Tissue inhibitor of matrix metalloproteinases type-1 (timp-1) as a cancer marker and postoperative marker for minimal residual disease or recurrent disease in patients with a prior history of cancer

Abstract

The present invention describes a method for determining whether an individual is suffering from cancer by determining a parameter representing the TIMP-1 concentration in body fluid samples from the individual. The present invention furthermore describes a method for determining whether an individual is suffering from minimal residual disease or recurrent cancer after being treated for the primary cancer by determining a parameter representing the post-operative TIMP-1 concentration in body fluid samples from the individual. In addition, the invention describes the additive effect of combined post-operative measurements of plasma TIMP-1 and serum CEA.

1 . A method for determining whether an individual is likely to have minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer, after being treated for the primary cancer, the method comprising determining at least one first parameter representing a post-operative concentration of TIMP-1 in body fluid samples, and indicating the individual as having a high likelihood of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the at least one first parameter is at or beyond a discriminating value and indicating the individual as unlikely of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the parameter is not at or beyond the discriminating value. 
     
     
         2 . A method according to  claim 1 , wherein the discriminating value is a value which has been determined by measuring said at least one first parameter in both a healthy control population and in a population with known minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer, thereby determining the discriminating value which identifies the minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer population with a predetermined specificity or a predetermined sensitivity. 
     
     
         3 . A method according to  claim 1 , wherein the discriminating value is a value which has been determined by measuring said at least one first parameter in a healthy control population, thereby determining the discriminating value which identifies individuals with increased plasma TIMP-1 values. 
     
     
         4 . A method for determining whether an individual is likely to have minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer after being treated for the primary cancer, the method comprising determining a post-operative level of at least one first parameter representing the concentration of TIMP-1 in body fluid samples, and indicating the individual as unlikely of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the first parameter is below a discriminating value, and indicating the individual as having a high likelihood of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the first parameter is not below the discriminating value. 
     
     
         5 . A method according to  claim 4 , wherein the discriminating value is the pre-operative level of said at least one first parameter representing the concentration of TIMP-1 in body fluid samples. 
     
     
         6 . A method according to  claim 4 , wherein the post-operative level of the at least one first parameter representing the concentration of TIMP-1 in body fluid samples is below the discriminating value if the post-operative level of said first parameter is more than at least 0.001% below the discriminating value. 
     
     
         7 . A method according to  claim 6 , wherein the post-operative level of said at least one first parameter is obtained 2 weeks after the operation. 
     
     
         8 . A method according to  claim 1 , wherein the at least one first parameter is the total concentration of TIMP-1. 
     
     
         9 . A method according to  claim 1 , wherein the at least one first parameter is the value obtained by combining the concentration of total TIMP-1 with the concentration of free TIMP-1. 
     
     
         10 . A method according to  claim 1 , wherein the at least one first parameter is the value obtained by combining the concentration of total TIMP-1 with the concentration of a complex between TIMP-1 and a specific MMP. 
     
     
         11 . A method according to  claim 1 , wherein the at least one first parameter is the value obtained by combining the concentration of free TIMP-1 with the concentration of a complex between TIMP-1 and a specific MMP. 
     
     
         12 . A method according to  claim 9 , wherein the combining is performed by logistic regression analysis. 
     
     
         13 . A method according to  claim 1 , which comprises additionally determining at least one second parameter, the second parameter representing the concentration of an additional marker different from any form of TIMP-1, in a body fluid sample from the individual. 
     
     
         14 . A method according to  claim 13 , wherein the at least one first parameter representing the concentration of TIMP-1 in body fluid samples and the at least one second parameter different from any form of TIMP-1 are combined to result in a combined parameter and indicating the individual as having a high likelihood of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the combined parameter is at or beyond a discriminating value and indicating the individual as unlikely of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the combined parameter is not at or beyond the discriminating value. 
     
     
         15 . A method according to  claim 14 , wherein the combining is performed by logistic regression analysis. 
     
     
         16 . A method according to  claim 14 , wherein the discriminating value of the combined parameter is a value which has been determined by determining said combined parameter in both a healthy control population and a population with known minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer, thereby determining the discriminating value which identifies the population with minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer with a predetermined specificity or a predetermined sensitivity. 
     
