Granted Patent
B2
US 12,383,563 · App. 18/535,764 · Granted Aug 12, 2025
Methods of reducing mammographic breast density and/or breast cancer risk
Assignee:
Havah Therapeutics Pty Ltd.
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Abstract
The present disclosure is directed to generally methods and/or compositions for treating mammographic breast density and/or breast stiffness in a patient in need thereof, such as a pre-menopausal, a peri-menopausal or a post-menopausal patient, comprising the administration of an effective amount of androgenic agent and an effective amount of an aromatase inhibitor. The present disclosure is also directed to methods and/or compositions for reducing breast pain. The present disclosure is also directed to method and/or compositions for reducing elasticity and/or decreasing mechano-transduction on the genome of breast cells. The present disclosure is also directed to methods and/or compositions for stabilizing and/or increasing the levels of androgen receptor expression in breast tissue.
Claims (24)
1. A method for reducing breast tissue elasticity in a female patient in need thereof, comprising administering to the patient an effective amount of an androgenic agent in combination with an effective amount of an aromatase inhibitor, the reduction in breast tissue elasticity reducing or mitigating the risk of malignant transformation in the breast of the patient.
2. The method of claim 1 , wherein the aromatase inhibitor blocks conversion of the androgenic agent into an estrogen by aromatase enzyme.
3. The method of claim 1 , wherein the patient has an elevated level of mammographic breast density and/or breast stiffness and wherein the elevated level of mammographic breast density and/or breast stiffness is associated with an increased risk of the subject developing breast cancer.
4. The method of claim 1 , wherein the patient has, or is diagnosed with having, a breast with an area breast density percentage (ABD %) of 7.5% or greater and/or a volumetric breast density percentage (VBD %) of 7.5% or greater.
5. The method of claim 4 , wherein the patient has a mammographic breast density of 7.5% or greater.
6. The method of claim 1 , wherein the patient has a volumetric breast density percentage (VBD %) and/or an absolute volumetric breast density (AVBD) of 7.5% or greater.
7. The method of claim 6 , wherein the patient has an area breast density percentage (ABD %) and/or an absolute area of breast density (AABD) of 7.5% or greater.
8. The method of claim 1 , wherein the administration of the androgenic agent and the aromatase inhibitor provides one or more outcomes selected from the group consisting of:
i. stabilised or increased androgen receptor expression level in breast tissue of at least one breast of the patient;
ii. decreased mechano-transduction on the genome of breast tissue cells;
iii. increased GCDFP15 expression;
iv. increased CD36 expression; and
v. reduced risk of perturbation of the hypothalamic-pituitary axis in treatment of the patient with the androgenic agent.
9. The method of claim 8 , wherein the perturbation of the hypothalamic-pituitary axis is characterised by elevated follicle stimulating hormone (FSH) and/or luteinizing hormone (LH) in blood serum of the patient.
10. The method of claim 1 , wherein androgenic agent is testosterone or an ester of testosterone.
11. The method of claim 10 , wherein the androgenic agent is testosterone and the effective amount of testosterone is 2-200 mg.
12. The method of claim 1 wherein the androgenic agent is selected from the group consisting of testosterone, methyltestosterone, testosterone undecanoate, testosterone propionate, testosterone cypionate, and combinations thereof.
13. The method of claim 1 , wherein the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, exemestane, formestane, vorozole and fadrozole.
14. The method of claim 13 , wherein the aromatase inhibitor is anastrozole and the effective amount of anastrozole is 0.5-10 mg.
15. The method of claim 1 , wherein the androgenic agent is testosterone and the aromatase enzyme is anastrozole.
16. The method of claim 1 , wherein the androgenic agent and the aromatase inhibitor are administered together in the patient in the same composition.
17. The method of claim 1 , wherein the androgenic agent and the aromatase inhibitor are administered to the patient subcutaneously.
18. The method of claim 16 , wherein the androgenic agent and the aromatase inhibitor are administered by subcutaneous implant.
19. The method of claim 1 , wherein the patient is pre-menopausal, peri-menopausal or post-menopausal.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 31, 2025
From: BIRRELL, STEPHEN NIGEL
To: HAVAH THERAPEUTICS PTY LTD.
