US20190231718A1 - Treatment of breast cancer - Google Patents

Treatment of breast cancer Download PDF

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US20190231718A1
US20190231718A1 US16/341,033 US201716341033A US2019231718A1 US 20190231718 A1 US20190231718 A1 US 20190231718A1 US 201716341033 A US201716341033 A US 201716341033A US 2019231718 A1 US2019231718 A1 US 2019231718A1
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patient
inhibitor
mutation
therapy
gain
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Kaitlyn Andreano
Ching-Yi Chang
Donald P. McDonnell
Stephanie L. Gaillard
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Duke University
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
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    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • Estrogen receptor positive (ER + ) breast cancers are a group of breast cancers that express estrogen receptor ⁇ (ER ⁇ ). Approximately 70% of breast cancers are ER + and are, therefore, treated with endocrine therapy. Endocrine therapy has led to significant improvement in outcome of women with ER + breast cancer by lowering the level of estrogen or blocking estrogen signaling. However, its effectiveness is limited by intrinsic and acquired endocrine resistance.
  • ESR1 Estrogen Receptor 1
  • ER ⁇ expression constructs to express four ESR1 mutations in the ligand binding domain (LBD) of the ER ⁇ protein, Y537S, Y537N, Y537C, and D538G, and introduced these expression constructs into cells in culture. These mutations are found in ER + metastatic breast cancer patients who have been treated with endocrine therapy.
  • a method of treating locally advanced or metastatic breast cancer in women comprises selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) locally advanced or metastatic breast cancer, and administering to the selected patient an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • ER + estrogen receptor positive
  • the selected patient has previously been treated with one or more lines of endocrine therapy. In certain embodiments, the patient has previously been treated with a plurality of lines of endocrine therapy.
  • the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM). In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD).
  • SERM selective ER modulator
  • SESD selective ER degrader
  • the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor.
  • the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • the patient has disease progression after endocrine therapy. In some embodiments, the patient is resistant to endocrine therapy.
  • the patient's cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • the method further comprises determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, or E380.
  • the at least one gain of function missense mutation is in the amino acid D538. In some preferred embodiments the mutation is D538G.
  • the at least one gain of function missense mutation is in the amino acid Y537.
  • the mutation is Y537S, Y537N, Y537C, or Y537Q. In some preferred embodiments, the mutation is Y537C.
  • the at least one gain of function missense mutation is in the amino acid L536. In some embodiments, the mutation is L536R or L536Q.
  • the at least one gain of function missense mutation is in the amino acid P535. In some embodiments, the mutation is P535H.
  • the at least one gain of function missense mutation is in the amino acid V534. In some embodiments, the mutation is V534E.
  • the at least one gain of function missense mutation is in the amino acid S463. In some embodiments, the mutation is S463P.
  • the at least one gain of function missense mutation is in the amino acid V392. In some embodiments, the mutation is V392I.
  • the at least one gain of function missense mutation is in the amino acid E380. In some embodiments, the mutation is E380Q.
  • the serum estradiol level of the patient is at least 0.35 ng/dL. In some embodiments, the serum estradiol level of the patient is about 0.30 ng/dL to about 0.35 ng/dL. In yet some embodiments, the serum estradiol level of the patient is about 0.25 ng/dL to about 0.30 ng/dL.
  • the compound is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. In various embodiments, the compound is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.
  • the method further comprises treating the patient with at least one additional endocrine therapy.
  • the patient is treated with the additional endocrine therapy at original doses.
  • the patient is treated with the additional endocrine therapy at doses higher than original doses.
  • the additional endocrine therapy is treatment with lasofoxifene.
  • the additional endocrine therapy is treatment with an aromatase inhibitor.
  • the method further comprises administering to the ER + locally advanced or metastatic breast cancer patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
  • CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib.
  • the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.
  • mTOR mammalian target of rapamycin
  • the mTOR inhibitor is Everolimus.
  • the method further comprises administering to the patient an effective amount of phosphoinositide 3-kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.
  • PI3K phosphoinositide 3-kinase
  • HSP90 heat shock protein 90
  • the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.
  • HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).
  • the method further comprises administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.
  • Vorinostat Zaolinza®
  • the method further comprises administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervoy®).
  • the method further comprises administering to the patient an effective amount of cancer vaccine.
  • the patient is premenopausal. In certain embodiments, the patient has locally advanced or metastatic ER+/HER2-breast cancer. In some of these embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • fulvestrant AI in combination with a CDK4/6 inhibitor
  • fulvestrant in combination with a CDK4/6 inhibitor
  • the patient is perimenopausal. In certain embodiments, the patient has locally advanced or metastatic ER+/HER2 ⁇ breast cancer. In some of these embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • fulvestrant AI in combination with a CDK4/6 inhibitor
  • fulvestrant in combination with a CDK4/6 inhibitor
  • the patient is postmenopausal. In certain embodiments, the patient has locally advanced or metastatic ER+/HER2 ⁇ breast cancer. In some of these embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • fulvestrant AI in combination with a CDK4/6 inhibitor
  • fulvestrant in combination with a CDK4/6 inhibitor
  • a method of treating primary breast cancer in women comprises selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) primary breast cancer, and administering to the selected patient an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • ER + estrogen receptor positive
  • the compound is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.
  • the compound is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.
  • the method of treating ER + primary breast cancer further comprises treating the patient with at least one additional endocrine therapy.
  • the patient is treated with the additional endocrine therapy at original doses.
  • the patient is treated with the additional endocrine therapy at doses higher than original doses.
  • the additional endocrine therapy is treatment with lasofoxifene.
  • the additional endocrine therapy is treatment with an aromatase inhibitor.
  • the method further comprises administering to the ER + primary breast cancer patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
  • CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib.
  • the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.
  • mTOR mammalian target of rapamycin
  • the mTOR inhibitor is Everolimus.
  • the method further comprises administering to the patient an effective amount of phosphoinositide 3-kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.
