Preclinical Study of Lasofoxifene in Endocrine Therapy–Resistant Breast Cancer
Posted: Friday, August 20, 2021
Findings presented in Breast Cancer Research demonstrate the potential role of the third-generation selective estrogen receptor modulator (SERM) lasofoxifene in treating women with advanced or metastatic estrogen receptor–positive breast cancer that is resistant to endocrine therapy. Geoffrey L. Greene, MD, PhD, of the University of Chicago, and colleagues noted that when compared with the estrogen receptor fulvestrant, lasofoxifene had greater antitumor activities in preclinical models of breast cancer with expression of Y537S and D538G estrogen receptor–alpha (ERa) mutations.
“These results have important clinical implications and demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic estrogen receptor–positive breast cancers expressing constitutively active ESR1 mutations,” the authors said.
In this trial, MCF7 cells with wild-type Y537S or D538G ERa mutations were injected into the mammary ducts of mice. The mice were then treated with either lasofoxifene or fulvestrant as single agents or in combination with palbociclib.
The authors found that as monotherapy lasofoxifene appeared to be more effective than fulvestrant in inhibiting primary tumor growth and in reducing metastases in the mice. In both treatments, adding palbociclib improved the effectiveness of tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with palbociclib and lasofoxifene generally considered to be more potent than fulvestrant alone, according to the study authors. Furthermore, the investigators noted that the ability of lasofoxifene to promote an antagonist conformation of Y537S, along with the modulator’s long half-life and bioavailability, “likely” contribute to its inhibition of primary tumor growth and metastasis of Y537S cells.
Moving forward, the study authors believe further clinical data regarding the use of lasofoxifene may come from ELAINE 2. This ongoing phase II trial is testing lasofoxifene in women with advanced or metastatic ER-positive/HER2-negative breast cancer expressing ERa mutants.
Disclosure: For full disclosures of the study authors, visit breast-cancer-research.com.