Tissue inhibitor of matrix metalloproteinases type-1 (timp-1) as a cancer marker

Abstract

The present invention describes a method for determining whether an individual is likely to suffer from cancer by determining a parameter representing the TIMP-1 concentration in body fluid samples from the individual.

1 . A method for determining whether an individual is likely to have cancer, the method comprising determining a first parameter representing the concentration of TIMP-1 in body fluid samples, and indicating the individual as having a high likelihood of having cancer if the parameter is at or beyond a discriminating value and indicating the individual as unlikely of having cancer if the parameter is not at or beyond the discriminating value. 
     
     
         2 - 33 . (canceled) 
     
     
         34 . A method according to  claims 38 ,  43 ,  44 ,  46  or  47 , wherein the concentration determination is performed by means of an immuno assay or an activity assay. 
     
     
         35 . A method according to  claim 34 , wherein the immuno assay is an ELISA. 
     
     
         36 . A method according to  claim 34 , wherein the activity assay is zymography. 
     
     
         37 . (canceled) 
     
     
         38 . A method for determining whether an individual is likely to have metastatic breast cancer, the method comprising:
 a) determining a total concentration of TIMP-1 in a plasma sample of said individual;   b) constructing a percentile plot of total plasma TIMP-1 concentrations obtained from a non-metastatic breast cancer population;   c) constructing a ROC (receiver operating characteristics) curve based on total plasma TIMP-1 concentrations determined in a non-metastatic breast cancer population and on total plasma TIMP-1 concentrations determined in a metastatic breast cancer population;   d) selecting a desired sensitivity;   e) determining from the ROC curve the specificity corresponding to the desired sensitivity;   f) determining from the percentile plot the total plasma TIMP-1 concentration value corresponding to the determined specificity; and   g) indicating the individual as likely to have metastatic breast cancer if the total concentration of TIMP-1 in the plasma sample of the individual is equal to or higher than said total plasma TIMP-1 concentration value corresponding to the determined specificity and indicating the individual as unlikely to have metastatic breast cancer if the total concentration of TIMP-1 in the plasma sample of the individual is lower than said total plasma TIMP-1 concentration value corresponding to the determined specificity.   
     
     
         39 . A method according to  claim 44  or  47 , wherein the combining the total concentration of TIMP-1 in the plasma sample of the individual with the concentration of free TIMP-1 in the plasma sample of the individual to result in the combined parameter of the individual and the combining the total plasma TIMP-1 concentration of the non-metastatic breast cancer population with the free plasma TIMP-1 concentration of the non-metastatic breast cancer population to result in the non-metastatic breast cancer benchmark combined parameter are performed by logistic regression analysis. 
     
     
         40 . A method according to  claim 38 ,  43 ,  44 ,  46  or  47 , wherein the individual is a member of a population not already identified as having an increased risk of developing metastatic breast cancer. 
     
     
         41 . A method for determining whether an individual is likely to have metastatic breast cancer, the method comprising:
 a) determining a total concentration of TIMP-1 in a plasma sample of said individual, and a concentration of free TIMP-1 in a plasma sample of said individual;   b) combining the total concentration of TIMP-1 in the plasma sample of the individual with the concentration of free TIMP-1 in the plasma sample of the individual to result in a combined parameter of the individual;   c) combining a total plasma TIMP-1 concentration of a non-metastatic breast cancer population with a free plasma TIMP-1 concentration of the non-metastatic breast cancer population, the resulting combination being referred to herein as a non-metastatic breast cancer benchmark combined parameter;   d) combining a total plasma TIMP-1 concentration of a metastatic breast cancer population with a free plasma TIMP-1 concentration of the metastatic breast cancer population, the resulting combination being referred to herein as a metastatic breast cancer benchmark combined parameter;   e) constructing a percentile plot of the non-metastatic breast cancer benchmark combined parameter;   f) constructing a ROC (receiver operating characteristics) curve based on the non-metastatic breast cancer benchmark combined parameter and the metastatic breast cancer benchmark combined parameter;   g) selecting a desired sensitivity;   h) determining from the ROC curve the specificity corresponding to the desired sensitivity;   i) determining from the percentile plot the non-metastatic breast cancer benchmark combined parameter value corresponding to the determined specificity; and   j) indicating the individual as likely to have metastatic breast cancer if the combined parameter of the individual is equal to or higher than said non-metastatic breast cancer benchmark combined parameter value corresponding to the determined specificity and indicating the individual as unlikely to have metastatic breast cancer if the combined parameter of the individual is lower than said non-metastatic breast cancer benchmark combined parameter value corresponding to the determined specificity.   
     