  • PI3K phosphoinositide 3-kinase
  • HSP90 heat shock protein 90
  • the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.
  • HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).
  • the method further comprises administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.
  • Vorinostat Zaolinza®
  • the method further comprises administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervoy®).
  • the method further comprises administering to the patient an effective amount of cancer vaccine.
  • the patient is premenopausal. In certain embodiments, the patient is perimenopausal. In certain embodiments, the patient is postmenopausal.
  • a method of adjuvant therapy for estrogen receptor positive (ER+) breast cancer comprises administering to a patient who has received primary treatment for ER+ breast cancer an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof, in combination with an aromatase inhibitor.
  • the compound is administered continuously during the administration of the aromatase inhibitor. In some embodiments, the compound is administered cyclically during the administration of the aromatase inhibitor. In certain embodiments, the dosing regimen of the compound is different from the dosing regimen of the aromatase inhibitor.
  • the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).
  • the compound is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. In various embodiments, the compound is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.
  • the method of adjuvant therapy for estrogen receptor positive (ER+) breast cancer further comprises treating the patient with at least one additional endocrine therapy.
  • the additional endocrine therapy is treatment with lasofoxifene.
  • the method of adjuvant therapy for estrogen receptor positive (ER+) breast cancer further comprises administering to the patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
  • CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib.
  • the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.
  • mTOR mammalian target of rapamycin
  • the mTOR inhibitor is Everolimus.
  • the method further comprises administering to the patient an effective amount of phosphoinositide 3-kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.
  • PI3K phosphoinositide 3-kinase
  • HSP90 heat shock protein 90
  • the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.
  • HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).
  • the method further comprises administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.
  • Vorinostat Zaolinza®
  • the method further comprises administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervoy®).
  • the method further comprises administering to the patient an effective amount of cancer vaccine.
  • the patient is premenopausal. In certain embodiments, the patient is perimenopausal. In certain embodiments, the patient is postmenopausal.
  • a method of treating cancers other than breast cancer in women comprises selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) cancer, other than breast cancer, and has at least one gain of function mutations in the Estrogen Receptor 1 (ESR1) gene, and administering to the selected patient an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the patient has been diagnosed with ER + ovarian cancer.
  • the patient has been diagnosed with ER + lung cancer.
  • the compound is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.
  • the compound is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.
  • the method of treating ER + cancer, other than breast cancer further comprises treating the patient with at least one additional endocrine therapy.
  • the patient is treated with the additional endocrine therapy at original doses.
  • the patient is treated with the additional endocrine therapy at doses higher than original doses.
  • the additional endocrine therapy is treatment with lasofoxifene.
  • the additional endocrine therapy is treatment with an aromatase inhibitor.
  • the method further comprises administering to the patient with ER + cancer, other than breast cancer, an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor.
  • CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib.
  • the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.
  • mTOR mammalian target of rapamycin
  • the mTOR inhibitor is Everolimus.
  • the method further comprises administering to the patient an effective amount of phosphoinositide 3-kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.
  • PI3K phosphoinositide 3-kinase
  • HSP90 heat shock protein 90
  • the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.
  • HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).
  • the method further comprises administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.
  • Vorinostat Zaolinza®
  • the method further comprises administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervoy®).
  • the method further comprises administering to the patient an effective amount of cancer vaccine.
  • the patient is premenopausal. In certain embodiments, the patient is perimenopausal. In certain embodiments, the patient is postmenopausal.
  • the patient has primary breast cancer.
  • the primary breast cancer is locally advanced.
  • the patient has been treated with endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii).
  • SERM selective ER modulator
  • SELD selective ER degrader
  • AI aromatase inhibitor
  • the primary breast cancer is locally advanced.
  • the patient has been treated with endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii).
  • SERM selective ER modulator
  • SELD selective ER degrader
  • AI aromatase inhibitor
  • the selected patient has previously been treated with one or more lines of endocrine therapy. In certain embodiments, the patient has previously been treated with a plurality of lines of endocrine therapy.
  • the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM). In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD).
  • SERM selective ER modulator
  • SESD selective ER degrader
  • the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor.
  • the aromatase inhibitor is exemestane (Aromasin®), letrozole (Ferrara®), or anastrozole (Arimidex®).
  • the patient's cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • the method further comprises determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • the at least one gain of function missense mutation is in the amino acid L536. In some embodiments, the mutation is L536R or L536Q.
  • the at least one gain of function missense mutation is in the amino acid V534. In some embodiments, the mutation is V534E.
  • the at least one gain of function missense mutation is in the amino acid S463. In some embodiments, the mutation is S463P.
  • the at least one gain of function missense mutation is in the amino acid E380. In some embodiments, the mutation is E380Q.
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.
  • Vorinostat Zaolinza®
  • the method further comprises administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervoy®).
  • the method further comprises administering to the patient an effective amount of cancer vaccine.
  • the patient is premenopausal. In certain embodiments, the patient has locally advanced or metastatic ER+/HER2 ⁇ breast cancer. In some of these embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • fulvestrant AI in combination with a CDK4/6 inhibitor
  • fulvestrant in combination with a CDK4/6 inhibitor
  • FIGS. 1A, 1B, 1C, 1D, 1E, and 1F show the effects of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant on ESR1 wild type and ligand binding domain (“LBD”) mutations in Caov2 ovarian carcinoma cells, with FIG. 1A demonstrating that the mutant receptors are constitutively active and do not respond to 17- ⁇ estradiol (“E2”), FIG.
