Concurrent Antitumor and Bone-Protective Effects of Everolimus in Osteotropic Breast Cancer

Andrew J. Browne; Marie L. Kubasch; Andy Göbel; Peyman Hadji; David Chen; Martina Rauner; Friedrich Stölzel; Lorenz C. Hofbauer; and Tilman D. Rachner


Breast Cancer Res. 2017;19(92) 

In This Article


Maintaining bone health is a major clinical challenge in patients with breast cancer. Both the disease itself and most forms of treatment exert negative effects on bone metabolism.[1,2] In particular, hormone-ablative treatment approaches in women with hormone receptor-positive cancers result in a rapid increase in bone resorption.[3,4] In addition to the risk of osteoporosis, bone metastases are often seen as a late complication of apparently successfully treated patients with breast cancer,[5] and novel antitumor agents are warranted that maintain bone health.[6,7]

The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of many cellular growth and disease processes.[8] Notably, activation of mTOR signaling is closely related to endocrine resistance in breast cancer.[9,10,11] The ability to overcome endocrine resistance was assessed in the pivotal phase III BOLERO-2 trial, where the mTOR inhibitor everolimus was assessed in postmenopausal women with estrogen receptor (ER)-positive breast cancer, whose disease progressed despite nonsteroidal aromatase inhibition using exemestane.[12] Exploratory analyses of bone turnover markers at 6 and 12 weeks revealed an expected increase in the exemestane cohort, but markers of bone turnover were significantly lower when combined with everolimus. In addition, the rate of metastatic bone disease was also lower in the combination group.[13]

Of interest, a role for mTOR signaling has previously been attributed to different aspects of bone biology.[14] The activity of bone-resorbing osteoclasts depends on the mTOR pathway because the osteoclast differentiation factor receptor activator of nuclear factor κB ligand (RANKL) signals through the mTOR/p70 S6 kinase axis.[15] In osteoblasts, an increase of bone-protective osteoprotegerin (OPG) has been observed following mTOR inhibition by rapamycin,[16] and in an ovariectomized (OVX) rat model, everolimus was shown to decrease osteoclast-mediated bone resorption and to inhibit the in vitro production of cathepsin K.[17] In this study, we sought to delineate the effects seen in the BOLERO-2 trial of everolimus-mediated mTOR inhibition on the individual cell types of the bone microenvironment in vitro, as well as in the context of the hormone-deprived environment often associated with osteolytic malignant bone disease in vivo.