Estrogen receptor mutations and uses thereof
Inventors
Cronin, Maureen T. • Frampton, Garrett Michael • Lipson, Doron • Miller, Vincent A. • Palmer, Gary • Ross, Jeffrey S. • Stephens, Philip James • Yelensky, Roman
Assignees
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Publication Number
US-12116638-B2
Publication Date
2024-10-15
Expiration Date
Abstract
Novel mutant ESR1 molecules and uses are disclosed.
Core Innovation
The invention relates to the detection of mutant estrogen receptor 1 (ESR1) polypeptides and mutant ESR1 nucleic acid molecules encoding those polypeptides in subjects with ER+ breast cancer, and to treating the breast cancer by administering an anti-estrogen agent. The description identifies novel ESR1 mutations in the ligand binding/hinge domains, including an in-frame deletion of nucleotides 1046–1051 of SEQ ID NO: 1, which causes deletion of amino acids LAD 349–351 and a histidine insertion at amino acid 349 of SEQ ID NO: 2.
The disclosed mutant ESR1 alterations also include specified missense variants and other indels within the same functional regions, including T311M, S341L, A350E, R394H, Q414*, S433P, R503W, Y537N, Y537C, and D538G. The mutant ESR1 alterations are linked to ER+ cancers, with emphasis on breast cancer, and are associated with altered estrogen/SERM responsiveness and hormone resistance, as well as disease progression. The use of these mutant ESR1 alterations is presented for selecting subjects and managing disease in ER+ breast cancer.
The invention further encompasses compositions and diagnostics including mutant ESR1 nucleic acids and mutant ESR1 polypeptides, detection reagents and kits, antibody reagents, and methods for detecting mutant ESR1 in tumor samples and circulating samples. Detection is described using hybridization approaches and sequencing/NGS, including PCR and allele-specific detection, as well as cytogenetic methods and protein assays. The disclosed diagnostic concepts include interrogation-position concepts, report generation, and reporter-based evaluation/screening for ESR1 modulators/antagonists.
Claims Coverage
The independent claim covers one inventive feature: a treatment method driven by detecting mutant ESR1 in ER+ breast cancer and then administering an anti-estrogen agent.
Mutant ESR1 detection and anti-estrogen treatment in ER+ breast cancer
Detecting in a sample from the subject a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, and an ER+ breast cancer, wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide comprises one or more of: missense mutations at amino acid positions 311, 341, 350, 394, 414, 433, 503, or 538 of SEQ ID NO: 2; a deletion of nucleotides 1046–1051 of SEQ ID NO: 1; an insertion between amino acid positions 344 and 345 of SEQ ID NO: 2; or a tyrosine to cysteine substitution at amino acid position 537 (Y537C) of SEQ ID NO: 2; and administering to the subject an effective amount of an anti-estrogen agent, thereby treating the breast cancer in the subject.
Overall claim coverage is centered on detecting specified mutant ESR1 alterations in a subject with ER+ breast cancer and administering an effective amount of an anti-estrogen agent to treat the breast cancer.
Stated Advantages
Provides a method for treating ER+ breast cancer by administering an anti-estrogen agent based on detecting specified mutant ESR1 alterations.
Documented Applications
Patient stratification and monitoring in ER+ breast cancer using detection of mutant ESR1 polypeptides or mutant ESR1 nucleic acid molecules in tumor samples and circulating samples.
Modified therapy decisions in ER+ breast cancer based on mutant ESR1 status, including using anti-estrogen strategies and related agent classes, including SERMs, SERDs such as fulvestrant, aromatase inhibitors, and mTOR pathway inhibitors.
Detection and diagnostic use cases for mutant ESR1 compositions, including mutant ESR1 nucleic acids and mutant ESR1 polypeptides, detection reagents, kits, and antibody reagents, and methods for detecting mutant ESR1 in tissues or circulating samples using hybridization, PCR/NGS sequencing, cytogenetic methods, and protein assays.
Screening and evaluation use cases for ESR1 modulators/antagonists using reporter-based evaluation/screening and interrogation-position concepts.
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