Evidence Lacking That Denosumab Alters the Course of Breast Cancer

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I am writing to provide personal context to my column on adjuvant denosumab or bisphosphonates for resected breast cancer, which appears on page 52 in this issue of The ASCO Post.

I have been upset since 2013 that adjuvant zoledronate has been recommended for women with breast cancer onset after age 55 without a positive trial restricted to this population showing benefits in the incidence of bone or other distant metastases, disease-free survival, or overall survival.1 To my knowledge, no such trial has yet been reported. The recommendation for zoledronate or clodronate is based on an amalgamation of subgroup analyses, most of them unplanned.

When Michael Gnant, MD, presented and published the primary analysis of the Austrian Breast Cancer Study Group (ABCSG)-18 trial2 demonstrating a halving of the rate of fractures on anastrozole, this seemed to me enough to recommend it to my colleagues and my patients for the purpose of fracture prevention.3

At the San Antonio Breast Cancer Symposium presentation in 2015 of the disease-free survival analysis of ABCSG-18, I stood at the microphone after the presentation to ask which disease-free survival events were prevented by giving denosumab (local recurrences, contralateral new breast primaries, regional recurrences, death without recurrence, new other primary cancers, or distant metastases). We had to wait until June 2018, to find out that denosumab affected disease-free survival nearly completely by an associated reduction in new, nonbreast, primary cancers.4 A reduction in new primaries was not confirmed in a 4,509-patient international trial (D-CARE) using a higher, more-toxic dose of denosumab.5 D-CARE is likely correct, and the prevention of second primaries is likely a chance event in ABCSG-18.

Clinical Implications: Not so Fast

I favor gently recommending denosumab when giving adjuvant aromatase inhibitors to prevent fractures in 8% of the women under treatment. As stated in my current column, I am not convinced that adjuvant zoledronate should be given to prevent breast cancer events in women older than age 55. Nonetheless,I have no difficulty in recommending denosumab to prevent fractures. If we believe that adjuvant zoledronate prevents metastases and death, then we would have to give zoledronate instead of denosumab, since the two given together have been shown to be neither safe nor effective for prevention of either fractures or metastases.

I hope the U.S. Food and Drug Administration and the European Medicines Agency do not allow Amgen to market adjuvant denosumab as a drug that improves disease-free survival. This would wrongly imply that it alters the course of breast cancer. The evidence suggests strongly that it does not. 

Steven E. Vogl, MD
Bronx, New York

Disclaimer: Letters to the Editor represent the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.

DISCLOSURE: Dr. Vogl has an immediate family member who owns stock in Amgen.


1. Vogl S: Adjuvant bisphosphonates: Does the meta-analysis presented at SABCS change anything? Clinical Oncology News, April 8, 2014.

2. Gnant M, Pfeiler G, Dubsky PC, et al: Adjuvant denosumab in breast cancer (ABCSG-18): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386:433-443, 2015.

3. Vogl S: Adjuvant denosumab to prevent fractures—At least! Clin Oncol News, March 10, 2016.

4. Gnant M, Pfeiler G, Steger GG, et al: Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): Disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:339-351 2019.

5. Coleman RE, Finkelstein D, Barrios CH, et al: Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo controlled D-CARE study. 2018 ASCO Annual Meeting. Abstract 501. Presented June 4, 2018.

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