  • FIG. 1B demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (“4OHT”), the 4-hydroxy metabolite of etacstil (“GW-7604”), and fulvestrant (“ICI”) each inhibits activity of the ESR1 wild type receptor
  • FIG. 1C showing that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the Y537N mutant receptor activity in a dose-response manner
  • FIG. 1D demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the Y537S mutant receptor activity in a dose-response manner
  • FIG. 1E demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the Y537C mutant receptor activity in a dose-response manner
  • FIGS. 2A, 2B, 2C, 2D, and 2E show the effects of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant on ESR1 wild type and LBD mutations in Caov2 ovarian carcinoma cells
  • FIG. 2A demonstrates that fulvestrant (ICI) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 2B demonstrating that 4-hydroxytamoxifen (4OHT) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 2C demonstrating that raloxifene inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 2A demonstrating that fulvestrant (ICI) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 2B demonstrating that 4-hydroxytamoxifen (4OHT) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIGS. 3A, 3B, 3C, 3D, 3E, and 3F show the effects of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant on ESR1 wild type and LBD mutations in SKBR3 breast adenocarcinoma cells, with FIG. 3A demonstrating that the mutant receptors are constitutively active and do not respond to 17- ⁇ estradiol (E2), FIG. 3B demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the ESR1 wild type receptor activity, FIG.
  • FIG. 3C demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the Y537N mutant receptor activity in a dose-response manner
  • FIG. 3D showing that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the Y537S mutant receptor activity in a dose-response manner
  • FIG. 3E demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the Y537C mutant receptor activity in a dose-response manner
  • FIG. 3F demonstrating that raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), the 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each inhibits the D538G mutant receptor activity in a dose-response manner.
  • FIGS. 4A, 4B, 4C, 4D, and 4E show the effects of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant on ESR1 wild type and LBD mutations in SKBR3 breast adenocarcinoma cells
  • FIG. 4A demonstrates that fulvestrant (ICI) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 4B showing that 4-hydroxytamoxifen (4OHT) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 4C demonstrating that raloxifene inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 4A demonstrating that fulvestrant (ICI) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 4B showing that 4-hydroxytamoxifen (4OHT) inhibits the ESR1 wild type and the ESR1 LBD mutant
  • FIG. 4D demonstrating that adoxifene inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity
  • FIG. 4E demonstrating that the 4-hydroxy metabolite of etacstil (GW-7604) inhibits the ESR1 wild type and the ESR1 LBD mutant receptor activity.
  • Endocrine therapy is often used for treatment and prevention of ER + breast cancers.
  • Different types of endocrine therapy include selective ER modulators (SERMs), selective ER degraders (SERDs), and aromatase inhibitors (AIs).
  • SERMs selective ER modulators
  • SELDs selective ER degraders
  • AIs aromatase inhibitors
  • ESR1 Estrogen Receptor 1
  • raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant each inhibits the mutant receptor activity in a dose-responsive manner, newly making possible methods of treating ER + locally advanced or metastatic breast cancer, ER + primary breast cancer, and other ER + cancers, including cancers having ESR1 mutations, using raloxifene, apeledoxifene, tamoxifen, etacstil, or fulvestrant, whose effectiveness is not precluded by endocrine resistance.
  • ER + estrogen receptor positive
  • methods of treating cancers in women comprising selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) cancer.
  • the selected patient is treated with an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the patient has been diagnosed with ER + cancer by immunohistochemistry (IHC) performed on a sample of the patient's cancer.
  • IHC immunohistochemistry
  • the patient has been diagnosed with locally advanced or metastatic ER + breast cancer. In some embodiments, the patient has been diagnosed with ER + primary breast cancer. In some embodiments, the patient has been diagnosed with an ER + cancer other than breast cancer. In some of these embodiments, the patient has been diagnosed with ER + ovarian cancer. In some of these embodiments, the patient has been diagnosed with ER + lung cancer.
  • cells of the patient's cancer have acquired a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.
  • LBD ligand binding domain
  • ESR1 Estrogen Receptor 1
  • the patient is at risk of acquiring resistance to endocrine therapy.
  • the patient is at risk of acquiring resistance to endocrine therapy due to the increased expression of estrogen receptor.
  • the patient is at risk of acquiring resistance to endocrine therapy due to the increased expression of co-activators of estrogen receptor.
  • the patient is at risk of acquiring resistance to endocrine therapy due to increased phosphorylation level and activity of estrogen receptor and its co-activators.
  • the patient is at risk of acquiring resistance to endocrine therapy due to change of tumor microenvironment and other host related factors.
  • the patient is at risk of acquiring resistance to endocrine therapy due to mutations in the Estrogen Receptor 1 (ESR1) gene.
  • ESR1 Estrogen Receptor 1
  • resistance to endocrine therapy is resistance to (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii).
  • SERM selective ER modulator
  • SELD selective ER degrader
  • AI aromatase inhibitor
  • the ER + cancer patient has previously been treated with one or more lines of endocrine therapy. In certain embodiments, the patient has previously been treated with one line of endocrine therapy. In certain other embodiments, the patient has previously been treated with a plurality of lines of endocrine therapy. In some embodiments, the patient has previously been treated with two lines of endocrine therapy. In some embodiments, the patient has previously been treated with three lines of endocrine therapy. In some embodiments, the patient has previously been treated with four or more lines of endocrine therapy.
  • the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM).
  • SERM selective ER modulator
  • the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD).
  • SESD selective ER degrader
  • the selective ER degrader binds to the estrogen receptor and leads to the proteasomal degradation of the receptor.
  • the endocrine therapy with which the patient has previously been treated is an aromatase inhibitor (AI).
  • AI aromatase inhibitor
  • the aromatase inhibitor blocks the production of estrogen.
  • the aromatase inhibitor is selected from exemestane (Aromasin®), letrozole (Ferrara®), and anastrozole (Arimidex®).
  • the endocrine therapy that the patient has previously been treated with is ovarian suppression.
  • ovarian suppression is achieved by oophorectomy.
  • ovarian suppression is achieved by administration of a GnRH antagonist.
  • the patient's cancer has progressed or relapsed after the previous endocrine therapy treatment. In some embodiments, the patient's cancer has progressed or relapsed after aromatase inhibitor treatment. In some of these embodiments, the patient's cancer has progressed or relapsed after multiple lines of endocrine therapy treatment.
