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Application of bone-modifying agents (BMA) in the adjuvant treatment of breast cancer
Editor’s commentary by Dr. Anton Snegovoy
Most cancers metastasize to the bone, for example cancer of the breast, prostate, thyroid gland, kidney, bladder and lung. The clinical picture of metastatic bone disease is characterized by pain, hypercalcemia, fractures and neurological symptoms. The appearance of skeletal complications is accompanied by increased mortality and decreased quality of life. According to an observational study by Lipton et al., involving 751 patients with breast cancer and bone metastases, more than 60% had marked skeletal complications, accounting for 3.7 cases per year . Therefore, prophylactic use of BMA is an option in order to reduce the risk of skeletal complications and recurrence of the disease.
In 1998, Prof. Diel published a study which was the first to evaluate the use of clodronate in adjuvant therapy for breast cancer . However, despite the positive data obtained in this study, subsequent results were contradictory. In 2015, only two studies were published which confirm the possibility of reducing the risk of skeletal complications in patients receiving adjuvant hormonal therapy for breast cancer and anti-tumor effects of the BMA [3,4].
The ABCSG-18 trial is the most interesting trial: it compares the time from randomization to the first episode of fracture characteristic of osteoporosis, as well as disease-free survival (DFS) . This trial included a total of 3,420 postmenopausal patients with early hormone receptor-positive breast cancer receiving aromatase inhibitor therapy. The patients were randomized in a 1:1 ratio to one of the following two groups: every 6 months, patients in the first group received denosumab 60 mg (n = 1,711) and patients in the second group received placebo (n = 1,709). Denosumab significantly reduced the total number of fractures (92 vs. 176 in the placebo group); this pattern was maintained in all subgroups, including patients with initially reduced bone mineral density. The frequency and severity of side effects were not significantly different in the two groups. The main adverse effects were those associated with aromatase inhibitors, in particular arthralgia; no cases of osteonecrosis of the jaw were observed. The authors conclude that denosumab is effective and safe in the prevention of osteoporosis and related fractures in patients with early hormone receptor-positive breast cancer receiving adjuvant aromatase inhibitors.
The results with regard to DFS were presented by Prof. Gnant during the San Antonio Breast Cancer Symposium . With a median follow-up of 4 years, progression of breast cancer was found in 370 women (203 from the placebo group, 167 from the denosumab group). For women treated with denosumab the risk of disease recurrence was 18% lower compared to the control group. The results were close to statistical significance (OR 0.816, 95% CI 0,66–1,00, p = 0,051). In the words of Prof. Gnant: “In absolute numbers advantage in DFS of 1.2% after 3 years of follow up, 2.1% and 3.1% after 5 and 7 years of observation, respectively.” He added that “the advantage of the higher than previously launched denosumab therapy in conjunction with an aromatase inhibitor is more pronounced in patients with tumor size greater than 2 cm and a high level of expression of the receptor.” Results for overall survival in the ABCSG-18 trial are expected soon. This study is the first to demonstrate the effectiveness of the antibody on DFS.
 Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized placebo-controlled trials. Cancer 2000; 88(5): 1082–90 http://www.ncbi.nlm.nih.gov/pubmed/10699899
 Diel IJ, Solomayer E, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Eng J Med 1998; 339(6): 357–63 http://www.ncbi.nlm.nih.gov/pubmed/9691101
 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 2015; 386 (10001): 1353–61 http://www.sciencedirect.com/science/article/pii/S0140673615609084
 Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo controlled trial. Lancet 2015; 386(9992): 433–43 http://www.sciencedirect.com/science/article/pii/S0140673615609953
 Gnant M, Pfeiler G, Dubsky PC, et al. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. San Antonio Breast Cancer Symposium (SABCS) 2015: Abstract S2-02. https://www.sabcs.org/Portals/SABCS/Documents/SABCS_2015_Issue1.pdf