CHICAGO—Findings suggest that lasofoxifene, in combination with CDK4/6 inhibitors like palbociclib, is a promising approach for the treatment of endocrine therapy resistant ER+ metastatic breast cancer patients (Abstract 1056).
“Lasofoxifene is a legacy molecule originally developed for the treatment of osteoporosis and vaginal dryness,” noted Geoffrey L. Greene, PhD, Virginia and D. K. Ludwig Professor and Chair of the Ben May Department for Cancer Research at the University of Chicago. “However, as a selective estrogen receptor modulator, lasofoxifene, when examined in preclinical models of breast cancer, was shown to demonstrate efficacy in the inhibition of cancer cell proliferation.
“Data generated and patented at Duke University not only supported the fact that lasofoxifene effectively inhibited human breast cancer proliferation, but also was shown in vitro to inhibit transcriptional regulation by a variety of estrogen receptor constructs bearing ligand-binding domain mutations commonly seen in metastatic human breast cancer.”
Greene and his colleagues at the University of Chicago undertook the current research to “expand upon the Duke findings in appropriate and translatable animal models in order to support our hypothesis that lasofoxifene would effectively inhibit tumor growth and metastatic invasion.
“These data supported moving forward with clinical trials, and since we also demonstrated improved efficacy compared to fulvestrant, we felt that a comparative study to the gold standard hormonal therapy was in order,” explained Greene, who is also Professor at the Department of Biochemistry and Molecular Biology, and Associate Director of Basic Sciences at the University of Chicago Comprehensive Cancer Center. “Additionally, with current clinical practice embracing combination therapy approaches, we have run studies to evaluate the synergistic and/or additive effects of combining lasofoxifene with CDK4/6 inhibitors.”
The study compares lasofoxifene + palbociclib to fulvestrant + palbociclib, both as far as their level of synergy goes, if any, on both tumor growth and metastases, noted Greene.
Researchers first determined the optimal dose of lasofoxifene in an intraductal (MIND) xenograft model of MCF-7 cells that express active ERα Y537S and D538G. “Subsequently, we performed combination studies with lasofoxifene (10 mg/kg 5/week SQ) +/- palbociclib (100 mg/kg gavage, 5/week) or fulvestrant (5 mg/mouse/week, SQ) +/- palbociclib,” the study authors reported.
“The animal model is a relatively newly developed one; instead of injecting the tumor cells into the fat pad of the recipient mouse, they are injected intraductally into the mammary gland,” explained Greene. “This more ‘natural’ environment results in the cells maintaining their phenotypic and genotypic character, unlike what often occurs when placed into the fat pad.
“Hypothetically, the response to test drugs would therefore be more predictive and provide more sound rationale for moving on to human clinical assessment,” he continued.
The findings demonstrated that lasofoxifene alone was significantly more effective than fulvestrant at inhibiting the metastasis of both MCF7 Y537S and D538G tumors to the lungs and liver, according to Greene.
Additionally, he reported that lasofoxifene plus palbociclib was more effective than fulvestrant in combination with palbociclib at reducing primary tumor growth and both combinations demonstrated an increased response compared to their individual efficacy.
“Lasofoxifene plus palbociclib was more effective at inhibiting liver metastasis than either drug alone and was more effective than fulvestrant plus palbociclib at reducing metastasis to the liver and lung,” Greene told Oncology Times.
In addition, “structural studies showed that lasofoxifene effectively disrupts the active conformation of the ERα Y537S ligand-binding domain providing a rationale for lasofoxifene’s efficacy with an ER that is constitutively active,” he outlined.
This study supports the additional study of this treatment approach. “This research lends further justification for the evaluation of lasofoxifene as a therapy for hormone treatment resistant metastatic breast cancer and for potentially improved efficacy when combined with a CDK4/6 inhibitor,” emphasized Greene.
“Not only does lasofoxifene demonstrate improved efficacy compared to the commonly utilized fulvestrant (intramuscular injection—painful and not well-tolerated), but it is dosed orally, once/day, has a well-established safety and tolerability profile, and also would have positive effects on the skeleton and vagina in this post-menopausal population of women.”
The next steps for the research team are to repeat the combination studies prior to publication and expand the combination studies looking at other CDK4/6 inhibitors (e.g., abemaciclib) and possibly mTOR inhibitors, according to Greene.
The FDA recently granted Fast Track designation for lasofoxifene as a potential precision medicine treatment for patients with estrogen receptor-positive (ER+) metastatic breast cancer with an ESR1 mutation.
“This could help expedite [the] phase II open-label, randomized, multi-center Evaluation of Lasofoxifene in ESR1 Mutations(ELAINE) clinical study,” Greene noted. “The study will assess the activity of oral lasofoxifene versus intramuscular fulvestrant for the treatment of postmenopausal women with locally advanced or metastatic estrogen receptor-positive (ER+)/HER2- breast cancer with an ESR1 mutation.”