  • the ER + cancer patient has not been treated previously with endocrine therapy.
  • the patient is resistant to endocrine therapy.
  • the patient has intrinsic endocrine resistance.
  • the patient has acquired endocrine resistance.
  • the patient is resistant to endocrine therapy due to the increased expression of estrogen receptor.
  • the patient is resistant to endocrine therapy due to the increased expression of co-activators of estrogen receptor.
  • the patient is resistant to endocrine therapy due to increased phosphorylation level and activity of estrogen receptor and its co-activators.
  • the patient is resistant to endocrine therapy due to change of tumor microenvironment and other host related factors.
  • the patient is resistant to endocrine therapy due to gene mutations in the Estrogen Receptor 1 (ESR1) gene.
  • the patient is resistant to clinical doses of one or more SERMs. In various embodiments, the patient is resistant to clinical doses of one or more SERDs. In various embodiments, the patient is resistant to clinical doses of one or more aromatase inhibitors. In various embodiments, the patient is resistant to higher than clinical doses of one or more SERMs. In various embodiments, the patient is resistant to higher than clinical doses of one or more SERDs. In various embodiments, the patient is resistant to higher than clinical doses of one or more aromatase inhibitors.
  • the ER + cancer patient has not been demonstrated to have endocrine resistance. In some of these embodiments, the patient has not been demonstrated to have endocrine resistance due to the limitations of the detection methods.
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered to the ER + cancer patient after completion of cancer treatment. In some of these embodiments, the compound is administered to the patient to treat occult micrometastasis.
  • the ER + cancer patient is premenopausal.
  • the patient is premenopausal and has locally advanced or metastatic ER + cancer.
  • the patient is premenopausal and has locally advanced or metastatic ER + breast cancer.
  • the ER + cancer patient is perimenopausal.
  • the patient is perimenopausal and has locally advanced or metastatic ER + cancer.
  • the patient is perimenopausal and has locally advanced or metastatic ER + breast cancer.
  • the ER + cancer patient is postmenopausal.
  • the patient is postmenopausal and has locally advanced or metastatic ER + cancer.
  • the patient is postmenopausal and has locally advanced or metastatic ER + breast cancer.
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered to a premenopausal woman with locally advanced or metastatic ER + /HER2 ⁇ breast cancer.
  • the compound is administered to a premenopausal woman with locally advanced or metastatic ER + /HER2 ⁇ breast cancer who has progressed while on her first hormonal treatment with a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered to a perimenopausal woman with locally advanced or metastatic ER + /HER2 ⁇ breast cancer.
  • the compound is administered to a perimenopausal woman with locally advanced or metastatic ER + /HER2 ⁇ breast cancer who has progressed while on her first hormonal treatment with a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered to a postmenopausal woman with locally advanced or metastatic ER + /HER2 ⁇ breast cancer.
  • the compound is administered to a postmenopausal woman with locally advanced or metastatic ER + /HER2 ⁇ breast cancer who has progressed while on her first hormonal treatment with a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.
  • AI non-steroid aromatase inhibitor
  • the patient has an ER + cancer, cells of which have at least one mutation in the Estrogen Receptor 1(ESR1) gene, which encodes the Estrogen Receptor ⁇ (ER ⁇ ) protein.
  • the mutation leads to the ligand-independent activity of the estrogen receptor.
  • the mutation leads to enhanced ligand stimulated activity of estrogen receptor.
  • the mutation leads to resistance to endocrine therapy.
  • the mutation promotes tumor growth.
  • the mutation enhances metastatic activity of cancer.
  • the mutation enhances metastatic activity of ER + metastatic breast cancer.
  • the mutation arises from a rare and undetectable pre-existing clone.
  • the mutation is acquired de novo during the course of endocrine therapy treatment.
  • the mutation is acquired de novo during the course of endocrine therapy treatment of breast cancer.
  • the mutation is acquired de novo after multiple lines of endocrine therapy treatment.
  • the mutation is acquired de novo after multiple lines of endocrine therapy treatment of metastatic breast cancer.
  • the mutant clone expands to become a more dominant clone over the course of successive lines of endocrine therapy.
  • the mutation in the ESR1 gene is missense point mutation. In some embodiments, the mutation in the ESR1 gene is truncating mutation. In some embodiments, the mutation in the ESR1 gene is gene amplification. In some embodiments, the mutation in the ESR1 gene is genomic rearrangement.
  • the patient has an ER + cancer that has at least one gain of function missense mutation within the ligand binding domain (LBD) of the ESR1 gene.
  • LBD ligand binding domain
  • at least one of the mutations is in an amino acid selected from D538, Y537, L536, P535, V534, S463, V392, and E380. (The amino acids are numbered according to the ESR1 protein with the NCBI accession number NP_000116.2.)
  • the mutation increases the stability of the agonist conformation of Helix 12 of the ER ⁇ protein. In some of these embodiments, the mutation increases the binding of the estrogen receptor to its co-activators. In some of these embodiments, the mutation leads to hormone independent activity of estrogen receptor. In some of these embodiments, the mutation leads to resistance to a SERM, a SERD, and/or an aromatase inhibitor.
  • the mutation is in the amino acid D538. In certain preferred embodiments, the mutation is D538G.
  • the mutation is in the amino acid Y537. In some of these embodiments, the mutation is Y537S, Y537N, Y537C, or Y537Q. In certain preferred embodiments, the mutation is Y537C.
  • the mutation is in the amino acid L536. In certain embodiments, the mutation is L536R or L536Q.
  • the mutation is in the amino acid P535. In certain embodiments, the mutation is P535H.
  • the mutation is in the amino acid V534. In certain embodiments, the mutation is V534E.
  • the mutation is in the amino acid S463. In certain embodiments, the mutation is S463P.
  • the mutation is in the amino acid V392. In certain embodiments, the mutation is V392I.
  • the mutation is in the amino acid E380. In certain embodiments, the mutation is E380Q.
  • the patient has been previously determined to have at least one mutation in the ESR1 gene.
