Identifying, Monitoring and treating women with breast precancer or cancer

Abstract

The invention is to methods for screening women for breast cancer and precancer by determining a level of an estrogen-related marker. The invention further provides methods of treating such patients identified as having one or more abnormal ductal epithelial cells and an estrogen-related marker. The invention provides methods for screening patient for hormone replacement therapy (HRT), and of monitoring such patients once they begin HRT. The invention provides methods of treating peri-, menopausal or postmenopausal women for both cancer risk reduction and menopausal symptoms (or other conditions related to lowered systemic estrogen levels). The invention also provides kits for the screening, monitoring, and treating methods described.

What is claimed is:  
     
         1 . A method of screening women for breast cancer or precancer said method comprising: 
 providing a ductal fluid sample from at least one duct of a breast of the patient; and    determining in the sample a level of a marker selected from the group consisting of aromatase enzyme, aromatase activity, a biproduct of estrogen synthesis and a protein effector acting upstream of estrogen synthesis; wherein a detectable level above a normal value indicates an increased risk for breast cancer or precancer.    
     
     
         2 . A method as in  claim 1 , further comprising detecting one or more precancerous or cancerous ductal epithelial cells in the sample; wherein the presence of precancerous or cancerous cells indicates that the patient has an increased chance of benefiting from administration of an estrogen activity modulator.  
     
     
         3 . A method as in  claim 2 , wherein detecting comprises detecting cells as a stage selected from the group consisting of ductal hyperplasia, atypical ductal hyperplasia, and low grade ductal carcinoma in situ (LG-DCIS).  
     
     
         4 . A method as in  claim 2 , wherein detecting comprises detecting cells as a stage selected from the group consisting of high-grade ductal carcinoma in situ (HG-DCIS) and invasive carcinoma.  
     
     
         5 . A method as in  claim 1  or  2 , further determining in the sample a level of estrogen or estrogen metabolite, wherein the level above normal indicates a risk for developing abnormal cells in the duct.  
     
     
         6 . A method as in  claim 2  or  5 , further comprising examining any abnormal cells to detect the presence of an estrogen receptor on the surface, wherein the presence of the estrogen receptor indicates that the cell is hormone responsive.  
     
     
         7 . A method as in  claim 1 , wherein the woman is postmenopausal and on hormone replacement therapy (HRT).  
     
     
         8 . A method as in  claim 7 , further comprising detecting precancerous or cancerous ductal epithelial cells in the sample; wherein the presence of precancerous or cancerous ductal epithelial cells indicates that the patient has an increased chance of benefiting from at least one administration of an estrogen activity modulator, stopping the HRT, reducing the dosage of hormone in the HRT, and/or switching to a different hormone or agent for treating menopausal symptoms or osteoporosis.  
     
     
         9 . A method as in  claim 8 , further comprising determining in the sample a level of estrogen or estrogen metabolite, wherein a level above normal indicates an increase risk for developing cancer or precancer in the breast.  
     
     
         10 . A method as in  claim 8  further examining any abnormal cells to detect the presence of an estrogen receptor on the surface, wherein the presence of the estrogen receptor indicates that the cell is hormone responsive.  
     
     
         11 . A method as in  claim 8 , wherein the action selected comprises administration of an estrogen activity modulator, and the estrogen activity modulator is administered intraductally to an affected duct or ducts.  
     
     
         12 . A method as in  claim 1 , wherein providing the ductal fluid sample comprises obtaining the sample from the breast.  
     
     
         13 . A method as in  claim 1 , wherein providing the ductal fluid comprises receiving a sample that has been previously obtained.  
     
     
         14 . A method as in  claim 1 , wherein the fluid was obtained by nipple aspiration or by ductal lavage of at least one breast milk duct.  
     
     
         15 . A method as in  claim 2  or  8  wherein examining the ductal fluid sample comprises cytological examination of ductal epithelial cells.  
     
     
         16 . A method of treating a woman who has been determined to have one or more precancerous or cancerous ductal epithelial cells in a breast duct and an elevated level of a marker selected from the group consisting of aromatase enzyme, aromatase activity, a biproduct of estrogen synthesis, and a protein acting upstream of estrogen synthesis in a ductal fluid sample said method comprising: 
 administering at least one dose of an aromatase inhibitor to the woman.    
     
     
         17 . A method as in  claim 16 , wherein the aromatase inhibitor comprises an agent selected from the group consisting of toremifene, anastrozole, letrozole, fadrozole, lentaron, formestane, and rivizor.  
     
     
         18 . A method as in  claim 16 , wherein administrating comprises intraductal delivery of the aromatase inhibitor.  
     
