Cancer diagnosis using ki-67

Abstract

The present invention provides methods and compositions for detection, diagnosis, prognosis, monitoring treatment and monitoring progression of cancer by detecting the level of Ki-67 protein in an individual.

1 . A method for diagnosing an individual as having leukemia or lymphoma, said method comprising,
 determining the level of Ki-67 protein in an acellular body fluid sample from said individual;   comparing the level of Ki-67 protein from said individual to a pre-determined cutoff value, and   identifying the individual as having leukemia or lymphoma when said Ki-67 protein level of said individual is higher than said cutoff value.   
     
     
         2 . The method according to  claim 1 , wherein said leukemia is acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL). 
     
     
         3 . The method according to  claim 1 , wherein said acellular body fluid is plasma. 
     
     
         4 . The method according to  claim 1 , wherein said cutoff level is about 900-1500 U/ml. 
     
     
         5 . The method according to  claim 1 , further comprising measuring the level of β2-microglobulin, wherein an elevated level of β2-microglobulin relative to the level measured in disease-free individuals is indicative of the individual having leukemia or lymphoma. 
     
     
         6 . A method for diagnosing an individual as having leukemia or lymphoma, said method comprising,
 measuring the concentration of Ki-67 protein in an acellular body fluid sample from said individual;   measuring the concentration of lymphocytes in blood;   calculating a Ki-67 index by dividing the Ki-67 protein concentration by the lymphocyte concentration;   comparing the Ki-67 index to a pre-determined cutoff value, and   identifying the individual as having leukemia or lymphoma when the Ki-67 protein index is higher than said cutoff value.   
     
     
         7 . The method according to  claim 6 , wherein said leukemia is acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL). 
     
     
         8 . The method according to  claim 6 , wherein said acellular body fluid is plasma. 
     
     
         9 . The method of  claim 6 , wherein the Ki-67 index is expressed as units of Ki-67 per number of lymphocytes. 
     
     
         10 . The method of  claim 9 , wherein the cutoff value is about 1.5-2.25 U/1000 lymphocytes. 
     
     
         11 . The method of  claim 10 , wherein the cutoff value is about 1.88 U/1000 lymphocytes. 
     
     
         12 . A method for determining the prognosis of an individual with leukemia or lymphoma, said method comprising,
 measuring the concentration of Ki-67 protein in an acellular body fluid sample from said individual;   measuring the concentration of lymphocytes in blood;   calculating a Ki-67 index by dividing the Ki-67 protein concentration by the lymphocyte concentration;   comparing the Ki-67 index to a pre-determined cutoff value, and   identifying the individual as having leukemia or lymphoma when the Ki-67 protein index is higher than said cutoff value.   
     
     
         13 . The method of  claim 11 , wherein said leukemia is acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL). 
     
     
         14 . The method of  claim 11 , wherein said prognosis is selected from the group consisting of survival time, complete remission, and remission duration 
     
     
         15 . The method of  claim 12 , wherein the Ki-67 index is expressed as units of Ki-67 per number of lymphocytes. 
     
     
         16 . The method of  claim 15 , wherein the cutoff value is about 1.5-2.25 U/1000 lymphocytes. 
     
     
         17 . The method of  claim 16 , wherein the cutoff value is about 1.88 U/1000 lymphocytes. 
     
     
         18 . A method for modifying the dosage of chemotherapy administered to an individual diagnosed as having leukemia or lymphoma, said method comprising,
 determining a Ki-67 protein index in a first acellular body fluid sample from the individual;   determining the Ki-67 protein index in a second acellular body fluid sample from the individual, wherein said second sample is obtained at a later time than said first sample, wherein chemotherapy is administered between obtaining the first and second sample; and   modifying said dosage of chemotherapy based on the difference in the Ki-67 protein index in the second sample relative to the first sample, wherein the dosage of chemotherapy in increased when the Ki-67 protein index is higher in the second sample compared to the first sample or decreasing or maintaining the dosage of chemotherapy when the Ki-67 protein index is lower in the second sample compared to the first sample.   
     
     
         19 . The method of  claim 18 , wherein said leukemia is acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL). 
     
     
         20 . The method of  claim 18 , wherein the acellular body fluid is plasma. 
     
     
         21 . The method of  claim 18 , wherein the Ki-67 protein index is the concentration of Ki-67 protein in the acellular body fluid. 
     
     
         22 . The method of  claim 18 , wherein the Ki-67 protein index is the concentration of Ki-67 protein in the acellular body fluid normalized to the number of lymphocytes per unit volume of the acellular body fluid. 
     
     
         23 . The method of  claim 22 , wherein the leukemia is CML in the chronic phase. 
     
     
         24 . The method of  claim 18 , wherein the chemotherapy is Chlorambucil, Cytoxan, or Fludarabine.