  • Some embodiments of the methods described herein further include the step of detecting mutations in the ESR1 gene.
  • massively parallel next generation sequencing is used for detecting the estrogen receptor mutations in the patient's cancer.
  • the entire genome is sequenced.
  • selected gene panels of cancer-related genes are sequenced.
  • all coding exons within a given set of genes are sequenced.
  • known “hotspot” regions within a given set of genes are sequenced.
  • the inherent error rate of current next generation sequencing techniques is up to 1%, limiting the sensitivity and specificity of detection.
  • targeted sequencing is used for detecting the presence of the ESR1 mutations. Although targeted sequencing allows deeper sequencing, it is also currently limited by the 1% error rate. In some embodiments, methods with reduced sequencing error rate are used.
  • Safe-Sequencing System (Safe-SeqS) is used, which tags each template molecule to allow for confident identification of rare variants. See kinde et al., Proceedings of the National Academy of Sciences 108(23): 9530-9535 (2011).
  • ultrasensitive Duplex sequencing is used, which independently tags and sequences each of the two strands of a DNA duplex. See Schmitt et al., Proceedings of the National Academy of Sciences 109(36): 14508-14513 (2012).
  • digital droplet PCR is used, which emulsifies DNA in thousands to millions of droplets to encapsulate single DNA molecules, designed with mutant specific primers. See Vogelstein and Kinzler, Proceedings of the National Academy of Sciences 96(16): 2322-2326 (1999) and Huggett et al., Clinical Chemistry 61(1): 79-88 (2014).
  • the detection of the ESR1 mutations takes place at the initial diagnosis. In some embodiments, the detection of the mutations takes place at the time of disease progression, relapse, or recurrence. In some embodiments, the detection of the mutations takes place at the time of disease progression. In some embodiments, the detection of the mutations takes place at the time when the disease is stable.
  • one or more tissue specimens are obtained for detection of the mutations.
  • the tissue specimen is a tumor biopsy.
  • the tissue specimen is a biopsy of metastases.
  • liquid biopsies are obtained for detection of the mutations.
  • the liquid biopsy is circulating tumor cells (CTCs).
  • the liquid biopsy is cell-free DNA from blood samples.
  • the ESR1 mutations are monitored by circulating tumor DNA (ctDNA) analysis.
  • the ctDNA analysis is performed throughout the course of treatment.
  • the ctDNA is extracted from patient blood samples.
  • the ctDNA is evaluated by digital PCR analysis of the ESR1 mutations.
  • the patient selected for treatment based on presence of ESR1 gene mutations is further selected based on serum estradiol level.
  • the serum estradiol level of the patient with the ER + cancer having an ESR1 gene mutation is at least 0.20 ng/dL, such as at least 0.25 ng/dL, at least 0.30 ng/dL, at least 0.35 ng/dL, at least 0.40 ng/dL, at least 0.45 ng/dL, at least 0.50 ng/dL, at least 0.55 ng/dL, at least 0.60 ng/dL, at least 0.65 ng/dL, at least 0.70 ng/dL, at least 0.75 ng/dL, at least 0.80 ng/dL, at least 0.85 ng/dL, at least 0.90 ng/dL, at least 0.95 ng/dL, or at least 1.0 ng/dL.
  • the serum estradiol level of the patient with the ESR1 gene mutation is about 0.20 ng/dL to about 1.0 ng/dL, such as about 0.20 ng/dL to about 0.25 ng/dL, about 0.25 ng/dL to about 0.30 ng/dL, about 0.30 ng/dL to about 0.35 ng/dL, about 0.35 ng/dL to about 0.40 ng/dL, about 0.40 ng/dL to about 0.45 ng/dL, about 0.45 ng/dL to about 0.50 ng/dL, about 0.50 ng/dL to about 0.55 ng/dL, about 0.55 ng/dL to about 0.60 ng/dL, about 0.60 ng/dL to about 0.65 ng/dL, about 0.65 ng/dL to about 0.70 ng/dL, about 0.70 ng/dL to about 0.75 ng/dL, about 0.75 ng/dL to about 0.80 ng
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered to the patient as adjuvant treatment.
  • the compound is administered to the patient as adjuvant treatment alone.
  • the compound is administered to the patient as adjuvant treatment in combination with other endocrine therapies.
  • the compound is administered to the patient after the primary treatment. In some of these embodiments, the compound is administered to the patient after surgical removal or debulking of the cancer.
  • the compound is administered to the patient as adjuvant therapy in combination with an aromatase inhibitor (AI).
  • AI aromatase inhibitor
  • the aromatase inhibitor is exemestane (Aromasin®), letrozole (Ferrara®), or anastrozole (Arimidex®).
  • the compound is administered continuously during the administration of the aromatase inhibitor. In some other embodiments, the compound is administered cyclically during the administration of the aromatase inhibitor. In some embodiments, the compound and the aromatase inhibitor are administered together (simultaneously). In some other embodiments, the compound and the aromatase inhibitor are administered separately (sequentially).
  • the dosing regimen of the compound is different from the dosing regimen of the aromatase inhibitor.
  • the dosing quantity of the compound is different from the dosing quantity of the aromatase inhibitor.
  • the dosing schedule of the compound is different from the dosing schedule of the aromatase inhibitor.
  • the route of administration of the compound is different from the route of administration of the aromatase inhibitor.
  • the dosing regimen of the compound is the same as the dosing regimen of the aromatase inhibitor.
  • the dosing quantity of the compound is the same as the dosing quantity of the aromatase inhibitor.
  • the dosing schedule of the compound is the same as the dosing schedule of the aromatase inhibitor.
  • the route of administration of the compound is the same as the route of administration of the aromatase inhibitor.
  • the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for one year. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for two years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for three years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for four years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for five years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for six years.
  • the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for seven years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for eight years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for nine years. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for ten years. In some other embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for more than ten years. In certain embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor until the patient's cancer progresses on therapy.