     
         19 . A method as in  claim 18 , wherein the intraductal delivery comprises accessing the breast duct with a ductal access device and delivering the aromatase inhibitor.  
     
     
         20 . A method as in  claim 18 , wherein the aromatase inhibitor comprises a time release formulation.  
     
     
         21 . A method of treating a woman who has been determined to have one or both of (a) precancerous or cancerous ductal epithelial cells in a breast duct, and (b) an increased level of estrogen or estrogen metabolite in a ductal fluid sample comprising: 
 administering at least one dose of an estrogen activity modulator intraductally.    
     
     
         22 . A method as in  claim 21 , wherein the estrogen activity modulator is selected from the group consisting of an estrogen antagonist, an aromatase inhibitor, a selective estrogen receptor modulator, a modulator of a protein effector acting upstream of estrogen synthesis, and a cocktail of estrogen activity modulators.  
     
     
         23 . A method of screening patients for postmenopausal hormone replacement therapy (HRT), said method comprising: 
 providing a ductal fluid sample from at least one duct of a breast of the patient, and    examining the ductal fluid sample for the presence of a precancerous or cancerous ductal epithelial cell;    wherein HRT is contradicted in patients having precancerous or cancerous ductal epithelial cells in the ductal fluid sample.    
     
     
         24 . A method as in  claim 23 , wherein the precancerous ductal epithelial cell comprises a cell at a stage selected from the group consisting of ductal hyperplasia, atypical ductal hyperplasia, and low grade ductal carcinoma in situ (LG-DCIS).  
     
     
         25 . A method as in  claim 23 , wherein the cancerous ductal epithelial cell comprises a cell at a stage selected from the group consisting of high grade ductal carcinoma in situ (HG-DCIS) and invasive carcinoma.  
     
     
         26 . A method as in  claim 23 , further comprising determining in the sample a level of a marker selected from the group consisting of aromatase enzyme, aromatase activity, estrogen, estrogen metabolite, a biproduct of estrogen synthesis, and a protein acting upstream of estrogen synthesis in a ductal fluid, wherein a level above normal indicates an increased risk for developing cancer or precancer in the breast.  
     
     
         27 . A method as in  claim 23  or  26 , further comprising examining the cancerous or precancerous ductal epithelial cells to detect the presence of an estrogen receptor, wherein the presence of the estrogen receptor indicates that the cell is hormone responsive.  
     
     
         28 . A method as in  claim 23 , wherein the patient is surgically postmenopausal.  
     
     
         29 . A method as in  claim 26  or  27 , further comprising detecting precancerous or cancerous ductal epithelial cells in the sample, wherein the presence of precancerous or cancerous ductal epithelial cells indicates the patient has an increased chance of benefiting from at least one of administration of a lower dosage of hormone in the HRT, close monitoring of markers and ductal epithelial cell changes while the patient is on HRT, selecting an agent for HRT that provides a reduced breast cancer risk, not placing the patient on HRT, and administering an estrogen activity modulator to an affected duct or ducts intraductally.  
     
     
         30 . A method as in  claim 29 , wherein when a marker is increased, and the ductal epithelial cells are normal, the patient is placed on HRT and monitored periodically for changes in marker levels and ductal epithelial cells.  
     
     
         31 . A method as in  claim 23 , wherein providing the ductal fluid sample comprises obtaining the sample from the breast.  
     
     
         32 . A method as in  claim 23 , wherein providing the ductal fluid sample comprises receiving a sample which has been previously obtained.  
     
     
         33 . A method as in  claim 23 , wherein the fluid was obtained by nipple aspiration or by ductal lavage of at least one milk duct.  
     
     
         34 . A method as in  claim 23 , wherein the fluid is collected from a single duct.  
     
     
         35 . A method as in  claim 23 , wherein examining the ductal fluid comprises cytological examination of ductal epithelial cells in the sample to determine whether they are precancerous or cancerous.  
     
     
         36 . A method of monitoring a menopausal or postmenopausal woman on hormone replacement therapy (HRT) comprising: 
 providing a ductal fluid sample from one or more ducts of a breast of a patient, and    examining the ductal fluid sample for a precancerous or cancerous ductal epithelial cell,    wherein indicated therapies for patients found to have one or more precancerous or cancerous epithelial cells include stopping HRT, reducing a dosage of hormone in the HRT, taking an estrogen activity modulator systemically, taking an estrogen activity modulator intraductally, switching to a different drug to reduce menopausal symptoms, and switching to a different drug to reduce bone loss.    
     
