.g., alendronate or etidronate) or to RANK-ligand inhibitors (denosumab).

Despite the hope and promise of ongoing personalized, targeted breast cancer therapy – apart from menopausal status – clinicians have no other stratification factor or biomarker to determine which postmenopausal woman will derive the greatest benefit from adjuvant bisphosphonate therapy. The data is what the data is, as no further placebo-controlled adjuvant bisphosphonate trials are planned for the future.
— CARE Breast Cancer Faculty