Reel/Frame 070078/0768 →
Continuity (6)
Continuation
15520278
Provisional Application
62067297
· Oct 22, 2014
References Cited (230)
US 4147783A
· Van Der Vies
· 1979
[cited by applicant]
US 4412993A
· Sokolowski
· 1983
[cited by applicant]
US 5824286A
· Hodgen
· 1998
[cited by applicant]
US 5861387A
· Labrie
· 1999
[cited by applicant]
US 6200593B1
· Place
· 2001
[cited by applicant]
US 6241529B1
· Place
· 2001
[cited by applicant]
US 6569896B2
· Dalton
· 2003
[cited by applicant]
US 6593313B2
· Place
· 2003
[cited by applicant]
US 6696432B1
· Elliesen
· 2004
[cited by applicant]
US 6995284B2
· Dalton
· 2006
[cited by applicant]
US 7772433B2
· Dalton
· 2010
[cited by applicant]
US 8003689B2
· Veverka
· 2011
[cited by applicant]
US 8008348B2
· Steiner
· 2011
[cited by applicant]
US 8980569B2
· Weinberg
· 2015
[cited by applicant]
US 8980840B2
· Truitt, III
· 2015
[cited by applicant]
US 9150501B2
· Dalton
· 2015
[cited by applicant]
US 9168302B2
· Birrell
· 2015
[cited by applicant]
US 9351977B2
· Birrell
· 2016
[cited by applicant]
US 9616072B2
· Birrell
· 2017
[cited by applicant]
US 20030087885A1
· Masini-Eteve
· 2003
[cited by applicant]
US 20040191311A1
· Liang
· 2004
[cited by applicant]
US 20050032750A1
· Steiner
· 2005
[cited by applicant]
US 20050233970A1
· Garnick
· 2005
[cited by applicant]
US 20060069067A1
· Bhatnagar
· 2006
[cited by applicant]
US 20070066568A1
· Dalton
· 2007
[cited by applicant]
US 20080085874A1
· Kushner
· 2008
[cited by applicant]
US 20090264534A1
· Dalton
· 2009
[cited by applicant]
US 20100144687A1
· Glaser
· 2010
[cited by applicant]
US 20140162991A1
· Glaser
· 2014
[cited by applicant]
WO 1990010462
· 1990
[cited by applicant]
WO 1994016709
· 1994
[cited by applicant]
WO 2000069467
· 2000
[cited by applicant]
WO 2001087334
· 2001
[cited by applicant]
WO 2002009721
· 2002
[cited by applicant]
WO 2002030355
· 2002
[cited by applicant]
WO 2004034978
· 2004
[cited by applicant]
WO 2004035739
· 2004
[cited by applicant]
WO 2004064747
· 2004
[cited by applicant]
WO 2005011705
· 2005
[cited by applicant]
WO 2005037263
· 2005
[cited by applicant]
WO 2005070434
· 2005
[cited by applicant]
WO 2007045027
· 2007
[cited by applicant]
WO 2008127717
· 2008
[cited by applicant]
WO 2009036566
· 2009
[cited by applicant]
WO 2010065358
· 2010
[cited by applicant]
WO 2010118287
· 2010
[cited by applicant]
WO 2013067170
· 2013
[cited by applicant]
WO 2016061615
· 2016
[cited by applicant]
WO 2017066827
· 2017
[cited by applicant]
WO 2020243777
· 2020
[cited by applicant]
Abu Hashim, H. et al., “Randomized Comparison of Superovulation with Letrozole vs. Clomiphene Citrate in an IUI Program for Women with Recently Surgically Treated Minimal to Mild Endometriosis”, Acta. Obstet. Gynecol. S…
[cited by applicant]
Alexander, H. et al., “Proteomic Analysis to Identify Breast Cancer Biomarkers in Nipple Aspirate Fluid”, Clin. Cancer Res., 10(22):7500-7510, (2004).
[cited by applicant]
Arendt, L. et al., “Working Stiff: How Obesity Boosts Cancer Risk”, Sci. Transl. Med., 7(301), 301fs34, 3 pages, (2015).
[cited by applicant]
Ashbeck, E. et al., “Benign Breast Biopsy Diagnosis and Subsequent Risk of Breast Cancer”, Cancer Epidemiol Biomarkers Prev., 16(3):467-472, (2007).
[cited by applicant]
Atakpa, E. et al., “Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review”, Cochrane Database Syst Rev., 10(10):CD013091, (2021).
[cited by applicant]
Baker, E. et al., “Cancer Cell Stiffness: Integrated Roles of Three-Dimensional Matrix Stiffness and Transforming Potential”, Biophys J., 99(7):2048-57, (2010).
[cited by applicant]
Beattie, M. et al., “Endogenous Sex Hormones, Breast Cancer Risk, and Tamoxifen Response: An Ancillary Study in the NSABP Breast Cancer Prevention Trial (P-1)”, J. Natl. Cancer Inst., 98(2):110-115, (2006).
[cited by applicant]
Beckmann, K. et al., “Impact of Hormone Replacement Therapy use on Mammographic Screening Outcomes”, Cancer Causes Control, 24(7):1417-1426, (2013).
[cited by applicant]
Beer, B. et al., “Development and Validation of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Quantification of Tamoxifen, Anastrozole, and Letrozole in Human Plasma and its Application to…
[cited by applicant]
Bercoff, J., “ShareWave TM Elastography—White Paper” Super Sonic Imagine, S.A. copyright (2008).
[cited by applicant]
Bhasin, S. et al., “Selective Androgen Receptor Modulators (SARMs) as Function Promoting Therapies”, Curr. Opin. Clin. Nutr. Metab. Care, 12(3):232-240, (2009).
[cited by applicant]
Birrell, S. et al., “Combined Hormone Replacement Therapy and Breast Cancer”, Expert Report, 34 pages, dated Apr. 1, 2008.
[cited by applicant]
Birrell, S. et al., “Disruption of Androgen Receptor Signaling by Synthetic Progestins May Increase Risk of Developing Breast Cancer”, FASEB J., 21(10):2285-2293, (2007).
[cited by applicant]
Bolduc, C. et al., “Transcriptomic Characterization of the Long-Term Dihydrotestosterone Effects in Adipose Tissue”, Obesity, 15(5):1107-1132, (2007).
