New Options for Limiting the Side Effects of Anti-Estrogen Breast Cancer Therapy
Clinical trial results show that the monoclonal antibody denosumab is effective in preventing fractures associated with anti-estrogen therapy and extends disease-free survival of breast cancer patients.
Estrogen receptor (ER)-positive breast cancer patients typically receive hormone therapies that block estrogen signaling. Not only do these therapies block the actions of estrogen on the tumors, but they also block the action of estrogens on bones. Consequently, cancer patients receiving such estrogen-blocking hormone therapies are at an increased risk of breaking bones. The current standard of care is to use bisphosphonates, which are small molecule drugs, to reduce this risk of fractures.
Bisphosphonates can be given through an infusion (intravenously) or by taking tablets orally. Both routes of delivery are associated with bone, joint, and muscle pain, and fatigue. People receiving the drugs intravenously may experience flu-like symptoms. People taking the tablets may experience heartburn, stomach ulcers, and irritation of the esophagus. These side effects can be limiting, so that patients stop taking them. In 2017, new guidelines by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) recommended a less frequent dosing schedule to once every 6 months for zoledronic acid, which is given by infusion, and 1600 mg/daily for orally taken clodronate.
Denosumab is a different kind of medicine called a biologic agent. It is an antibody that also prevents fractures associated with osteoporosis, including the reduction in bone density caused by estrogen-blocking cancer therapies. are complications of osteoporosis, including those caused by breast cancer. Disease-free survival results of the ABCSG-18 clinical trial were published in May 2019. This clinical trial assessed the effectiveness of denosumab in reducing fractures and in promoting disease-free cancer survival. The patients were all post-menopausal with ER-positive breast cancer who had received the first treatment (surgery, radiation, chemotherapy, or a combination thereof). After this first line of therapy, all of the patients were placed on an inhibitor of an enzyme required to synthesize estrogen. For the clinical trial, the patients were randomly assigned to either receive placebo or denosumab (60 mg by infusion every 6 months).
The 2015 report from the ABCSG-18 trial examined the frequency of fractures and adverse effects. Those data showed that denosumab provided protection from fractures, increasing the time to the first fracture and reducing the overall number of fractures that occurred in the treated group compared with the placebo group. The major adverse effect reported was joint pain.
Now, the 2019 report showed that denosumab was slightly, but significantly, more effective than the placebo at extending disease-free survival. Whether denosumab would be better than bisphosphonates for extending disease-free survival awaits a randomized, double-blind study comparing these two options. Future studies are also needed to ensure that, as patients stop taking denosumab, an increase in fracture risk does not happen. In the meantime, the results are encouraging that breast cancer patients have at least two options to prevent serious side effects of anti-estrogen therapy: Bisphosphonates or denosumab.
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