  • the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to increase the disease-free survival of the breast cancer patient. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to decrease the incidence of contralateral breast cancer. In some embodiments, the compound is administered as adjuvant therapy in combination with an aromatase inhibitor to prevent the recurrence and progression of the cancer.
  • the selected patient is treated with an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the compound is raloxifene.
  • the compound is apeledoxifene.
  • the compound is tamoxifen.
  • the compound is etacstil.
  • the compound is fulvestrant.
  • pharmaceutically acceptable salt refers to non-toxic pharmaceutically acceptable salts. See Gould, International Journal of Pharmaceutics 33: 201-217 (1986) and Berge et al., Journal of Pharmaceutical Sciences 66(1): 1-19 (1977). Other salts well known to those in the art may, however, be used.
  • organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.
  • Organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • Embodiments also include prodrugs of the compounds disclosed herein.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “ Design of Prodrugs”, H. Bundgaard, Elsevier, 1985.
  • Some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.
  • the processes for the preparation of the compounds as disclosed herein give rise to mixtures of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid.
  • the compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, cis-trans isomers, and enantiomers thereof are encompassed by some embodiments.
  • Methods for treatment of estrogen receptor positive (ER + ) cancers include administering a therapeutically effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • the compound, the pharmaceutically acceptable salt, or the prodrug of the invention can be formulated in pharmaceutical compositions.
  • the composition further comprises a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material can depend on the route of administration, e.g. oral, intravenous, intramuscular, transdermal, vaginal topical, or vaginal ring.
  • compositions for oral administration can be in tablet, capsule, powder or liquid form.
  • a tablet can include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal oil, vegetable oil, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can also be included.
  • the compound will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilizers, buffers, antioxidants and/or other additives can be included, as required.
  • compositions for vaginal topical administration can be in the form of ointment, cream, gel or lotion.
  • the pharmaceutical compositions for vaginal topical administration often include water, alcohol, animal oil, vegetable oil, mineral oil or synthetic oil. Hydrocarbon (paraffin), wool fat, beeswax, macrogols, emulsifying wax or cetrimide can also be included.
  • a composition can be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.
  • treatment In the methods of administering an effective amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant in the form of a pharmaceutical composition as described above for treatment of ER + cancer, the terms “treatment”, “treating”, and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic, in terms of completely or partially preventing a disease, condition, or symptoms thereof, and/or may be therapeutic in terms of a partial or complete cure for a disease or condition and/or adverse effect, such as a symptom, attributable to the disease or condition.
  • Treatment covers any treatment of a disease or condition of a mammal, particularly a human, and includes: (a) preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition (e.g., arresting its development); or (c) relieving the disease or condition (e.g., causing regression of the disease or condition, providing improvement in one or more symptoms). Improvements in any conditions can be readily assessed according to standard methods and techniques known in the art.
  • the population of subjects treated by the method of the disease includes subjects suffering from the undesirable condition or disease, as well as subjects at risk for development of the condition or disease.
  • the term “effective amount” means a dose that produces the desired effect for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques. See Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999).
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered by oral, intravenous, intramuscular, transdermal, vaginal topical, or vaginal ring administration.
  • the compound is administered to the patient by oral administration.
  • raloxifene is administered at about 10 mg/day per os to about 200 mg/day per os, such as about 20 mg/day per os to about 150 mg/day per os, about 30 mg/day per os to about 100 mg/day per os, or about 40 mg/day per os to about 80 mg/day per os.
  • raloxifene is administered at about 10 mg/day per os, 20 mg/day per os, 40 mg/day per os, 60 mg/day per os, 80 mg/day per os, 100 mg/day per os, 120 mg/day per os, or 200 mg/day per os.
  • bazedoxifene is administered at about 2 mg/day per os to about 100 mg/day per os, such as about 5 mg/day per os to about 80 mg/day per os, about 10 mg/day per os to about 50 mg/day per os, or about 20 mg/day per os to about 40 mg/day per os.
  • tamoxifen is administered at about 2 mg/day per os, 5 mg/day per os, 10 mg/day per os, 20 mg/day per os, 30 mg/day per os, 40 mg/day per os, 50 mg/day per os, or 100 mg/day per os.
  • tamoxifen is administered at about 2 mg/day per os to about 100 mg/day per os, such as about 5 mg/day per os to about 80 mg/day per os, about 10 mg/day per os to about 50 mg/day per os, or about 20 mg/day per os to about 40 mg/day per os.
  • tamoxifen is administered at about 2 mg/day per os, 5 mg/day per os, 10 mg/day per os, 20 mg/day per os, 30 mg/day per os, 40 mg/day per os, 50 mg/day per os, or 100 mg/day per os.
  • the compound is administered once every day. In certain embodiments, the compound is administered once every two days. In certain embodiments, the compound is administered once every three days. In certain embodiments, the compound is administered once every four days. In certain embodiments, the compound is administered once every five days. In certain embodiments, the compound is administered once every six days. In certain embodiments, the compound is administered once every week. In certain embodiments, the compound is administered once every two weeks. In certain embodiments, the compound is administered once every three weeks. In certain embodiments, the compound is administered once every month.
  • the compound is administered to the patient by intramuscular administration.
  • fulvestrant is administered at about 100 mg to about 2000 mg, such as about 200 mg to about 1500 mg, about 400 mg to about 1000 mg, or about 500 mg to about 800 mg.
  • apeledoxifene is administered at about 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, or 2000 mg.
  • the compound is administered once every day.
  • the compound is administered once every two days.
  • the compound is administered once every three days.
  • the compound is administered once every four days.
  • the compound is administered once every five days.
  • the compound is administered once every six days.
  • the compound is administered once every week.
  • the compound is administered once every two weeks.
  • the compound is administered once every three weeks.
  • the compound is administered once every month.