[cited by applicant]
Boyd, N. et al., “Breast-Tissue Composition and Other Risk Factors for Breast Cancer in Young Women: A Cross-Sectional Study”, Lancet Oncol., 10(6), 569-580, (2009).
[cited by applicant]
Boyd, N. et al., “Evidence That Breast Tissue Stiffness Is Associated with Risk of Breast Cancer”, PLOS One, 9(7):e100937, 8 pages, (2014).
[cited by applicant]
Boyd, N. et al., “Mammographic Densities and Breast Cancer Risk”, Breast Dis., 10(3,4):113-126, (1998).
[cited by applicant]
Boyd, N. et al., “Mammographic Density, Response to Hormones, and Breast Cancer Risk”, J. Clin. Oncol., 29(22):2985-2992, (2011).
[cited by applicant]
Braunstein, G., “Safety of Testosterone Treatment in Postmenopausal Women”, Fertil. Steril., 88(1):1-17, (2007).
[cited by applicant]
Brown, P., “Targeted Therapy—Anastrozole Prevents Breast Cancer”, Nature Reviews Clinical Oncology, 11:127-128, (2014).
[cited by applicant]
Byrne, C. et al., “Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk”, J. Natl. Cancer Inst., 109(9):djx001, 7 pages, (2017).
[cited by applicant]
Chen, R. et al., “Antiproliferative Effects of Anastrozole on MCF-7 Human Breast Cancer Cells In Vitro are Significantly Enhanced by Combined Treatment with Testosterone Undecanoate”, Mol. Med. Rep., 12(1):769-775, (201…
[cited by applicant]
Cheng, Q. et al., “Overexpression of CD36 in mammary fibroblasts suppresses colony growth in breast cancer cell lines”, Biochem Biophys Res Commun., 526(1):41-7, (2020).
[cited by applicant]
Chiu, S. et al., “Effect of Baseline Breast Density on Breast Cancer Incidence, Stage, Mortality, and Screening Parameters: 25-Year Follow-up of a Swedish Mammographic Screening”, Cancer Epidemiol. Biomarkers Prev., 19(…
[cited by applicant]
Chlebowski, R. et al., “Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women's Health Initiative Randomized Trial”, JAMA, 289(24):3243-3253, (2003).
[cited by applicant]
Cigler, T. et al., “A randomized, placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women”, Breast Cancer Res Treat., 120(2…
[cited by applicant]
Cilotti, A. et al., “Male Osteoporosis and Androgenic Therapy: From Testosterone to SARMs”, Clin. Cases Miner. Bone Metab., 6(3):229-233, (2009).
[cited by applicant]
Crandall, C. et al., “Breast Tenderness After Initiation of Conjugated Equine Estrogens and Mammographic Density Change”, Breast Cancer Res. Treat., 131(3):969-979, (2012).
[cited by applicant]
Cuzick, J. et al., “Impact of Preventive Therapy on the Risk of Breast Cancer Among Women with Benign Breast Disease”, Breast, 24:S51-S55, (2015).
[cited by applicant]
Cuzick, J. et al., “Tamoxifen-Induced Reduction in Mammographic Density and Breast Cancer Risk Reduction: A Nested Case-Control Study”, J. Natl. Cancer Inst., 103(9):744-752, (2011).
[cited by applicant]
D'Orsi, C. et al., “Breast Imaging Reporting and Data System”, ACR BI-RADS® Atlas, Reston, VA: American College of Radiology, (2013).
[cited by applicant]
Dalton, J. et al., “The Selective Androgen Receptor Modulator GTx-024 (Enobosarm) Improves Lean Body Mass and Physical Function in Healthy Elderly Men and Postmenopausal Women: Results of a Double-Blind, Placebo-Control…
[cited by applicant]
Das, L. et al., “Idiopathic gigantomastia: newer mechanistic insights implicating the paracrine milieu”, Endocrine, 66(2):166-77, (2019).
[cited by applicant]
Davis, S. et al., “The effect of transdermal testosterone on mammographic density in postmenopausal women not receiving systemic estrogen therapy”, J Clin Endocrinol Metab., 94(12):4907-13, (2009).
[cited by applicant]
Davis, S. et al., “Androgen Treatment of Postmenopausal Women”, J. Steroid Biochem. Mol. Biol., 142:107-114, (2014).
[cited by applicant]
Dawson, C. et al., “Tissue-resident ductal macrophages survey the mammary epithelium and facilitate tissue remodelling”, Nat Cell Biol., 22(5):546-58, (2020).
[cited by applicant]
De Gooyer, M. et al., “Tibolone is not converted by human aromatase to 7α-methyl-17α-ethynylestradiol (7α-MEE): analyses with sensitive bioassays for estrogens and androgens and with LC-MSMS”, Steroids, 68(3):235-43, (2…
[cited by applicant]
Defilippis, R. et al., “CD36 Repression Activates a Multicellular Stromal Program Shared by High Mammographic Density and Tumor Tissues”, Cancer Discov., 2(9):826-839, (2012).
[cited by applicant]
Defilippis, R. et al., “Stress Signaling from Human Mammary Epithelial Cells Contributes to Phenotypes of Mammographic Density”, Cancer Res., 74(18):5032-5044, (2014).
