Prognostic and diagnostic methods for colorectal cancer

Abstract

Provided herein are methods for selecting a drug therapy for a patient with cancer, such as colorectal cancer, pancreatic cancer, lung cancer or breast cancer. The method includes determining or measuring the level of RasGRP1 polynucleotide or polypeptide in a sample from the patient. Also provided herein are methods for determining the likelihood of a good prognosis for a patient with cancer. Additionally, provided herein are methods for predicting the likelihood of a negative clinical response to an anti-EGFR therapy in a subject with cancer.

What is claimed is: 
     
         1 . A method for selecting a drug therapy for a subject with a cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer colorectal cancer, said method comprising:
 (a) determining the level of RasGRP1 in a sample obtained from the subject; and   (b) selecting a non anti-EGFR therapy for the subject if the level of RasGRP1 is higher than a threshold value   
     
     
         2 . The method of  claim 1 , further comprising determining the presence or absence of a KRAS mutation in an equivalent sample obtained from the subject, wherein the KRAS mutation is G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, G34T, G34A, G34C, G35T, G35C, G35A, G37T, G37C, G37A, G48T, G38A, G38A, Q61K, Q61L, Q61R, Q61H, K117N, A146P, A146T or A146V. 
     
     
         3 . The method of  claim 1 , wherein the non anti-EGFR therapy comprises a BRAF inhibitor, IGFR inhibitor, MEK inhibitor, PI3K inhibitor, VEGR inhibitor or other kinase inhibitor. 
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the cancer is colorectal cancer. 
     
     
         5 . The method of  claim 1 , wherein the sample is a tumor biopsy sample. 
     
     
         6 . The method of  claim 1 , wherein the level of RasGRP1 is the level of RasGRP1 polynucleotide or the level of RasGRP1 polypeptide. 
     
     
         7 . The method of  claim 6 , wherein determining the level of RasGRP1 polynucleotide comprises an amplification assay or a hybridization assay. 
     
     
         8 . The method of  claim 7 , wherein the amplification assay is a probe-based quantitative amplification assay. 
     
     
         9 . The method of  claim 6 , wherein determining the level of RasGRP1 polypeptide comprises an immunoassay, immunohistochemistry, western blot or mass spectrometry. 
     
     
         10 . The method of  claim 1 , further comprising administering an effective amount of the non anti-EGFR therapy to the subject to alleviate at least one symptom of the cancer. 
     
     
         11 . A method for predicting a likelihood of a good prognosis for a subject with a cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer, said method comprising:
 (a) determining the level of RasGRP1 in a sample obtained from the subject; and   (b) predicting a likelihood of a good prognosis for the subject if the level of RasGRP1 is higher than a threshold value.   
     
     
         12 . The method of  claim 11 , wherein the good prognosis comprises overall survival, progression-free survival, or response to therapy. 
     
     
         13 . The method of  claim 11 , further comprising determining the presence or absence of a KRAS mutation in an equivalent sample obtained from the subject, wherein the KRAS mutation is G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, G34T, G34A, G34C, G35T, G35C, G35A, G37T, G37C, G37A, G48T, G38A, G38A, Q61K, Q61L, Q61R, Q61H, K117N, A146P, A146T or A146V. 
     
     
         14 . The method of  claim 11 , wherein the cancer is colorectal cancer. 
     
     
         15 . The method of  claim 11 , wherein the sample is a tumor biopsy sample. 
     
     
         16 . The method of  claim 11 , wherein the level of RasGRP1 is the level of RasGRP1 polynucleotide or the level of RasGRP1 polypeptide. 
     
     
         17 . The method of  claim 16 , wherein determining the level of RasGRP1 polynucleotide comprises an amplification assay or a hybridization assay. 
     
     
         18 . The method of  claim 17 , wherein the amplification assay is a probe-based quantitative amplification assay. 
     
     
         19 . The method of  claim 16 , wherein determining the level of RasGRP1 polypeptide comprises an immunoassay, immunohistochemistry, western blot or mass spectrometry. 
     
     
         20 . The method of  claim 11 , further comprising recording that the subject is a candidate for a non anti-EGFR therapy or further comprising or administering a non anti-EGFR therapy to the subject. 
     
     
         21 . A method for determining a likelihood of a negative clinical response to an anti-EGFR therapy in a subject with cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer, said method comprising:
 (a) determining the level of RasGRP1 in a sample obtained from the subject; and   (b) recording a likelihood of a negative clinical response to the anti-EGFR therapy if the level of RasGRP1 is higher than a control value.   
     
     
         22 . The method of  claim 21 , further comprising determining the presence or absence of a KRAS mutation in an equivalent sample obtained from the subject, wherein the KRAS mutation is G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, G34T, G34A, G34C, G35T, G35C, G35A, G37T, G37C, G37A, G48T, G38A, G38A, Q61K, Q61L, Q61R, Q61H, K117N, A146P, A146T or A146V. 
     
     
         23 . The method of  claim 21 , wherein the cancer is colorectal cancer. 
     