  • the compound is administered to ER + cancer patient for one year. In some embodiments, the compound is administered to the patient for two years. In some embodiments, the compound is administered to the patient for three years. In some embodiments, the compound is administered to the patient for four years. In some embodiments, the compound is administered to the patient for five years. In some other embodiments, the compound is administered to the patient for more than five years. In certain embodiments, the compound is administered to the patient until the patient's cancer progresses on therapy.
  • the compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant is administered either alone or in combination with other therapies.
  • the compound is administered in combination with at least one other therapy.
  • the compound and other therapies are administered together (simultaneously). In some other embodiments, the compound and other therapies are administered at different times (sequentially).
  • the additional therapy that the patient is treated with is endocrine therapy.
  • the patient is treated with at least one line of additional endocrine therapy.
  • the patient is treated with one line of additional endocrine therapy.
  • the patient is treated with multiple lines of additional endocrine therapy.
  • the patient is treated with the additional endocrine therapy at the original doses. In some other embodiments, the patient is treated with the additional endocrine therapy at doses higher than original doses. In certain embodiments, the patient is treated with the additional endocrine therapy at doses lower than original doses.
  • the additional endocrine therapy is treatment with a selective ER modulator (SERM) other than the compound.
  • SERM selective ER modulator
  • the additional endocrine therapy is treatment with a selective ER degrader (SERD) other than the compound.
  • SESD selective ER degrader
  • the additional endocrine therapy is treatment with an aromatase inhibitor.
  • the aromatase inhibitor is selected from exemestane (Aromasin®), letrozole (Ferrara®), and anastrozole (Arimidex®).
  • the additional therapy is administration to the patient of an effective amount of a cell cycle inhibitor. In certain embodiments, the additional therapy is administration of an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. In some embodiments, the additional therapy is a CDK4/6 inhibitor selected from the group of palbociclib, abemaciclib, and ribociclib.
  • the additional therapy is administration to the patient of an inhibitor of a pathway that cross-talks with and activates the ER transcriptional activity.
  • the additional therapy is a mammalian target of rapamycin (mTOR) inhibitor.
  • the mTOR inhibitor is Everolimus.
  • the compound in combination with Everolimus is administered to a postmenopausal woman with locally advanced or metastatic breast cancer who has progressed on a non-steroidal AI and/or fulvestrant either as monotherapy or in combination with a CDK4/6 inhibitor.
  • the additional therapy is a phosphoinositide 3-kinase (PI3K) inhibitor or a heat shock protein 90 (HSP90) inhibitor.
  • PI3K phosphoinositide 3-kinase
  • HSP90 heat shock protein 90
  • the additional therapy is administration to the patient of an effective amount of a growth factor inhibitor.
  • the additional therapy is a human epidermal growth factor receptor 2 (HER2) inhibitor.
  • the HER2 inhibitor is trastuzumab (Herceptin®).
  • the HER2 inhibitor is ado-trastuzumab emtansine (Kadcyla®).
  • the additional therapy is administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • the HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996,
  • the HDAC inhibitor is entinostat (MS-275). In certain other embodiments, the HDAC inhibitor is vorinostat (Zolinza®). In yet certain other embodiments, the HDAC inhibitor is romidepsin (Istodax®).
  • the additional therapy is administering to the patient an effective amount of a checkpoint inhibitor.
  • the checkpoint inhibitor is an antibody.
  • the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).
  • the CTLA-4 antibody is ipilimumab (Yervo®).
  • the additional therapy is administering to the patient an effective amount of cancer vaccine.
  • the additional therapy is administering to the patient an effective amount of denosumab.
  • the additional therapy is administering to the patient an effective amount of a serotonin-norepinephrine reuptake inhibitor (SNRI), a selective serotonin reuptake inhibitor (SSRI), or gabapentin.
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • SSRI selective serotonin reuptake inhibitor
  • gabapentin gabapentin.
  • the SNRI is venlafaxine (Effexor®).
  • the method comprises administering an amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant effective to increase the disease-free survival of the ER + cancer patient. In some embodiments, the method comprises administering an amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant in an amount effective to reduce recurrence of ER + cancer.
  • the method comprises administering an amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant in an amount effective to increase time to recurrence of ER + cancer. In some embodiments, the method comprises administering an amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant in an amount effective to reduce metastasis of ER + cancer.
  • the method comprises administering an amount of a compound selected from the group consisting of raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant in an amount effective to increase duration of progression-free survival of the ER + cancer patient.
  • the method increases the disease-free survival of the ER + breast cancer patient. In certain embodiments, the method reduces recurrence of ER + breast cancer. In certain embodiments, the method increases time to recurrence of ER + breast cancer. In certain embodiments, the method reduces metastasis of ER + breast cancer to bone. In certain embodiments, the method reduces metastasis of ER + breast cancer to tissues other than bone. In certain embodiments, the method increases duration of progression-free survival of the ER + breast cancer patient.
  • the method increases the disease-free survival in ER + cancer patient with endocrine resistance. In some embodiments, the method reduces recurrence of cancer in patient with endocrine resistance. In some embodiments, the method increases time to recurrence of cancer in patient with endocrine resistance. In some embodiments, the method reduces metastasis of cancer in patient with endocrine resistance. In some embodiments, the method increases duration of progression-free survival in ER + cancer patient with endocrine resistance.
  • the method increases disease-free survival, reduces recurrence, increases time to recurrence, reduces metastasis, and/or increases duration of progression-free survival in patients with ER + locally advanced or metastatic breast cancer that has developed endocrine resistance.
  • the breast cancer has developed endocrine resistance by acquiring one or more of the ESR1 mutations discussed herein.
  • the method reduces the selective pressure and prevents the expansion of the endocrine resistant clones in ER + locally advanced or metastatic breast cancer during treatment.
  • the method is effective to prevent fracture and bone loss in women who are concurrently being treated with one or more drugs causing or predisposing to osteoporosis.
  • the method is effective to decrease vaginal pH, increase vaginal lubrication, and/or improve vaginal cell maturation index in women who are concurrently being treated with one or more drugs causing or predisposing to vulvovaginal atrophy (VVA).