[cited by applicant]
Dilley, W. et al., “Androgen Stimulation of Gross Cystic Disease Fluid Protein and Carcinoembryonic Antigen in Patients with Metastatic Breast Carcinoma”, J. Natl. Cancer Inst., 70(1):69-74, (1983).
[cited by applicant]
Dixon, JM et al., “Risk of Breast Cancer in Women with Palpable Breast Cysts: A Prospective Study”, Lancet, 353:1742-1745, (1999).
[cited by applicant]
Duhan, N. et al., “Role of the Aromatase Inhibitor Letrozole in the Management of Uterine Leiomyomas in Premenopausal Women”, Eur. J. Obstet. Gynecol. Reprod. Biol., 171:329-332, (2013).
[cited by applicant]
Eigeliene, N. et al., “Androgens Inhibit the Stimulatory Action of 17beta-Estradiol on Normal Human Breast Tissue in Explant Cultures”, J. Clin. Endocrinol. Metab., 97(7), 12 pages, (2012).
[cited by applicant]
European Patent No. 1945224; Extended European Search Report and Written Opinion, dated Aug. 24, 2009; 7 pages.
[cited by applicant]
European Patent No. 3209301; Extended European Search Report and Written Opinion, dated Feb. 12, 2018; 8 pages.
[cited by applicant]
Fabian, C. et al., “Reduction in proliferation with six months of letrozole in women on hormone replacement therapy”, Breast Cancer Res Treat., 106(1):75-84, (2007).
[cited by applicant]
Freer, P., “Mammographic Breast Density: Impact on Breast Cancer Risk and Implications for Screening”, RadioGraphics, 35(2)302-315, (2015).
[cited by applicant]
Gao, W. et al., “Expanding the Therapeutic use of Androgens via Selective Androgen Receptor Modulators (SARMs)”, Drug Discov. Today, 12(5-6):241-248, (2007).
[cited by applicant]
Gao, W. et al., “Ockham's Razor and Selective Androgen Receptor Modulators (SARMs): Are We Overlooking the Role of 5alpha-Reductase?”, Mol. Interv., 7(1):10-13, (2007).
[cited by applicant]
Gascard, P. et al., “Epigenetic and Transcriptional Determinants of the Human Breast”, Nat. Commun., 6:6351, 10 pages (2015).
[cited by applicant]
Gaubin, M. et al., “Potent Inhibition of CD4/TCR-Mediated T Cell Apoptosis by a CD4-Binding Glycoprotein Secreted from Breast Tumor and Seminal Vesicle Cells”, J. Immunol., 162:2631-2638, (1999).
[cited by applicant]
Ghajar, C., “A Stiffness-Mediated Oncogenic Hammer”, Sci. Transl. Med., 6(237):237fs21, 3 pages, (2014).
[cited by applicant]
Ghosh, S. et al., “Mechanical Phenotype is Important for Stromal Aromatase Expression”, Steroids, 76(8):797-801, (2011).
[cited by applicant]
Giess, C. et al., “Background Parenchymal Enhancement at Breast MR Imaging: Normal Patterns, Diagnostic Challenges, and Potential for False-Positive and False-Negative Interpretation”, RadioGraphics, 34(1):234-247, (201…
[cited by applicant]
Gilliver, SC et al., “5alpha-Dihydrotestosterone (DHT) Retards Wound Closure by Inhibiting Re-Epithelialization”, J. Pathol., 217:73-82, (2009).
[cited by applicant]
Glaser, R. “Subcutaneous Testosterone-Anastrozole Implant Therapy in Breast Cancer Survivors”, 2010 Breast Cancer Symposium, Abstract 221, Jan. 2010; 1 page.
[cited by applicant]
Glaser, R. et al., “Beneficial Effects of Testosterone Therapy in Women Measured by the Validated Menopause Rating Scale {MRS)”, Maturitas, 68(4):355-361, (2011).
[cited by applicant]
Glaser, R. et al., “Rapid Response of Breast Cancer to Neoadjuvant Intramammary Testosterone-Anastrozole Therapy: Neoadjuvant Hormone Therapy in Breast Cancer”, Menopause, 21(6):673-678, (2014).
[cited by applicant]
Glaser, R. et al., “Reduced Breast Cancer Incidence in Women Treated with Subcutaneous Testosterone, or Testosterone with Anastrozole: A Perspective, Observational Study”, Maturitas, 76:342-349, (2013).
[cited by applicant]
Glaser, R. et al., “Subcutaneous Testosterone-Letrozole Therapy Before and Concurrent with Neoadjuvant Breast Chemotherapy: Clinical Response and Therapeutic Implications”, Menopause: The Journal of the North American M…
[cited by applicant]
Glaser, R. et al., “Subgroups of Patients Treated With an Aromatase Inhibitor (Anastrozole) Delivered Subcutaneously in Combination With Testosterone”, Abstract, 9th European Congress on Menopause and Andropause, Maturi…
[cited by applicant]
Glaser, R. et al., “Testosterone and Breast Cancer Prevention”, Maturitas, 82(3), 290-294, (2015).
