Adjuvant bisphosphonate therapy in breast cancer

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Published: 19 Dec 2013
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Prof Michael Gnant - Medical University of Vienna, Vienna, Austria

Prof Gnant talks to ecancertv at SABCS 2013 about his plenary talk.

Breast cancer patients face challenges to skeletal integrity, both by caused by the disease but also as a side effect of standard endocrine therapy.

Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved as standard therapy for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss.

Bisphosphonates also have demonstrated anti-cancer activity preclinically and in clinical trials during adjuvant breast cancer therapy. The metastasis-preventing effect of bisphosphonates has been explained by their putative effects on the bone marrow microenvironment, which provides a site for cancer cells to evade immune surveillance and adjuvant systemic anti-cancer therapy. Dormant tumor micrometastases are believed to be the ultimate source of disease persistence and relapse, and it has been suggested that adjuvant bisphosphonate treatment renders the bone marrow microenvironment less conducive to cancer (stem) cell survival.

However, key questions remain surrounding the role of adjuvant bisphosphonates in breast cancer, including selecting patient populations actually deriving benefit and optimal timing/scheduling of therapy. Despite thousands of patients have been included in randomized clinical trials of adjuvant bisphosphonates, significant controversy persists about the usefulness of this therapeutic approach: current clinical data show clear-cut improvements in disease outcomes with bisphosphonates in many studies, although not in all patient subsets: Strongest support for the potential adjuvant anticancer benefits from bisphosphonates has been demonstrated in women with established menopause (i.e., very low circulating estrogen levels). Also, initiating bisphosphonates early and concomitantly with adjuvant therapy generally provided the greatest benefits.

In addition to earlier trials using oral bisphosphonates such as clodronate, recent clinical data from large phase 3 trials (e.g. ABCSG-12, ZO-FAST, and AZURE) demonstrate significantly improved disease-free survival with zoledronic acid in some patient populations with early breast cancer. Other bone-targeted treatment approaches such as denosumab are currently evaluated for adjuvant therapy in large clinical trials.