     
         24 . The method of  claim 21 , where the sample is a tumor biopsy sample. 
     
     
         25 . The method of  claim 21 , wherein the level of RasGRP1 is the level of RasGRP1 polynucleotide or the level of RasGRP1 polypeptide. 
     
     
         26 . The method of  claim 25 , wherein determining the level of RasGRP1 polynucleotide comprises an amplification assay or a hybridization assay. 
     
     
         27 . The method of  claim 26 , wherein the amplification assay is a a probe-based quantitative amplification assay. 
     
     
         28 . The method of  claim 25 , wherein determining the level of RasGRP1 polypeptide comprises an immunoassay, immunohistochemistry, western blot or mass spectrometry. 
     
     
         29 . The method of  claim 21 , further comprising administering an effective amount of the non anti-EGFR therapy to the subject to alleviate at least one symptom of the cancer. 
     
     
         30 . The method of  claim 29 , wherein the non anti-EGFR therapy comprises a BRAF inhibitor, AKT inhibitor, MEK inhibitor, cMET inhibitor, VEGR inhibitor or other kinase inhibitor. 
     
     
         31 . A method for determining a likelihood of a positive clinical response to an anti-EGFR therapy in a subject with cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer, said method comprising:
 (a) determining the level of RasGRP1 in a sample obtained from the subject; and   (b) recording a likelihood of a negative clinical response to the anti-EGFR therapy if the level of RasGRP1 is lower than a control value.   
     
     
         32 . The method of  claim 31 , further comprising selecting an anti-EGFR therapy to be administered to the subject; or further ocmprising or administering an anti-EGFR therapy to the subject. 
     
     
         33 . The method of  claim 32 , wherein the anti-EGFR therapy is an EGFR blocking antibody or an EGFR inhibitor drug. 
     
     
         34 . A computer-implemented method for selecting a drug therapy for a subject with a cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer colorectal cancer, said method comprising:
 (a) receiving, at one or more computer systems, information describing the level of RasGRP1 in a sample obtained from the subject;   (b) performing, with one or more processors associated with the computer system, a comparison of the level of RasGRP1 in the sample to a threshold value;   (c) generating, with the one or more processors associated with the one or more computer systems, a determination of whether the level of RasGRP1 is higher than the threshold value.   
     
     
         35 . The method of  claim 34 , further comprising generating a recommendation for a non-anti-EGFR therapy. 
     
     
         36 . The method of  claim 34 , wherein the cancer is colorectal cancer. 
     
     
         37 . The method of  claim 34 , wherein the sample is a tumor biopsy sample. 
     
     
         38 . The method of  claim 34 , wherein the level of RasGRP1 is the level of RasGRP1 polynucleotide in the sample. 
     
     
         39 . The method of  claim 34 , wherein the level of RasGRP1 is the level of RASGRP1 polypeptide in the sample. 
     
     
         40 . The method of  claim 1 , further comprising administering an effective amount of the non anti-EGFR therapy to the subject to alleviate at least one symptom of the cancer. 
     
     
         41 . A computer implemented method for predicting a likelihood of a good prognosis for a subject with a cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer, said method comprising:
 receiving, at one or more computer systems, information describing the level of expression of RASGRP1 in a sample obtained from the subject; and   performing, with one or more processors associated with the computer system, a comparison of the level of RasGRP1 in the sample to a threshold value;   generating, with the one or more processors associated with the one or more computer systems, a determination of whether the level of RasGRP1 is higher than the threshold value, wherein a level of RasGRP1 that is higher than the threshold value predicts a likelihood of a good prognosis for the subject.   
     
     
         42 . The method of  claim 41 , wherein the cancer is colorectal cancer. 
     
     
         43 . The method of  claim 41 , wherein the sample is a tumor biopsy sample. 
     
     
         44 . A computer-implemented method for determining a likelihood of a negative clinical response to an anti-EGFR therapy in a subject with cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer, said method comprising:
 receiving, at one or more computer systems, information describing the level of expression of RASGRP1 in a sample obtained from the subject;   performing, with one or more processors associated with the computer system, a comparison of the level of RasGRP1 in the sample to a control value;   generating, with the one or more processors associated with the one or more computer systems, a determination of whether the level of RasGRP1 is higher than the control value, wherein a level of RasGRP1 that is higher than the control value predicts a negative clinical response to an anti-EGFR therapy.   
     
     
         45 . A computer-implemented method for determining a likelihood of a positive clinical response to an anti-EGFR therapy in a subject with cancer selected from the group consisting of colorectal cancer, pancreatic cancer, lung cancer and breast cancer, said method comprising:
 receiving, at one or more computer systems, information describing the level of expression of RASGRP1 in a sample obtained from the subject;   performing, with one or more processors associated with the computer system, a comparison of the level of RasGRP1 in the sample to a control value;   generating, with the one or more processors associated with the one or more computer systems, a determination of whether the level of RasGRP1 is lower than the control value, wherein a level of RasGRP1 that is lower than the control value predicts a negative clinical response to an anti-EGFR therapy.