Identifying, monitoring, and treating women for 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.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] The present application is a continuation-in-part of U.S. application Ser. No. 09 / 313,463, filed on May 17, 1999, which claimed the benefit and priority of Provisional U.S. Application No. 60 / 117,281 filed on Jan. 26, 1999, under 37 CFR §1.78, the full disclosures of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The field of this invention is identifying, treating and monitoring women at risk for or having breast precancer or cancer. [0004] 2. Description of the Background Art [0005] The approximate age of menopause for women in the United States is 51, and the mean life expectancy of such women is 85 years; thus most American women will live a third of their lives without significant estrogen production. Estrogen supplementation was first used in 1935 to ameliorate menopausal symptoms, and a few years later findings indicated that estrogen supplementation had beneficial ...

AI Technical Summary

Benefits of technology

[0019] The invention provides a method of screening women for breast cancer or precancer 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 including 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. The method can further comprise 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. Detecting can comprise detecting cells at a stage including ductal hyperplasia, atypical ductal hyperplasia, low grade ductal carcinoma in situ (LG-DCIS), high grade ductal carcinoma in situ (HG-DCIS) and invasive carcinoma. The method can comprise 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. The method can further comprise 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. The method can comprise 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 of 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. The method can further comprise determining in the sample an elevated level of estrogen or estrogen metabolite, wherein a level above normal indicates an increase risk for developing cancer or precancer in the breast. The method can further include 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.

[0020] The invention further provides 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 the method comprising administering at least one dose of an aromatase inhibitor to the woman. Another method of treating a woman who has been determined to have one or more 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 can comprise administering at least one dose of an estrogen activity modulator intraductally. The estrogen activity modulator can include 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.

[0021] The invention also provides a method of screening patients for postmenopausal hormone replacement therapy (HRT), the 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. The method can further comprise determining in the sample a level of a marker including an aromatase enzyme, aromatase activity, estrogen, estrogen metabolite, a biproduct of estrogen synthesis, or 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. The method can further comprise 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 administering 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.

[0022] The invention also provides a method of monitoring a 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 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. When the action selected comprises taking an estrogen activity modulator, the estrogen activity modulator can be administered intraductally. The estrogen activity modulator can comprise an aromatase inhibitor. The method can further comprise assaying the ductal fluid for an elevated level of a marker including estrogen, an estrogen metabolite, aromatase enzyme, evidence of aromatase activity, biproducts of estrogen synthesis, or 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, or intraductal administration of an estrogen activity modulator to an affected duct or ducts. 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.

Problems solved by technology

In 1975 articles warned that continuous estrogen supplementation alone increased the risk of endometrial cancer.

Osteoporosis is associated with increased mortality due to increased fractures, particularly hip fractures and affects millions of people worldwide.

There is evidence that estrogen therapy decreases risk for coronary heart disease (and for hip fracture), but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase risk for breast cancer (See, Grady, D et al., Ann Intern Med 117(12): 1016-37 (1992)).