There is emerging evidence that progesterone-mediated up-regulation of the RANK/RANKL also plays a critical role in mammary gland epithelial cell proliferation, in mammary stem cell expansion, and in mammary carcinogenesis.6–10 Furthermore, preliminary findings from the adjuvant denosumab in breast cancer (ABCSG 18) double-blind, placebo-controlled trial showed improved disease-free survival among the women randomized to denosumab injected subcutaneously twice a year.11,12 The impact of denosumab on the incidence of a second primary cancer has yet to be reported. This evidence concerns the gene TNFSF11 and breast cancer.