[cited by applicant]
Glaser, R. et al., “Testosterone Implants in Women: Pharmacological Dosing for a Physiologic Effect,” Maturitas, 74:179-184, (2013).
[cited by applicant]
Glaser, R. et al., “Testosterone Therapy in Women: Myths and Misconceptions”, Maturitas, 74:230-234, (2013).
[cited by applicant]
Golatta, M. et al., “Evaluation of Virtual Touch Tissue Imaging Quantification, a New Shear Wave Velocity Imaging Method, for Breast Lesion Assessment by Ultrasound”, Biomed. Res. Int., 2014:960262, 7 pages, (2014).
[cited by applicant]
Goss, P. et al., “Anastrozole: A New Selective Nonsteroidal Aromatase Inhibitor”, Oncology, 11(11):Abstract only (Complete copy from www.cancernetwork.com), 8 pages, (1997).
[cited by applicant]
Goss, P. et al., “Chemoprevention with Aromatase Inhibitors—Trial Strategies”, J. Steroid Biochem. Mol. Biol., 79:143-149, (2001).
[cited by applicant]
Goulabchand, R.. et al., “Mastitis in Autoimmune Diseases: Review of the Literature, Diagnostic Pathway, and Pathophysiological Key Players”, J Clin Med., 9(4):958, (2020).
[cited by applicant]
Gubbels-Bupp, M. et al., “Androgen-Induced Immunosuppression”, Front Immunol., 9:974, (2018).
[cited by applicant]
Guhl, S. et al., “Testosterone exerts selective anti-inflammatory effects on human skin mast cells in a cell subset dependent manner”, Exp Dermatol., 21(11):878-80, (2012).
[cited by applicant]
Gunter, M. et al., “Circulating Adipokines and Inflammatory Markers and Postmenopausal Breast Cancer Risk”, J. Natl. Cancer Inst., 107(9), 10 pages, (2015).
[cited by applicant]
Haagensen, D. et al., “Breast Gross Cystic Disease Fluid Analysis. I. Isolation and Radioimmunoassay for a Major Component Protein”, J. Natl. Cancer Inst., 62(2):239-247, (1979).
[cited by applicant]
Henry, N. et al., “Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects”, Br J Cancer, 109(9):2331-9, (2013).
[cited by applicant]
Hodgson, M. et al., “Reduced Androgen Receptor Expression Accelerates the Onset of ERBB2 Induced Breast Tumors in Female Mice”, PLoS One, 8(4):e60455, 12 pages, (2013).
[cited by applicant]
Hubalek, M, et al., “Does Obesity Interfere With Anastrozole Treatment? Positive Association Between Body Mass Index and Anastrozole Plasma Levels”, Clin. Breast Cancer, 14(4), 6 pages, (2014).
[cited by applicant]
Imahori, K., “Substrate specificity of enzymatic reaction”, High Polymers, pp. 794-797, (1971).
[cited by applicant]
International Application No. PCT/AU2006/001539; International Search Report and Written Opinion of the International Searching Authority, Date of Mailing Jan. 3, 2007; 5 pages.
[cited by applicant]
International Application No. PCT/AU2015/000633; International Preliminary Report on Patentability, Date of Issuance Apr. 25, 2017; 6 pages.
[cited by applicant]
International Application No. PCT/AU2015/000633; International Search Report and Written Opinion of the International Searching Authority, Date of Mailing Dec. 16, 2015; 11 pages.
[cited by applicant]
International Application No. PCT/AU2016/050973; International Search Report and Written Opinion of the International Searching Authority, Date of Mailing Nov. 22, 2016; 9 pages.
[cited by applicant]
International Application No. PCT/AU2020/050562; International Search Report and Written Opinion of the International Searching Authority, Date of Mailing Sep. 2, 2020; 15 pages.
[cited by applicant]
Iobagiu, C. et al., “Loss of Heterozygosity in Tumor Tissue in Hormonal Receptor Genesis Associated with Poor Prognostic Criteria in Breast Cancer”, Cancer Genet., 208(4):135-142, (2015).
[cited by applicant]
Ironside, A. et al., “Stromal Characteristics May Hold the Key to Mammographic Density: The Evidence to Date”, Oncotarget, 13 pages, (2016).
[cited by applicant]
Japanese Application No. 2008-535845; Office Action with English Translation; dated Jul. 3, 2012; 7 pages.
[cited by applicant]
Javed, A. “Development of the Human Breast”, Semin. Plast. Surg., 27(1):5-12 (2013).
[cited by applicant]
Kass, L. et al., “Mammary Epithelial Cell: Influence of Extracellular Matrix Composition and Organization During Development and Tumorigenesis”, Int. J. Biochem. Cell Biol., 39(11):1987-1994, (2007).
[cited by applicant]
Li, C. et al., “Effect of Depo-Medroxyprogesterone Acetate on Breast Cancer Risk Among Women 20 to 44 Years of Age”, Cancer Res., 72(8):2028-2035, (2012).
[cited by applicant]
Li, G. et al., “Effects of aromatizable and nonaromatizable androgens on the sex inversion of red-spotted grouper (
[cited by applicant]
Li, X. et al., “Determination of the Elasticity of Breast Tissue During the Menstrual Cycle Using Real-Time Shear Wave Elastography”, Ultrasound Med. Biol., 41(12):3140-3147, (2015).
