Methods for making cancer prognoses based on subcellular localization of biomarkers

Abstract

This invention provides a method of making a prognosis for a patient afflicted with a type of cancer such as colon cancer, based upon quantification of biomarkers such as thymidylate synthase in subcellular compartments.

1 . A method of making a prognosis for a patient afflicted with a type of cancer which comprises determining a quantity of a particular biomarker present within a first subcellular compartment and a quantity of such particular biomarker present within a second subcellular compartment in cells of interest present in a tissue sample from the patient, obtaining a ratio of the quantity of the biomarker present within the first subcellular compartment relative to the quantity of the particular biomarker present within the second subcellular compartment, and correlating the ratio so obtained with a series of predetermined ratios associated with a series of prognoses so as to thereby make a prognosis for the patient. 
     
     
         2 . The method of  claim 1 , wherein the particular biomarker is thymidylate synthase. 
     
     
         3 . The method of  claim 1 , wherein the type of cancer is colon cancer. 
     
     
         4 . The method of  claim 1 , wherein the first subcellular compartment is a nuclear compartment and the second subcellular compartment is a cytoplasmic compartment. 
     
     
         5 . The method of  claim 1 , wherein predetermined ratios greater than one are associated with an unfavorable prognosis for the patient. 
     
     
         6 . The method of  claim 1 , wherein predetermined ratios less than one are associated with a favorable prognosis for the patient 
     
     
         7 . The method of  claim 1 , wherein the quantity of the particular biomarker present within the first and the quantity of the particular biomarker present within the second subcellular compartments is each determined using an automated pathology system. 
     
     
         8 . The method of  claim 1 , further comprising comparing the ratio obtained to a plurality of standard reference ratios, each of which is associated with a predicted survival time, wherein the prognosis for the patient is correlated with the reference ratio numerically closest to the ratio obtained. 
     
     
         9 . The method of  claim 1 , further comprising determining the relationship between (a) the ratio obtained and (b) the total of the quantity of the biomarker present within the first subcellular compartment and the quantity of the biomarker present within the second subcellular compartment and correlating the relationship so determined with the patient's prognosis. 
     
     
         10 . A method for determining a stage of advancement for a type of cancer in a patient which comprises:
 a. determining a quantity of a particular biomarker present within a first subcellular compartment and a quantity of a particular biomarker present within a second subcellular compartment in cells of interest present in a tissue sample from the patient;   b. obtaining a ratio of the quantity of the biomarker present within the first subcellular compartment relative to the quantity of the biomarker present within the second subcellular compartment;   c. comparing the ratio so obtained to a plurality of standard reference ratios associated with a series of stages of the type of cancer, and   d. determining the stage of advancement of the type of cancer based on the standard reference ratio closer to the ratio so obtained.   
     
     
         11 . The method of  claim 10 , wherein the particular biomarker is thymidylate synthase. 
     
     
         12 . The method of  claim 10 , wherein the type of cancer is colon cancer. 
     
     
         13 . The method of  claim 10 , wherein the first subcellular compartment is a nuclear compartment and the second subcellular compartment is a cytoplasmic compartment. 
     
     
         14 . The method of  claim 10 , wherein the quantity of the biomarker present within the first and the quantity of the biomarker present within the second subcellular compartments is each determined using an automated pathology system. 
     
     
         15 . The method of  claim 10 , wherein the patient is undergoing cancer therapy and the stage of advancement for the type of cancer is determined at specific time intervals so as to thereby assess the effectiveness of the therapy. 
     
     
         16 . A method for selecting an appropriate therapy for a patient afflicted with a type of cancer which comprises:
 a. determining a quantity of a particular biomarker present within a first subcellular compartment and a quantity of such biomarker present within a second subcellular compartment in cells of interest present in a tissue sample from the patient;   b. obtaining a ratio of the quantity of the biomarker present within the first subcellular compartment relative to the quantity of the particular biomarker present within the second subcellular compartment;   c. comparing the ratio so obtained to a plurality of standard reference ratios associated with responsiveness and nonresponsiveness of cells of such type of cancer to treatment with each of a number of possible therapies, wherein the appropriate therapy for the patient is selected based on the reference ratio numerically closest to the ratio obtained.   
     
     
         17 . The method of  claim 16 , wherein the particular biomarker is thymidylate synthase. 
     
     
         18 . The method of  claim 16 , wherein the type of cancer is colon cancer. 
     
     
         19 . The method of  claim 16 , wherein the first subcellular compartment is a nuclear compartment and the second subcellular compartment is a cytoplasmic compartment. 
     
     
         20 . The method of  claim 16 , wherein the quantity of the biomarker present within the first and the quantity of the biomarker present within the second subcellular compartments is determined using an automated pathology system. 
     
     
         21 . A method for determining the likelihood a particular therapy will be successful for a patient afflicted with a type of cancer comprising:
 a. determining a quantity of a particular biomarker present within a first subcellular compartment and a quantity of such biomarker present within a second subcellular compartment in cells of interest present in a tissue sample from the patient;   b. obtaining a ratio of the quantity of the biomarker present within the first subcellular compartment relative to the quantity of the particular biomarker present within the second subcellular compartment; and   c. comparing the ratio so obtained to a plurality of standard reference ratios associated with responsiveness and nonresponsiveness of such cells of such type of cancer to treatment with the particular therapy, wherein the likelihood of success of the particular therapy is determined based on the reference ratio numerically closest to the ratio obtained.   
     
     
         22 . The method of  claim 21 , wherein the particular biomarker is thymidylate synthase. 
     
     
         23 . The method of  claim 21 , wherein the type of cancer is colon cancer. 
     
     
         24 . The method of  claim 21 , wherein the first subcellular compartment is a nuclear compartment and the second subcellular compartment is a cytoplasmic compartment. 
     
     
         25 . The method of  claim 21 , wherein the quantity of the biomarker present within the first and the quantity of the biomarker present within the second subcellular compartments is each determined using an automated pathology system. 
     
     
         26 . A kit, comprising:
 a. a first stain specific for thymidylate synthase;   b. a second stain specific for a first subcellular compartment of a cell;   c. a third stain specific for a second subcellular compartment of a cell; and   d. instructions for using the kit.   
     
     
         27 . A kit of  claim 26 , further comprising standard reference ratios of nuclear/cytoplasmic thymidylate synthase levels in cells associated with survival, stage of disease, or response to therapy. 
     
     
         28 . A kit of  claim 26 , wherein the second stain is specific for a nuclear compartment and the third stain is specific for a cytoplasmic compartment. 
     
     
         29 . A kit of  claim 26 , wherein each of the first, the second and the third stains are fluorescent stains.