     
         37 . A method as in  claim 36 , wherein the precancerous ductal epithelial cell comprises a cell at a stage selected from the group consisting of ductal hyperplasia, atypical ductal hyperplasia, and low grade ductal carcinoma in situ (LG-DCIS).  
     
     
         38 . A method as in  claim 36 , wherein the cancerous ductal epithelial cell comprises a cell at a stage selected from the group consisting of high grade ductal carcinoma in situ (HG-DCIS) and invasive carcinoma.  
     
     
         39 . A method as in  claim 36 , further comprising examining the precancerous or cancerous ductal epithelial cells to detect the presence of an estrogen receptor, wherein the presence of an estrogen receptor indicates that the cell is hormone responsive.  
     
     
         40 . A method as in  claim 36 , wherein the action selected comprises taking an estrogen activity modulator, and the estrogen activity modulator is administered intraductally.  
     
     
         41 . A method as in  claim 40 , wherein the estrogen activity modulator comprises an aromatase inhibitor.  
     
     
         42 . A method as in  claim 36  or  39 , further comprising assaying the ductal fluid for an elevated level of a marker selected from the group consisting of estrogen, an estrogen metabolite, aromatase enzyme, evidence of aromatase activity, biproducts of estrogen synthesis, and a protein effector acting upstream of estrogen synthesis; wherein indicated therapies for patients having an elevated level of one or more markers above normal include administration of a lower dosage of hormone in the HRT, close monitoring of markers while the patient is on HRT, close monitoring of ductal epithelial cell changes while the patient is on HRT, selecting an agent for HRT that provides a reduced cancer risk, stopping the HRT, and intraductal administration of an estrogen activity modulator to an affected duct or ducts.  
     
     
         43 . A method as in  claim 42 , wherein when a marker is elevated above normal, and the ductal epithelial cells are normal, the patient is directed to remain on HRT and be monitored periodically for changes in marker levels and ductal epithelial cell character.  
     
     
         44 . A method as in  claim 36 , wherein providing the ductal fluid sample comprises obtaining the sample from the breast.  
     
     
         45 . A method as in  claim 36 , wherein providing the ductal fluid sample comprises receiving a sample which has been previously obtained.  
     
     
         46 . A method as in  claim 36 , wherein the fluid was obtained by nipple aspiration or by ductal lavage of at least one milk duct.  
     
     
         47 . A method as in  claim 36 , wherein the fluid is collected from a single duct.  
     
     
         48 . A method as in  claim 36 , wherein examining the ductal fluid comprises cytological examination of ductal epithelial cells in the sample to determine whether they are precancerous or cancerous.  
     
     
         49 . A method of treating a peri-, menopausal, or postmenopausal woman for both cancer risk and reduction of menopausal symptoms, osteoporosis, or cardiovascular risk wherein the peri-, menopausal, or postmenopausal woman has been found to have an elevated level of a marker selected from the group consisting of estrogen, an estrogen metabolite, aromatase enzyme, aromatase activity, a biproduct of estrogen synthesis, and a protein acting upstream of estrogen synthesis in a ductal fluid, said method comprising: 
 systemically administering estrogen hormone, and    locally administering an estrogen activity modulator to breast milk ducts that display an elevated level of one or more markers.    
     
     
         50 . A method as in  claim 49 , wherein locally administering an estrogen activity modulator comprises intraductal administration.  
     
     
         51 . A method as in  claim 49 , wherein the estrogen activity modulator comprises an estrogen antagonist, an aromatase inhibitor, or a cocktail of estrogen activity modulators.  
     
     
         52 . A method as in  claim 51 , wherein the estrogen activity modulator is an aromatase inhibitor selected from the group consisting of toremifene, anastrozole, letrozole, fadrozole, lentaron, formestane and rivizor.  
     
     
         53 . A method as in  claim 49 , further comprising monitoring one or more breast ducts of the patient for precancerous or cancerous ductal epithelial cells at time points selected from the group consisting of before, during, and after the systemic estrogen administration.  
     
     
         54 . A kit comprising a device for retrieving a ductal fluid sample from a breast duct and instructions for use setting forth a method according to any of claims? 
     
     
         55 . A kit as in  claim 54 , further comprising a therapeutic agent for intraductal delivery to a patient, wherein the therapeutic agent comprises an estrogen activity modulator.  
     
     
         56 . A kit as in  claim 55 , wherein the estrogen activity modulator comprises an aromatase inhibitor.  
     
     
         57 . A kit as in  claim 54 , further comprising a therapeutic agent for intraductal delivery to a patient, wherein the therapeutic agent comprises an estrogen activity modulator.  
     
     
         58 . A kit as in  claim 57 , wherein the estrogen activity modulator comprises an aromatase inhibitor.