[cited by applicant]
Lienart, V. et al., “Effect of Preventive Hormonal Therapy on Breast Density: A Systematic Qualitative Review”, Scientific World Journal, 2014:942386, 24 pages, (2014).
[cited by applicant]
Lillie, E. et al., “Polymorphism in the Androgen Receptor and Mammographic Density in Women Taking and Not Taking Estrogen and Progestin Therapy”, Cancer Res., 64(4):1237-1241, (2004).
[cited by applicant]
Linton, L. et al., “Associations of Serum Levels of Sex Hormones in Follicular and Luteal Phases of the Menstrual Cycle with Breast Tissue Characteristics in Young Women”, PLoS One, 11(10):e0163865, 14 pages, (2016).
[cited by applicant]
Liu, Y. et al., “Sinomenine hydrochloride inhibits the progression of plasma cell mastitis by regulating IL-6/JAK2/STAT3 pathway”, Int Immunopharmacol., 81:106025, (2020).
[cited by applicant]
Lombard, J. et al., “Aromatase Inhibitor Induced Musculoskelelal Syndrome: A Significant Problem with Limited Treatment Options”, Support Care Cancer, doi:10.1007/s00520-015-3001-5, 8 pages, (2015).
[cited by applicant]
Loprinzi, C., “Randomized Double-Blind Placebo Controlled Study of Testosterone in the Adjuvant Treatment of Postmenopausal Women with Aromatase Inhibitor Induced Arthralgias”, Alliance for Clinical Trials in Oncology, …
[cited by applicant]
Lowdon, R. et al., “Regulatory Network Decoded from Epigenomes of Surface Ectoderm-Derived Cell Types”, Nat. Commun., 5:5442, 27 pages, (2014).
[cited by applicant]
Lundin, K. et al., “Androgen Receptor Genotypes Predict Response to Endocrine Treatment in Breast Cancer Patients”, Br. J. Cancer, 105(11):1676-1683, (2011).
[cited by applicant]
Miller, WR et al., “The Therapeutic Potential of Aromatase Inhibitors”, Expert Opin. Invest. Drugs, 12(3):337-351, (2003).
[cited by applicant]
Mocellin, S. et al., “Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials”, J. Natl. Cancer Inst., 108(2), 9 pages, (2016).
[cited by applicant]
Mockus, M. et al., “First Pregnancy Characteristics, Postmenopausal Breast Density, and Salivary Sex Hormone Levels in a Population at High Risk for Breast Cancer”, BBA Clin., 3:189-195, (2015).
[cited by applicant]
Mor, G. et al., “17α-Methyl testosterone is a competitive inhibitor of aromatase activity in Jar choriocarcinoma cells and macrophage-like THP-1 cells in culture”, J Steroid Biochem Mol Biol., 79(1-5):239-46, (2001).
[cited by applicant]
Moshina, N. et al., “Mammographic Density and Histopathologic Characteristics of Screen-Detected Tumors in the Norwegian Breast Cancer Screening Program”, Acta Radiol. Open, 4(9), 4 pages, (2015).
[cited by applicant]
Mousa, N. et al., “Aromatase Inhibitors and Mammographic Breast Density in Postmenopausal Women Receiving Hormone Therapy” Menopause, 15(5):875-84, (2008).
[cited by applicant]
Mukawa, F., “Aromatase inhibitors”, J Synth Org Chem., 46(8):742-52, (2008).
[cited by applicant]
Narayanan, R. et al., “Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial: Mesenchymal Stem Cell Signaling”, PLoS One, 9(7):e103202, 12 pages, (2014).
[cited by applicant]
Ng, K-H et al., “Vision 20/20: Mammographic Breast Density and its Clinical Applications”, Med. Phys., 42(12):7059-7077, (2015).
[cited by applicant]
Niravath, P., “Aromatase Inhibitor-Induced Arthralgia: A Review”, Ann. Oncol., 24(6):1443-1449, (2013).
[cited by applicant]
Ochnik, A. et al., “Antiandrogenic Actions of Medroxyprogesterone Acetate on Epithelial Cells Within Normal Human Breast Tissues Cultured Ex Vivo”, Menopause, 21(1):79-88, (2014).
[cited by applicant]
Olsen, N. et al., “Evidence that Androgens Modulate Human Thymic T Cell Output”, J. Investig. Med., 59(1):32-35, (2011).
[cited by applicant]
Ouimet-Oliva, D. et al., “Effect of Danazol on the Radiographic Density of Breast Parenchyma”, Medline, XP002321074, Nov. 17, 2004; 1 page.
[cited by applicant]
Ozkaya, E. et al., “Is Hyperandrogenemia Protective for Fibrocystic Breast Disease in PCOS?”, Gynecol. Endocrinol., 28(6):468-471, (2012).
[cited by applicant]
Park, S. et al., “Androgen Receptor Expression is Significantly Associated With Better Outcomes in Estrogen Receptor-Positive Breast Cancers”, Annals of Oncology, 22:1755-1762, (2011).
