SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 231,840 new cases of invasive breast cancer will be diagnosed in 2015 and over 40,000 women will die of the disease. Approximately 75% of patients with breast cancer are hormone receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues. Tamoxifen is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. Anastrozole,Letrozole and Exemestane are Aromatase Inhibitors that bind reversibly to the aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. Aromatase inhibitors are associated with accelerated bone loss, leading to a decrease in Bone Mineral Density (BMD) and can thus cause osteopenia and osteoporosis, thereby increasing fracture risk. According to the WHO definitions, a healthy 30 year old adult (young adult) with the ideal Bone Mineral Density (BMD) is given a T-score of 0. A normal BMD is within 1 Standard Deviation-SD (+1 or −1) of the young adult mean. Osteopenia is between 1 and 2.5 SD below the young adult mean (−1 to −2.5 SD). Osteoporosis is 2.5 SD or more below the young adult mean (−2.5 SD or lower).
PROLIA® (Denosumab) is a monoclonal antibody that inhibits osteoclast formation, function and survival by selectively targeting the RANK ligand. In this randomized, double-blind, phase III trial, the authors evaluated the benefits of the anti-RANK ligand antibody PROLIA® (Denosumab) on bone health, in postmenopausal patients, with early stage hormone receptor-positive breast cancer, treated with Aromatase Inhibitors. Of the 3425 enrolled patients, 3420 patients were randomly assigned to receive PROLIA® 60 mg (N=1711) or placebo (N=1709) subcutaneously every 6 months. Majority of the patients participating in this study had breast cancer with good prognosis and only 25% of the patients required adjuvant chemotherapy. Patient received a median of 7 doses of PROLIA® . The primary endpoint was time from randomization to first clinical fracture.
Compared with placebo, PROLIA® significantly delayed time to first clinical fracture (HR=0.50; P<0•0001), with the PROLIA® group, half as likely to have a first clinical fracture as the placebo group. This benefit of lowering fracture risk was seen in subgroups of patients with BMD T-score of less than –1 as well as those with BMD T-score of -1 or greater. Further, patients in the PROLIA® group had improvements in BMD from baseline, of the lumbar spine, total hip, and femoral neck, compared to the placebo group, which showed worsening at all sites (P<0.0001). At 3 years, patients in the PROLIA® group had significantly lower risk of both new, or worsening vertebral fractures. No cases of osteonecrosis of the jaw bone were reported.
The authors concluded that PROLIA® administered in an adjuvant setting, significantly reduces the risk of fractures in postmenopausal women with breast cancer receiving Aromatase Inhibitors, without added toxicity. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Gnant M, Pfeiler G, Dubsky PC, et al. The Lancet 2015;386:433-443