  • VVA vulvovaginal atrophy
  • the method reduces one or more symptoms of sexual dysfunction in women who are concurrently being treated with one or more drugs causing or predisposing to sexual dysfunction.
  • the method treats hot flashes in women who are concurrently being treated with one or more drugs causing or predisposing to hot flashes.
  • the method increases one or more quality of life measures selected from joint ache, urogenital symptoms, bone loss, and bone fractures.
  • ExSite mutagenesis was performed using the corresponding primers as summarized in Table 1 below on a pENTR2B ER ⁇ WT construct using Pfu ultra taq polymerase.
  • the primers were PNK phosphorylated.
  • the products were digested with DpnI at 37° C. for 1 hr, followed by overnight ligation at 16° C.
  • Ligated products were transformed into DH5 ⁇ bacterial cells and grown on kanamycin resistant plates.
  • the pENTR clones were verified by sequencing and then swapped into the pcDNA-DEST vector using the Gateway system (Invitrogen) for expression analysis.
  • Caov2 ovarian carcinoma cells were grown in RPMI-1640 media (Gibco) supplemented with 8% Fetal Bovine Serum (FBS), Sodium Pyruvate (NaPyr) and non-essential amino acids (NEAA) and passaged every 2-3 days.
  • SKBR3 breast adenocarcinoma cells were grown in DMEM media (Gibco) supplemented with 8% Fetal Bovine Serum (FBS), Sodium Pyruvate (NaPyr) and non-essential amino acids (NEAA) and passaged every 2-3 days.
  • Cells were switched into a phenol-red free RPMI-1640 media supplemented with 8% charcoal stripped fetal bovine serum (CFS), NaPyr, and NEAA one day before plating for experiment. Cells were then plated in 96-well plates for experiment in the phenol red-free media an additional day before transfection.
  • CFS charcoal stripped fetal bovine serum
  • NaPyr NaPyr
  • NEAA fetal bovine serum
  • Caov2 cells were co-transfected with the 7X-TK-ERE-TATA luciferase reporter gene (Nagel et al., Endocrinology 142(11): 4721-4728 (2001)) and expression constructs for either wild-type or mutant receptors using Fugene transfection reagent (Promega).
  • SKBR3 cells were co-transfected with 3X-TK-ERE-TATA luciferase reporter gene in the same conditions.
  • pCMV- ⁇ -gal was used as a control for transfection efficiency and pcDNA was added for a final DNA concentration of 75 ng per triplicate group. Cells were treated with indicated ligand five hours post transfection.
  • ER ⁇ expression constructs were engineered to express one of four different ESR1 LBD mutations, Y537S, Y537N, Y537C, and D538G, which are found in metastatic breast cancer patients. See Jeselsohn et al., Nature Reviews Clinical Oncology 12(10): 573-583 (2015); Jeselsohn et al., Clinical Cancer Research 20(7): 1757-1767 (2014); Robinson et al., Nature Genetics 45(12): 1446-1451(2013); Thomas and Gustafsson, Trends in Endocrinology and Metabolism 26(9): 467-476 (2015); and Toy et al., Nature Genetics 45(12): 1439-1445 (2013).
  • raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) was next evaluated under the same conditions. All inhibition curves were done in the presence of 10 ⁇ 9 (1 nM) 17- ⁇ estradiol. Data normalization was done in respect to the “0” data point (no raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), 4-hydroxy metabolite of etacstil (GW-7604), or fulvestrant (ICI)) for each individual receptor.
  • the plots include data from five independent experiments and each value is an average of triplicates from each experiment.
  • raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) each effectively inhibited the transcriptional activity of all tested ER ⁇ LBD mutants in a dose-response manner ( FIGS. 1C-1F , FIGS. 3C-3F , FIGS. 4A-4E , and FIGS. 2A-2E ).
  • the transcriptional IC90 values of ER modulators were also evaluated under the same conditions in Caov2 ovarian carcinoma cells and SKBR3 breast adenocarcinoma cells.
  • the tests included raloxifene, apeledoxifene, 4-hydroxytamoxifen (4OHT), 4-hydroxy metabolite of etacstil (GW-7604), and fulvestrant (ICI) individually. See Maximov et al., Current Clinical Pharmacology 8(2): 135-155 (2013) and McDonnell et al., Journal of Medicinal Chemistry 58(12): 4883-4887 (2015).
  • the transcriptional IC90 values of ER modulators evaluated were compared to the Cmax of these compounds in blood at approved doses.
  • the WT receptor was the most responsive to anti-estrogen treatment, with each of the mutants exhibiting reduced response to the inhibitory actions of these compounds. Importantly, the pharmacology of each of the mutants was different, which highlights the need to match patients with the most appropriate drug.
  • the data suggest that raloxifene, apeledoxifene, tamoxifen, etacstil, and fulvestrant (ICI) are each effective for patients whose tumors express the ESR1 LBD mutations in both ovarian and breast cancer settings.
  • MCF7 estrogen receptor alpha positive (ER + ) breast cancer cells were engineered to stably express doxycycline (DOX)-inducible hemagglutinin (HA)-tagged full length ER with ligand binding domain mutations Y537S and D538G.
  • DOX doxycycline
  • HA hemagglutinin
  • the dose response studies were performed in full medium conditions. Cells were treated with DOX for the induction of HA-tagged mutated ER or with vehicle as control, and plated in triplicate. Subsequently, on day 5, cell counting was performed using the Celigo instrument with Hoechst dye staining to detect nucleated live cells and propidium iodide to quantify dead cells. Treatments included vehicle and increasing doses of 4-hydroxytamoxifen (4OHT) and fulvestrant starting from 10 ⁇ 12 M with 10 fold increments up to 10 ⁇ 6 M. The efficacy of the treatment is inversely proportional to the cell count.
  • 4OHT 4-hydroxytamoxifen
  • IC50 values were calculated using PRISM for 4-hydroxytamoxifen (4OHT) and fulvestrant. The results are summarized in Table 3.

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