Lasofoxifene treatment of aromatase-resistant ER+cancer
Inventors
Komm, Barry Samuel • Greene, Geoffrey L.
Assignees
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Publication Number
US-12023321-B2
Publication Date
2024-07-02
Expiration Date
Abstract
The disclosure provides methods for treating estrogen receptor positive (ER+) cancer in a patient who has progressed on an aromatase inhibitor. Of particular interest are ER+ cancers that do not harbor a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. The provided methods involve the administration of an effective amount of lasofoxifene, a pharmaceutically acceptable salt, prodrug or functional derivative thereof.
Core Innovation
The invention relates to a method of reducing the progression of estrogen receptor positive and human epidermal growth factor receptor 2 negative (ER+/HER2−) breast cancer in a patient whose breast cancer has progressed on an aromatase inhibitor. The method is limited to cases in which the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, and comprises administering an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof.
In a further approach, the invention provides a method for reducing progression of ER+/HER2− breast cancer in the same clinical setting by administering lasofoxifene in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. The CDK4/6 inhibitor is selected from palbociclib, abemaciclib, or ribociclib, with optional addition of an AKT inhibitor or an mTOR inhibitor in dependent formulations.
In another approach, the invention further requires that the cancer has at least one variant in at least one gene set forth in Table 1, in addition to lacking an ESR1 LBD gain-of-function missense mutation. The disclosed rationale includes that, in an AI-resistant model lacking ERα activating mutations, lasofoxifene alone and especially with palbociclib more effectively inhibits primary tumor growth and shows potential inhibition of bone metastasis compared with fulvestrant plus palbociclib.
Claims Coverage
Three independent claims are directed to reducing progression of ER+/HER2− breast cancer after progression on an aromatase inhibitor, with exclusion of ESR1 LBD gain-of-function missense mutations. The independent claims cover lasofoxifene monotherapy, lasofoxifene with a CDK4/6 inhibitor, and lasofoxifene for cancers additionally meeting a Table 1 variant requirement.
Lasofoxifene for ER+/HER2− breast cancer progressed on an aromatase inhibitor without ESR1 LBD gain-of-function missense mutation
Reducing progression of ER+/HER2− breast cancer progressed on an aromatase inhibitor, where the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, by administering an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof.
Lasofoxifene with a CDK4/6 inhibitor for ER+/HER2− breast cancer progressed on an aromatase inhibitor without ESR1 LBD gain-of-function missense mutation
Reducing progression of ER+/HER2− breast cancer progressed on an aromatase inhibitor, where the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, by administering an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof in combination with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
Lasofoxifene for ER+/HER2− breast cancer progressed on an aromatase inhibitor without ESR1 LBD gain-of-function missense mutation and with at least one Table 1 gene variant
Reducing progression of ER+/HER2− breast cancer progressed on an aromatase inhibitor, where the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, and where the cancer has at least one variant in at least one gene set forth in Table 1, by administering an effective amount of lasofoxifene or a pharmaceutically acceptable salt thereof.
Across the independent claims, the core inventive framework is lasofoxifene-based treatment for ER+/HER2− breast cancer progressed on an aromatase inhibitor, restricted to cancers lacking ESR1 LBD gain-of-function missense mutations, with additional independent coverage for treatment in combination with a CDK4/6 inhibitor and for tumors meeting a Table 1 gene-variant criterion.
Stated Advantages
Reduces progression of ER+/HER2− breast cancer in patients whose disease has progressed on an aromatase inhibitor and whose cancer lacks ESR1 LBD gain-of-function missense mutations.
In combination with a CDK4/6 inhibitor, potentially inhibits metastasis of breast cancer to the bone.
Documented Applications
Treatment of ER+/HER2− breast cancer that has progressed on an aromatase inhibitor, in patients whose tumors lack ESR1 LBD gain-of-function missense mutations, using lasofoxifene.
Combination therapy use case: lasofoxifene administered with a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib) for reducing progression of ER+/HER2− breast cancer meeting the ESR1 LBD exclusion criterion.
Biomarker-stratified use case requiring that the cancer has at least one variant in at least one gene set forth in Table 1, in addition to lacking ESR1 LBD gain-of-function missense mutations, followed by administration of lasofoxifene.
Model support described: in a letrozole-induced AI-resistant MCF-7 LTLT model lacking ERα activating mutations, lasofoxifene alone and especially with palbociclib inhibits primary tumor growth and shows potential inhibition of bone metastasis compared with fulvestrant plus palbociclib.
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