Methods of Reducing Mammographic Breast Density and/or Breast Cancer Risk

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-memopausal 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 reduing 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.

1 - 23 . (canceled) 
     
     
         24 . A method of reducing breast pain in a patient, comprising administering to the patient:
 i) an effective amount of a selective androgen receptor modulator; and   ii) an effective amount of an aromatase inhibitor.   
     
     
         25 . The method of  claim 24 , wherein the selective androgen receptor modulator is selected from the group consisting of:
 (2S)3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide (also known as Enobosarm, Ostarine, GTx-024, and MK-2866);   7R,7aS)-2-Chloro-4-(7-hydroxy-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (also known as BMS-564,929);   4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)-2-trifluoromethyl)benzonitrile (also known as LGD-4033, or Ligandrol);   4-(3-Hydroxy-8-aza-bicyclo[3.2.1]octyl)-naphthalene-1-carbonitrile also known as AC-262,356);   JNJ-28330835;   6-(bis-(2,2,2-trifluoroethyl)amino)-4-trifluoromethyl-1H-quinolin-2-one (also known as LGD-2226);   9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one (also known as LGD-3303);   2-[4-(dimethylamino)-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl]-2-methylpropan-1-ol (also known as S-40503); and   (2S)—N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluro-4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (also known as S-23);   or derivatives thereof.   
     
     
         26 . The method of  claim 24 , wherein the aromatase inhibitor is selected from the group consisting of exemestane, formestane, anastrozole, letrozole, vorozole, and fadrozole. 
     
     
         27 . The method of  claim 24 , wherein the selective androgen receptor modulator is selected from the group consisting of:
 i) (2S)3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide (also known as Enobosarm, Ostarine, GTx-024, and MK-2866);
 7R,7aS)-2-Chloro-4-(7-hydroxy-1,3-dioxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (also known as BMS-564,929); 
 4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-1-yl)-2-trifluoromethyl)benzonitrile (also known as LGD-4033, or Ligandrol); 
 4-(3-Hydroxy-8-aza-bicyclo[3.2.1]octyl)-naphthalene-1-carbonitrile also known as AC-262,356); 
 JNJ-28330835; 
 6-(bis-(2,2,2-trifluoroethyl)amino)-4-trifluoromethyl-1H-quinolin-2-one (also known as LGD-2226); 
 9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one (also known as LGD-3303); 
 2-[4-(dimethylamino)-6-nitro-1,2,3,4-tetrahydroquinolin-2-yl]-2-methylpropan-1-ol (also known as S-40503); and 
 (2S)—N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluro-4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (also known as S-23);
 or derivatives thereof; and 
 
   iii) wherein the aromatase inhibitor is selected from the group consisting of: exemestane, formestane, anastrozole, letrozole, vorozole, and fadrozole.   
     
     
         28 . The method of  claim 24 , wherein the method:
 i) reduces the patient's breast pain associated with having a mammography image taken;   ii) reduces the patient's breast pain in at least one of the patient's breasts between one or more annual intervening mammographic detections;   iii) reduces VBD % and/or AVBD in at least one of the patient's breasts between one or more annual intervening mammographic detections;   iv) reduces breast stiffness in at least one of the patient's breasts between one or more annual intervening mammographic detections;   v) stabilizes and/or increases levels of androgen receptor expression in breast tissue in at least one of the patient's breasts between one or more annual intervening mammographic detections; and/or   vi) reduces and/or treats macromastia in at least one of the patient's breasts between one or more annual intervening mammographic detections.   
     
     
         29 . The method of  claim 24 , wherein the method:
 i) mitigates or reduces the patient's pain during breast compression; and/or   ii) improves breast compression during mammographic visualization or detection of the breast between one or more annual intervening mammographic detections;   iii) reduces the treated patient's risk of developing breast cancer between one or more annual intervening mammographic detections;   iv) provides a reduction in breast elasticity;   v) provides a reduction in macromastia or a reduction in breast cysts;   vi) reduces breast inflammation associated with macromastia or breast cysts; and/or   vii) mitigates or reduces the patient's pain according to the visual analog scale (VAS) during breast compression.   
     
     
         30 . The method of  claim 24 , wherein the method reduces breast inflammation. 
     
     
         31 . The method of  claim 24 , wherein the method reduces breast pain in at least one of the patient's breasts between 20% to 100% over a 2 week, 3 month, 6 month, one year, two year, three year or five year treatment period. 
     
     
         32 . The method of  claim 24 , wherein the androgen receptor modulator is administered by subcutaneous implant. 
     
     
         33 . The method of  claim 24 , wherein:
 i) the effective amount of the androgen receptor modulator is 2-200 mg; and   ii) the effective amount of the aromatase inhibitor is 0.5-10 mg.   
     
     
         34 . The method of  claim 24 , wherein the patient is pre-menopausal, peri-menopausal, or post-menopausal. 
     
     
         35 . The method of  claim 24 , wherein the method increases or improves the patient's fat to breast tissue ratio from 1:19 to 19:1 over a 3 month period, over a 6 month period, over a 9 month period, over a 1 year period, or over a 5 year period. 
     
     
         36 . The method of  claim 24 , wherein the selective androgen receptor modulator is (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluromethyl)phenyl]-2-hydroxy-2-methylpropanamide. 
     
     
         37 . The method of  claim 24 , wherein the aromatase inhibitor is anastrozole. 
     
     
         38 . The method of  claim 24 , wherein the patient has, or is diagnosed with having, a breast with a mammographic breast density of 7.5% or greater. 
     
     
         39 . The method of  claim 24 , wherein the patient has, or is diagnosed with having, a breast with an area breast density percentage (ABD %) of 7.5% or greater. 
     
     
         40 . The method of  claim 39 , wherein the method reduces the ABD % or absolute area breast density (AABD) of the patient's breast by at least 2% over a 2 week, 1 month, 2 month, 3 month, 6 month, 9 month, or a 1 year period. 
     
     
         41 . The method of  claim 24 , wherein the patient has, or is diagnosed with having, a breast with a volume breast density percentage (VBD %) of 7.5% or greater. 
     
     
         42 . The method of  claim 41 , wherein the method reduces the VBD % or absolute volume breast density (AVBD) of the patient's breast by at least 2% over a 2 week, 1 month, 2 month, 3 month, 6 month, 9 month, or 1 year period. 
     
     
         43 . The method of  claim 24 , wherein the patient has, or is diagnosed with having, a breast with a BIRADS score of 3 or 4 (or c or d).