Predictors of patient response to treatment with egf receptor inhibitors

Abstract

The present invention provides methods and compositions to facilitate determining whether an EGFR-expressing cancer in an individual is an EGFR inhibitor-responsive cancer, as well as methods for determining the likelihood that a patient having an EGFR-expressing cancer will exhibit a beneficial response to an EGFR inhibitor therapy. The methods generally involve determining a normalized expression level of a gene product that correlates with EGFR inhibitor responsiveness.

1 . A method for predicting a likelihood that a human patient with an EGFR-expressing colorectal cancer will exhibit a beneficial response to an EGFR inhibitor comprising:
 (a) measuring, in a tumor sample obtained from the patient, level of a PTP4A3 RNA transcript, or its expression product;   (b) normalizing the level of the PTP4A3 RNA transcript, or its expression product, to obtain a normalized PTP4A3 expression level;   (c) comparing the normalized PTP4A3 level to a normalized PTP4A3 expression level in a population of patients with an EGFR-expressing colorectal cancer with known clinical outcome; and   (d) determining that the patient has an increased likelihood of a beneficial response to the EGFR inhibitor if the normalized PTP4A3 expression level is increased, or that the patient has a decreased likelihood of a beneficial response to the EGFR inhibitor if the normalized PTP4A3 expression level is decreased.   
     
     
         2 - 28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein the EGFR-expressing colorectal cancer is a KRAS-negative EGFR-expressing colorectal cancer. 
     
     
         30 . The method of  claim 1 , wherein the tumor sample is obtained from a tissue biopsy. 
     
     
         31 . The method of  claim 1 , wherein the tumor sample is a fixed, paraffin-embedded tissue sample. 
     
     
         32 . The method of  claim 1 , wherein the EGFR inhibitor is cetuximab. 
     
     
         33 . The method of  claim 1 , wherein the EGFR inhibitor is a small molecule. 
     
     
         34 . The method of  claim 33 , wherein the small molecule is an EGFR-selective tyrosine kinase inhibitor. 
     
     
         35 . The method of  claim 1 , wherein the level of the PTP4A3 RNA transcript is measured. 
     
     
         36 . The method of  claim 35 , wherein the level of the PTP4A3 RNA transcript is measured by reverse transcriptase polymerase chain reaction (RT-PCR). 
     
     
         37 . The method of  claim 1 , wherein beneficial response is expressed in terms of Overall Response Rate (ORR) or Disease Control (DC). 
     
     
         38 . The method of  claim 1 , wherein the normalized expression level is weighted by its contribution to response to the EGFR inhibitor. 
     
     
         39 . The method of  claim 1 , further comprising the step of creating a report summarizing said prediction. 
     
     
         40 . A method for predicting a likelihood that a human patient with an EGFR-expressing colorectal cancer will exhibit a beneficial response to an EGFR inhibitor comprising:
 extracting RNA from a tumor sample obtained from the patient;   reverse transcribing an RNA transcript of PTP4A3 to produce a cDNA of PTP4A3;   amplifying the cDNA of PTP4A3;   producing an amplicon of the RNA transcript of PTP4A3;   assaying a level of the amplicon of the RNA transcript of PTP4A3;   normalizing the level of the amplicon of the RNA transcript of PTP4A3 to provide a normalized PTP4A3 amplicon level;   comparing the normalized PTP4A3 amplicon level to a normalized PTP4A3 amplicon level in a population of patients with an EGFR-expressing colorectal cancer with known clinical outcome; and   determining that the patient has an increased likelihood of a beneficial response to the EGFR inhibitor if the normalized PTP4A3 amplicon level is increased, or that the patient has a decreased likelihood of a beneficial response to the EGFR inhibitor if the normalized PTP4A3 amplicon level is decreased.   
     
     
         41 . The method of  claim 40 , wherein the EGFR-expressing colorectal cancer is a KRAS-negative EGFR-expressing colorectal cancer. 
     
     
         42 . The method of  claim 40 , wherein the tumor sample is obtained from a tissue biopsy. 
     
     
         43 . The method of  claim 40 , wherein the tumor sample is a fixed, paraffin-embedded tissue sample. 
     
     
         44 . The method of  claim 40 , wherein the EGFR inhibitor is an antibody specific for EGFR. 
     
     
         45 . The method of  claim 44 , wherein the EGFR inhibitor is cetuximab. 
     
     
         46 . The method of  claim 40 , wherein the amplifying step is performed by polymerase chain reaction (PCR). 
     
     
         47 . The method of  claim 40 , wherein beneficial response is expressed in terms of Overall Response Rate (ORR) or Disease Control (DC).