     
         17 . A method according to  claim 14 , wherein the discriminating value of the combined parameter is a value which has been determined by measuring said combined parameter in a healthy control population, thereby determining the discriminating value which identifies individuals with increased plasma TIMP-1 values. 
     
     
         18 . A method according  claim 13 , wherein the at least one first parameter representing the concentration of TIMP-1 in body fluid samples and the at least one second parameter different from any form of TIMP-1 are combined to result in a combined parameter and indicating the individual as unlikely of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if a post-operative value of the combined parameter is below a discriminating value and indicating the individual as having a high likelihood of having minimal residual disease, recurrent cancer or a combination of minimal residual disease and recurrent cancer if the post-operative value of the combined parameter is not below the discriminating value. 
     
     
         19 . A method according to  claim 18 , wherein the discriminating value is a pre-operative level of said combined parameter. 
     
     
         20 . A method according to  claim 18 , wherein the post-operative level of the combined parameter is below the discriminating value if the post-operative level of the combined parameter is more than at least 0.001% below the discriminating value. 
     
     
         21 . A method according to  claim 20 , wherein the post-operative level of the combined parameter is obtained 2 weeks after the operation. 
     
     
         22 . A method according to  claim 18 , wherein the combining is performed by logistic regression analysis. 
     
     
         23 . A method according to  claim 13 , wherein the at least one second parameter determined is a parameter representing the concentration of a tumour marker. 
     
     
         24 . A method according to  claim 23 , wherein the tumour marker is selected from the group consisting of CEA, soluble u-PAR, cathepsin B, cathepsin H, HER2-neu, CA15-3 and YKL-40, 19.9 and CA242. 
     
     
         25 . A method according to  claim 24 , wherein the at least one second parameter determined is the concentration of CEA. 
     
     
         26 . A method according to  claim 1 , wherein the individual is a member of a population already identified as having an increased risk of developing recurrent cancer. 
     
     
         27 . A method according to  claim 1 , wherein the determination is performed at several time points at intervals as part of a monitoring of a cancer patient after the treatment for primary cancer. 
     
     
         28 . A method according to  claim 1 , wherein the body fluid is selected from the group consisting of blood, serum, plasma, saliva, faeces, urine and cerebrospinal fluid. 
     
     
         29 . A method according to  claim 28 , wherein the body fluid is plasma. 
     
     
         30 . A method according to  claim 28 , wherein the body fluid is blood. 
     
     
         31 . A method according to  claim 28 , wherein the body fluid is saliva. 
     
     
         32 . A method according to  claim 28 , wherein the body fluid is urine. 
     
     
         33 . A method according to  claim 1 , wherein the concentration determination is performed by means of an immuno assay or an activity assay. 
     
     
         34 . A method according to  claim 33 , wherein the immuno assay is an ELISA. 
     
     
         35 . A method according to  claim 33 , wherein the activity assay is zymography. 
     
     
         36 . A method according to  claim 1 , wherein the cancer is a gastrointestinal cancer. 
     
     
         37 . A method according to  claim 36 , wherein the cancer is selected from the group consisting of colon cancer and rectal cancer. 
     
     
         38 . A method according to  claim 3 , wherein the individuals with increased TIMP-1 values are those whose values of the first parameter are equal to or greater than the value of the first parameter in 95 percentile of a healthy control population. 
     
     
         39 . A method according to  claim 7 , wherein the post-operative value of said first parameter is obtained at a time comprising 1 month post-operation, 1.5 month post-operation, 2 month post-operation, 3 month post-operation, 4 month post-operation, 5 month post-operation, 6 month post-operation, 7 month post-operation or 8 month post-operation. 
     
     
         40 . A method according to  claim 10 , wherein the combining is performed by logistic regression analysis. 
     
     
         41 . A method according to  claim 11 , wherein the combining is performed by logistic regression analysis. 
     
     
         42 . A method according to  claim 17 , wherein the individuals with increased plasma TIMP-1 values are those whose values of the combined parameter are equal to or greater than the value of the combined parameter in 95 percentile of a healthy control population. 
     
     
         43 . A method according to  claim 21 , wherein the post-operative level of the combined parameter is obtained at a time comprising 1 month post-operation, 1.5 month post-operation, 2 month post-operation, 3 month post-operation, 4 month post-operation, 5 month post-operation, 6 month post-operation, 7 month post-operation or 8 month post-operation.