Prevention of Symptomatic Skeletal Events in Postmenopausal Women with Advanced ER-Positive Breast Cancer

Hormonal Treatment and Bone Health

Treatment of advanced breast cancer with estrogen receptors (ER⁺) in postmenopausal women uses anti-estrogen drugs such as aromatase inhibitors. Hormonal therapy reduces the risk of relapse and metastasis but also has unwanted side effects. The skeletal system of women reacts to the deepened absence of estrogen signaling, leading to rapid bone mass loss, decreased bone mineral density (BMD), and increased risk of skeletal events. Effective prevention can be achieved with the monoclonal antibody against RANKL, denosumab (DN), or zoledronic acid (ZA) belonging to the bisphosphonate drug group.

Study Methodology and Course

The primary goal of the retrospective study was to assess the effect of DN and ZA on SSE in Asian postmenopausal women with advanced ER⁺ breast cancer. Data from 242 women over 60 years old with histologically or cytologically confirmed advanced ER⁺ breast cancer diagnosed between March 2011 and 2013 were analyzed.

Patients underwent surgery and/or completed radiation and chemotherapy treatments ≥ 4 weeks before joining the retrospective study and simultaneously started prophylaxis with antiresorptive drugs: 120 received subcutaneous DN at a dose of 120 mg every 4 weeks, and 122 were administered intravenous ZA at a dose of 4 mg every 4 weeks. Vitamin D and calcium supplementation was recommended for the patients.

The primary endpoint was the time to the first SSE in the study, assessed either clinically or using routine x-rays. SSEs were defined as radiation therapy to the bones, pathological fractures (excluding trauma), bone surgery, or spinal cord compression. The median study duration at the cutoff date for the primary analysis was 37 months (interquartile range [IQR] 25.1–45.3) for patients with DN and 38 months (IQR 26.2–45.8) for patients with ZA.

Results

Both groups were comparable in terms of clinical and demographic characteristics. The median time to the first SSE in the study was 16.5 months in the DN group and 11.7 months in the ZA group (hazard ratio [HR] 0.44; 95% confidence interval [CI] 0.71–2.95; p = 0.0002). Patients treated with DN had a significantly prolonged time to the overall first SSE (HR 0.65; 95% CI 0.29–1.45; p < 0.0001) compared to the ZA group.

Increased incidence of SSE was detected after 16 months of follow-up in patients in the ZA group (10.7% versus 2.1% in the DN group; p = 0.033). At the end of the follow-up, the difference between the groups persisted: SSE incidence in the ZA group was 17.2% versus 8.3% in the DN group (p < 0.05).

The incidence of SSE in this study was lower than, for example, in the BIG1-98 study involving a non-Asian patient population. In the BIG1-98 study, the incidence of SSE reached 19.5% after 40 months of follow-up. Differences in SSE occurrence may be associated with biological differences between Asian and Caucasian populations.

Conclusion

In the cited study, denosumab significantly reduced the risk of skeletal events compared to zoledronic acid in Asian postmenopausal women with ER⁺ breast cancer. The results of the retrospective analysis should be prospectively verified in a broader population for broader clinical application.

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Sources: Zhang C., Zhang F., Liang G. et al. Denosumab versus zoledronic acid for preventing symptomatic skeletal events in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer: an outcome analysis with a mean follow-up of 3 years. BMC Musculoskelet Disord 2018; 19 (1): 424, doi: 10.1186/s12891-018-2338-6.