Methods for diagnosis, prognosis and treatment of primary and metastatic basal-like breast cancer and other cancer types

Abstract

In one embodiment, methods of theranostic classification of a breast cancer tumor are provided, wherein the classification is determined by detecting an expression level of FOXC1. In other embodiments, methods for predicting a prognosis of a basal-like breast cancer and methods of treating a basal-like breast cancer are provided. In other embodiments, methods for diagnosing metastatic breast cancer using the expression ratio of FOXC1/FOXA1 in a population of breast cancer tumor cells are provided. The methods also entail administering a treatment for metastatic breast cancer if the expression ratio of FOXC1/FOXA1 in the population of breast cancer tumor cells is elevated as compared to a control. Other embodiments provide methods for treating breast cancer with a proteasome inhibitor alone or in combination with a Wnt inhibitor in subjects with tumor cells expressing FOXC1 in a subject.

1 . A method of theranostic classification of a breast cancer tumor, the method comprising:
 obtaining a breast cancer tumor sample from a subject;   detecting an expression level of FOXC1;   comparing the expression level of FOXC1 to a predetermined cutoff level; and   classifying the breast cancer tumor sample as belonging to a theranostic basal-like breast cancer tumor subtype or a theranostic hybrid basal-like breast cancer tumor subtype when the expression level of FOXC1 is higher than the predetermined cutoff level.   
     
     
         2 . The method of  claim 1 , wherein the breast cancer tumor sample is a formalin-fixed paraffin embedded (FFPE) sample. 
     
     
         3 . The method of  claim 2 , wherein the expression level of FOXC1 is determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or a Quantigene® FFPE assay. 
     
     
         4 . The method of  claim 1 , wherein the predetermined cutoff level is determined by a 90th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising all breast cancer subtypes. 
     
     
         5 . The method of  claim 1 , further comprising:
 determining an expression status for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2); and   classifying the breast cancer tumor sample as belonging to a theranostic hybrid basal-like/HER2+ breast cancer tumor subtype when the expression status of ER is negative (ER−), the expression status of PR is negative (PR−), the expression status of HER2 is positive (HER2+) and the expression level of FOXC1 is higher than the predetermined cutoff level.   
     
     
         6 . The method of  claim 5 , wherein the predetermined cutoff level is determined by a 50th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising tumors having a HER2+ status. 
     
     
         7 . The method of  claim 1 , further comprising:
 determining an expression status of ER, PR, and HER2 of the breast cancer tumor sample; and   classifying the breast cancer tumor sample as belonging to a theranostic hybrid basal-like/triple-negative breast cancer tumor subtype when the expression status of ER is negative (ER−), the expression status of PR is negative (PR−), the expression status of HER2 is negative (HER2−) and the expression level of FOXC1 is higher than the predetermined cutoff level.   
     
     
         8 . The method of  claim 7 , wherein the predetermined cutoff level is determined by a 50th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising tumors having an ER−/PR−/HER2− status. 
     
     
         9 . The method of  claim 1 , further comprising:
 determining an expression status of ER, PR, and HER2 of the breast cancer tumor sample; and   classifying the breast cancer tumor sample as belonging to a theranostic hybrid basal-like/luminal breast cancer tumor subtype when the expression status of ER is positive (ER+), the expression status of PR is negative or positive (PR−/PR+), the expression status of HER2 is negative or positive (HER2−/HER2+) and the expression level of FOXC1 is higher than the predetermined cutoff level.   
     
     
         10 . The method of  claim 9 , wherein the predetermined cutoff level is determined by a 50th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising tumors having an ER+ status. 
     
     
         11 . A method for predicting a prognosis of a basal-like breast cancer, the method comprising:
 obtaining a breast cancer tumor sample from a subject;   detecting an expression level of FOXC1;   comparing the expression level of FOXC1 to a predetermined cutoff level;   predicting a poor prognosis of the basal-like breast cancer when the expression level of FOXC1 is higher than the predetermined cutoff level.   
     
     
         12 . The method of  claim 11 , wherein the breast cancer tumor sample is a formalin-fixed paraffin embedded (FFPE) sample. 
     
     
         13 . The method of  claim 12 , wherein the expression level of FOXC1 is determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or a Quantigene® FFPE assay. 
     
     
         14 . The method of  claim 11 , wherein the predetermined cutoff level is determined by a 90th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising all breast cancer subtypes. 
     
     
         15 . The method of  claim 11 , wherein the basal-like breast cancer is a hybrid basal-like/HER2+ breast cancer and the predetermined cutoff level is determined by a 50th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising tumors having a HER2+ status. 
     
     
         16 . The method of  claim 11 , wherein the basal-like breast cancer is a hybrid basal-like/luminal breast cancer and the predetermined cutoff level is determined by a 50th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising tumors having an ER+ status. 
     
     
         17 . The method of  claim 11 , wherein the basal-like breast cancer is a hybrid basal-like/triple-negative breast cancer and the predetermined cutoff level is determined by a 50th percentile level of FOXC1 expression levels for a dataset of breast cancer tumors, the dataset comprising tumors having an ER−/PR−/HER2− status. 
     
     
         18 . The method of  claim 11 , wherein the prognosis is overall survival or recurrence free survival. 
     
     
         19 . The method of  claim 11 , wherein the prognosis is a propensity of developing a distant metastasis or a time to a distant metastasis. 
     
     
         20 . The method of  claim 19 , wherein the distant metastasis is brain metastasis. 
     
     
         21 . The method of  claim 11 , wherein the prognosis is a propensity for resistance to a targeted cancer therapy. 
     
     
         22 . The method of  claim 21 , wherein the targeted therapy is a substance that inhibits HER2 expression and/or activity or a substance that inhibits ER expression and/or activity. 
     
     
         23 . The method of  claim 22 , wherein the substance that inhibits HER2 expression and/or activity is a trastuzumab (Herceptin®). 
     
     
         24 . The method of  claim 22 , wherein the substance that inhibits ER expression and/or activity is tamoxifen or an aromatase inhibitor.