Lasofoxifene is a bone protective treatment option for estrogen receptor positive breast cancers

Estrogen receptor positive (ER+) breast cancer primarily metastasizes to the bone microenvironment, and patients with ER+ disease are almost twice as likely to develop bone metastasis as those with other subtypes. Treatment with current endocrine therapies frequently results in osteoporosis and subsequent bone turnover which can potentially accelerate metastatic progression. This underscores the need for new treatments which will simultaneously inhibit tumor growth and preserve the bone microenvironment. Standard treatments like aromatase inhibitors and ER-antagonists, like fulvestrant, indiscriminately suppress ER signaling, in both breast and bone. Lasofoxifene, a selective ER modulator, exhibits tissue-selective ER-agonist activity in bone and is currently being evaluated in the ELAINE-III clinical trial [NCT05696626] in combination with abemaciclib for the treatment of ESR1-mutant advanced or metastatic ER+ breast cancer. Here, we investigated the physiological relevance of lasofoxifene's bone-selective ER-agonist activity and its impact on metastatic progression. Animal models of ovariectomy-induced osteoporosis were treated with lasofoxifene or standard endocrine therapies, and femurs were analyzed by histology and micro-CT histomorphometry. In parallel, anti-tumor effects of lasofoxifene were evaluated in vitro and in vivo in clinically relevant endocrine therapy-sensitive and -resistant primary and metastatic Patient-Derived Xenograft models. Additionally, drug synergism studies with lasofoxifene and the NCI NExT Oncology Interrogation Tools Set of 555 drugs were performed which identified pathways that were vulnerable to pharmacological inhibition in lasofoxifene-treated cells. We found that lasofoxifene protected against hormone withdrawal-induced bone loss and maintained a robust anti-tumor response in primary and metastatic models of ER+ breast cancer. Drug synergy screens have defined choices for rational combination with lasofoxifene to further potentiate its anti-tumor activity. Overall, this study supports the use of lasofoxifene-based treatment combinations which will concurrently protect bone architecture while suppressing ER+ metastasis progression in the bone niche.