Lasofoxifene as a Potential Treatment for Therapy-Resistant ER-Positive Metastatic Breast Cancer

Muriel Lainé; Sean W. Fanning; Ya-Fang Chang; Bradley Green; Marianne E. Greene; Barry Komm; Justyna D. Kurleto; Linda Phung; Geoffrey L. Greene


Breast Cancer Res. 2021;23(54) 

In This Article

Abstract and Introduction


Background: Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated.

Methods: Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis.

Results: As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells.

Conclusions: We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.


Breast cancer is the most common cause of cancer mortality in women worldwide.[1] Approximately 80% of breast cancers are estrogen receptor positive (ER+).[2] Evidence suggests that estrogen receptor alpha (ERα, encoded by ESR1), a member of the nuclear receptor family of transcription factors, is involved in the initiation and progression of ER+ breast tumors.[3] Estradiol (E2) binding to the ER causes receptor dimerization to its active form for coactivator binding, leading to enhanced proliferation and survival of breast epithelial cells through the transcriptional modulation of genes.[3,4]

Endocrine therapy that inhibits ERα activity remains the mainstay of treatment for ER+ breast cancer. Tamoxifen, a selective estrogen receptor modulator (SERM), acts as a partial antagonist for ERα, and aromatase inhibitors (AIs) inhibit estrogen production.[3] However, a number of patients either are de novo resistant to these therapies[5] or become resistant after prolonged exposure to these drugs,[6] and experience cancer recurrence in the 5 to 20 years following treatment completion.[7] Fulvestrant (FUL), the only approved selective estrogen receptor down regulator (SERD), has been shown to be effective in treating endocrine therapy-resistant tumors,[8] but the challenges of drug resistance remain even for FUL.[9]

Several mechanisms have been suggested for endocrine-therapy resistance.[4,6] One important mechanism involves acquired ESR1 mutations under the selective pressure of endocrine therapy treatments, especially aromatase inhibitors. The ESR1 mutations are detected almost exclusively in the ligand binding domain (LBD), which includes the major transcriptional activating function-2 (AF2).[3] In patients with metastatic ER+ breast cancer, these mutations have been observed at a frequency of 10–40%, but are rarely detected in primary tumors.[10–12] The two most common ESR1 mutations are Y537S and D538G, located at the N-terminus of helix 12 (H12), a key structural regulator of coactivator recruitment in the LBD of ERα.[10–13] The conformational changes in H12 caused by these mutations give rise to a constitutively active receptor that can interact with coactivators, independent of ligand, and has reduced affinity for agonists and antagonists, thereby conferring reduced sensitivity of the mutants to endocrine drugs such as tamoxifen or FUL.[10–14] Additionally, allele-specific neomorphic properties found in these mutants could also contribute to cancer metastasis.[15] These limitations prompted the search for new treatment strategies that would be effective against breast cancers expressing known ERα mutants, including a SERM that might also alleviate postmenopausal symptoms related to estrogen loss, while inhibiting breast cancer progression. Raloxifene is the only SERM other than tamoxifen currently approved for reducing invasive breast cancer risk in postmenopausal women.[16] Bazedoxifene, a third-generation SERM, has shown potential anti-tumor effects in animal models with therapy-resistant breast cancer.[17,18]

Lasofoxifene (LAS), also a third-generation SERM, was developed to treat postmenopausal vaginal atrophy and osteoporosis[19] and approved but not used in Europe for osteoporosis treatment in postmenopausal women at increased risk of fracture.[20] In the Postmenopausal Evaluation and Risk-Reduction with Lasofoxifene (PEARL) trial, 5 years of LAS was associated with reduced risk of 79% for total breast cancers and 83% for invasive ER+ breast cancer and had beneficial effects on vertebral and non-vertebral fractures, coronary heart disease events, and stroke.[21] A network meta-analysis of randomized controlled trials on breast cancer chemoprevention agents showed that similar to raloxifene, LAS elicited a better benefit-risk profile than tamoxifen and AIs.[22] However, LAS has not been tested as a therapeutic option for progressive breast cancer. A recent cell-based study showed that the antagonist activity of LAS on ER+ breast cancer cells was not affected by the expression level of activating ERα mutants relative to wild-type (WT) ERα, a property not observed for other agents tested, including tamoxifen, bazedoxifene, raloxifene, and FUL.[23]

The objective of these studies was to investigate the potential benefit of LAS on endocrine-resistant ER+ metastatic breast cancer (MBC) in human-derived xenograft models harboring Y537S and D538G ESR1 mutations, the most commonly observed ERα mutations. In addition, effectiveness on tumor inhibition by LAS combined with palbociclib (PAL), a CDK4/6 inhibitor that blocks cell-cycle progression and has been shown to enhance the efficacy of endocrine agents,[24,25] was evaluated. Notably, LAS alone or in combination with PAL was an effective inhibitor of tumor growth in the MCF7 Y537S ERα+ MBC xenograft model. Additionally, the LAS/PAL combinations were notably more effective than the FUL/PAL combinations at inhibiting tumor growth and metastasis to the lung, liver, brain, and long bones. Structural analyses showed that LAS stabilizes an antagonist conformation of both WT and Y537S ERα LBDs.