[cited by applicant]
Parsanezhad, M. et al., “A Randomized, Controlled Clinical Trial Comparing the Effects of Aromatase Inhibitor (Letrozole) and Gonadotropin-Releasing Hormone Agonist (Triptorelin) on Uterine Leiomyoma Volume and Hormonal…
[cited by applicant]
Peres, J., “Why Is Breast Cancer Chemoprevention Such a Hard Sell?”, J. Natl. Cancer Inst., 106(5):4-6, (2014).
[cited by applicant]
Pettersson, A. et al., “Mammographic Density Phenotypes and Risk of Breast Cancer: A Meta-Analysis”, J. Natl. Cancer Inst., 106(5):dju078, 11 pages, (2014).
[cited by applicant]
Pike, MC et al., “Mammographic Density, MRI Background Parenchymal Enhancement and Breast Cancer Risk”, Ann. Oncol., 24(Suppl 8):viii37-viii41, (2013).
[cited by applicant]
Pitot, H., “The molecular biology of carcinogenesis”, Cancer, 72(S3):962-70, (1993).
[cited by applicant]
Plourde, P. et al., “Arimidex®: A Potent and Selective Fourth-Generation Aromatase Inhibitor”, Breast Cancer Res. Treat., 30:103-111, (1994).
[cited by applicant]
Priority document AU 2005905768, dated Oct. 19, 2005, for International Application No. PCT/AU2006/001539, publicly made available on WIPO on Feb. 26, 2007; 23 pages.
[cited by applicant]
Priority document U.S. Appl. No. 60/732,662, dated Nov. 3, 2005, for International Application No. PCT/AU2006/001539, publicly made available on WIPO on Feb. 26, 2007; 21 pages.
[cited by applicant]
Priority document U.S. Appl. No. 60/798,308, dated May 8, 2006, for International Application No. PCT/AU2006/001539, publicly made available on WIPO on Feb. 26, 2007; 33 pages.
[cited by applicant]
Rhoden, EL et al., “Treatment of Testosterone-Induced Gynecomastia with the Aromatase Inhibitor, Anastrozole”, Intl. J. of Impotence Res., 16:95-97, (2004).
[cited by applicant]
Rinsho, et al., Japanese Journal of Clinical and Experimental Medicine, 70(11):3428-3433, 7 pages, (1993).
[cited by applicant]
Robinson, J. et al., “Androgen Receptor Driven Transcription in Molecular Apocrine Breast Cancer is Mediated by FoxA1”, EMBO J., 30(15):3019-3027, (2011).
[cited by applicant]
Robinson, J. et al., “FoxA1 is a Key Mediator of Hormonal Response in Breast and Prostate Cancer”, Front. Endocrin., 3(68):1-6, (2012).
[cited by applicant]
Santen, R., “Recent Progress in Development of Aromatase Inhibitors”, J. Steroid Biochem. Molec. Biol., 37(6):1029-1035, (1990).
[cited by applicant]
Saria, M., “Overview of Cancer”, Oncol Nursing Soc., pp. 1-11, (2018).
[cited by applicant]
Scurr, J. et al., “The Prevalence, Severity, and Impact of Breast Pain in the General Population”, Breast J., 20(5):508-13, (2014).
[cited by applicant]
Shawky, M. et al., “Mammographic density: a potential monitoring biomarker for adjuvant and preventative breast cancer endocrine therapies”, Oncotarget, 8(3):5578-91, (2017).
[cited by applicant]
Simpson, E. et al., “Aromatase and its inhibitors: significance for breast cancer therapy”, Recent Prog Horm Res., 57:317-38, (2002).
[cited by applicant]
Smith, I. et al., “Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized P…
[cited by applicant]
Smith, J. et al., “A Pilot Study of Letrozole for One Year in Women at Enhanced Risk of Developing Breast Cancer: Effects on Mammographic Density”, Anticancer Res., 32(4):1327-31, (2012).
[cited by applicant]
Smith, R. et al., “Evaluation and Management of Breast Pain”, Mayo Clin. Proc., 79:353-372, (2004).
[cited by applicant]
Somboonporn, W. et al., “Postmenopausal Testosterone Therapy and Breast Cancer Risk”, Maturitas, 49:267-275, (2004).
[cited by applicant]
Tarone, R. et al., “Breast Reduction Surgery and Breast Cancer Risk: Does Reduction Mammaplasty Have a Role in Primary Prevention Strategies for Women at High Risk of Breast Cancer?”, Plasl. Reconstr. Surg., 113(7):2104…
[cited by applicant]
The Merck Index, 13th ed., Merck & Co., Inc., Entry Nos. 632 (p. 105), 3944 (p. 692) and 9255 (p. 1638), (2001).
[cited by applicant]
The North American Menopause Society, “The Role of Testosterone Therapy in Postmenopausal Women: Position Statement of the North American Menopause Society”, Menopause, 12(5):497-511, (2005).
[cited by applicant]
Titus-Ernstoff, L. et al., “Breast Cancer Risk Factors in Relation to Breast Density (United States)”, Cancer Causes Control, 17(10):1281-1290, (2006).
[cited by applicant]
Tiwary, B. et al., “Parallel Evolution Between Aromatase and Androgen Receptor in the Animal Kingdom”, Mol. Biol. Evol., 26(1):123-129, (2009).