     
         42 . A method according to  claim 38 ,  43 ,  44 ,  46  or  47 , wherein the individual has a genetic disposition for metastatic breast cancer, has been exposed to carcinogenic substances or has a metastatic breast cancer-predisposing or non-malignant diseases. 
     
     
         43 . A method for determining whether an individual is likely to have metastatic breast cancer, the method comprising:
 a) determining a total concentration of TIMP-1 in a plasma sample of said individual;   b) constructing a percentile plot of total plasma TIMP-1 concentrations obtained from a non-metastatic breast cancer population;   c) selecting a desired specificity;   d) determining from the percentile plot the total plasma TIMP-1 concentration value corresponding to the desired specificity; and   e) indicating the individual as likely to have metastatic breast cancer if the total concentration of TIMP-1 in the plasma sample of the individual is equal to or higher than said total plasma TIMP-1 concentration value corresponding to the desired specificity and indicating the individual as unlikely to have metastatic breast cancer if the total concentration of TIMP-1 in the plasma sample of the individual is lower than said total plasma TIMP-1 concentration value corresponding to the desired specificity.   
     
     
         44 . A method for determining whether an individual is likely to have metastatic breast cancer, the method comprising:
 a) determining a total concentration of TIMP-1 in a plasma sample of said individual and a concentration of free TIMP-1 in a plasma sample of said individual;   b) combining the total concentration of TIMP-1 in the plasma sample of said individual with the concentration of free TIMP-1 in the plasma sample of said individual to result in a combined parameter of the individual;   c) combining a total plasma TIMP-1 concentration of a non-metastatic breast cancer population with a free plasma TIMP-1 concentration of the non-metastatic breast cancer population, the resulting combination being referred to herein as a non-metastatic breast cancer benchmark combined parameter;   d) constructing a percentile plot of the non-metastatic breast cancer benchmark combined parameter;   e) selecting a desired specificity;   f) determining from the percentile plot the non-metastatic breast cancer benchmark combined parameter value corresponding to the desired specificity; and   g) indicating the individual as likely to have metastatic breast cancer if the combined parameter of the individual is equal to or higher than said non-metastatic breast cancer benchmark combined parameter value corresponding to the desired specificity and indicating the individual as unlikely to have metastatic breast cancer if the combined parameter of the individual is lower than said non-metastatic breast cancer benchmark combined parameter value corresponding to the desired specificity.   
     
     
         45 . A method according to  claim 38 ,  43 ,  44 ,  46  or  47 , wherein the total plasma concentration of TIMP-1 comprises the sum of the TIMP-1 in free form and the TIMP-1 in complex forms. 
     
     
         46 . A method for determining whether an individual is likely to have metastatic breast cancer, the method comprising determining a total concentration of TIMP-1 in a plasma sample of said individual, and indicating the individual as likely to have metastatic breast cancer if the total concentration of TIMP-1 in the plasma sample of the individual is equal to or higher than the total concentration of TIMP-1 measured in plasma in a non-metastatic breast cancer population, and indicating the individual as unlikely to have metastatic breast cancer if the total concentration of TIMP-1 in the plasma sample of the individual is lower than the total concentration of TIMP-1 measured in plasma in a non-metastatic breast cancer population. 
     
     
         47 . A method for determining whether an individual is likely to have metastatic breast cancer, the method comprising:
 a) determining a total concentration of TIMP-1 in a plasma sample of said individual and a concentration of free TIMP-1 in a plasma sample of said individual;   b) combining the total concentration of TIMP-1 in the plasma sample of the individual with the concentration of free TIMP-1 in the plasma sample of said individual to result in a combined parameter of the individual;   c) combining a total plasma TIMP-1 concentration of a non-metastatic breast cancer population with a free plasma TIMP-1 concentration of the non-metastatic breast cancer population, the resulting combination being referred to herein as a non-metastatic breast cancer benchmark combined parameter;   d) and indicating the individual as likely to have metastatic breast cancer if the combined parameter of the individual is equal to or higher than the non-metastatic breast cancer benchmark combined parameter, and indicating the individual as unlikely to have metastatic breast cancer if the combined parameter of the individual is lower than the non-metastatic breast cancer benchmark combined parameter.   
     
     
         48 . A method according to  claim 44  or  47  wherein the total plasma TIMP-1 concentration of the non-metastatic breast cancer population and the free plasma TIMP-1 concentration of the non-metastatic breast cancer population are determined prior to the sub-section c).