[cited by applicant]
Touraine, P. et al., “Breast inflammatory gigantomastia in a context of immune-mediated diseases”, J Clin Endocrinol Metab., 90(9):5287-94, (2005).
[cited by applicant]
U.S. Appl. No. 15/460,895; Non-Final Office Action, dated Dec. 19, 2017; 17 pages.
[cited by applicant]
U.S. Appl. No. 17/344,052; Notice of Allowance, dated Sep. 13, 2023; 13 pages.
[cited by applicant]
U.S. Appl. No. 17/437,525; Corrected Notice of Allowance, dated May 11, 2022; 6 pages.
[cited by applicant]
U.S. Appl. No. 17/437,525; Non-Final Office Action, dated Jan. 27, 2022; 36 pages.
[cited by applicant]
U.S. Appl. No. 17/437,525; Notice of Allowance, dated Apr. 26, 2022; 13 pages.
[cited by applicant]
Uray, I. et al., “Estradiol down-regulates CD36 expression in human breast cancer cells”, Cancer Lett., 207(1):101-7, (2004).
[cited by applicant]
Vachon, C. et al., “Mammographic Breast Density Response to Aromatase Inhibition”, Clin. Cancer Res., 19(8):2144-2153, (2013).
[cited by applicant]
Viacava, P. et al., “Spectrum of GCDFP-15 Expression in Human Fetal and Adult Normal Tissues”, Virchows Arch, 432:255-260, (1998).
[cited by applicant]
Walecki, M. et al., “Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells”, Mol Biol Cell., 26(15):2845-57, (2015).
[cited by applicant]
Wanders, J. et al., “The Effect of Weight Change on Changes in Breast Density Measures Over Menopause in a Breast Cancer Screening Cohort”, Breast Cancer Res., 8 pages, (2015).
[cited by applicant]
Wang, H. et al., “CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors”, Nat Immunol., 21(3):298-308, (2020).
[cited by applicant]
Warwick, J. et al., “Mammographic Breast Density Refines Tyrer-Cuzick Estimates of Breast Cancer Risk in High-Risk Women: Findings from the Placebo Arm of the International Breast Cancer Intervention Study I”, Breast Ca…
[cited by applicant]
Wasaff, Barbara, “Current Status of Hormonal Treatments for Metastatic Breast Cancer in Postmenopausal Nomen,” Oncol. Nurs. Forum, 24(9), 1515-1520 (1997).
[cited by applicant]
Wu, S. et al., “Quantitative Assessment of Background Parenchymal Enhancement in Breast MRI Predicts Response to Risk-Reducing Salpingo-Oophorectomy: Preliminary Evaluation in a Cohort of BRCA 1/2 Mutation Carriers”, Br…
[cited by applicant]
Yang, Y. et al., “Influence of Factors on Mammographic Density in Premenopausal Chinese Women”, Eur. J. Cancer Prev., 6 pages, (2015).
[cited by applicant]
Youk, J. et al., “Quantitative Lesion-to-Fat Elasticity Ratio Measured by Shear-Wave Elastography for Breast Mass: Which Area Should Be Selected as the Fat Reference?”, PLoS One, 10(9):e0138074, 11 pages, (2015).
[cited by applicant]
Zhong, A. et al., “Stromal-Epithelial Cell Interactions and Alteration of Branching Morphogenesis in Macromastic Mammary Glands”, J. Cell Mol. Med., 18(7):1257-1266, (2014).
[cited by applicant]
Zhou, J. et al., “Testosterone Inhibits Estrogen-Induced Mammary Epithelial Proliferation and Suppresses Estrogen Receptor Expression”, FASEB J., 14:1725-1730 (2000).
[cited by applicant]
Zimmerman, Y. et al., “The Effect of Combined Oral Contraception on Testosterone Levels in Healthy Women: A Systematic Review and Meta-Analysis,” Hum. Reprod. Update, 20(1):76-105, (2014).
[cited by applicant]
EP Application No. 20818587.6; Extended European Search Report and Written Opinion, dated Jun. 12, 2023; 6 pages.
[cited by applicant]
Glaser, R. et al., “Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale, Dosing, and Levels on Therapy”, Int J Pharma Compd., 23(4):325-39, (2019).
[cited by applicant]
Passaperuma, K. et al., “Is mammographic breast density a breast cancer risk factor in women with BRCA mutations?”, J Clin Oncol., 28(23):3779-83, (2010).
[cited by applicant]
Seo, J. et al., “Automated volumetric breast density estimation: a comparison with visual assessment”, Clin Radiol., 68(7):690-5, (2013).
[cited by applicant]
U.S. Appl. No. 17/661,215; Notice of Allowance, dated Aug. 19, 2024; 9 pages.
[cited by applicant]
U.S. Appl. No. 17/661,215; Notice of Allowance, dated Jul. 12, 2024; 19 pages.
[cited by applicant]
Handelsman, D. et al., “Pharmacokinetics and pharmacodynamics of testosterone pellets in man”, J Clin Endrocrinol Metab., 70(1):216-22, (1990).
[cited by applicant]
Lepori, D., “Inflammatory breast disease: The radiologist's role”, Diagn Interv Imaging, 96(10):1045-64, (2015).
[cited by applicant]