Genetic Markers for Predicting Responsiveness to Combination Therapy

Abstract

The invention provides compositions and methods for determining the likelihood of successful treatment with an effective amount of an anti-VEGF antibody or equivalent thereof, in combination with anti-EGFR antibody or equivalent thereof, and, in some aspects in combination with a topoisomerase inhibitor. The methods comprise determining the identity of a gene of interest in a patient sample and correlating the patient's genotype with the predictive response. Patients identified as responsive are then treated with the appropriate therapy.

1 . A method for determining if a human gastrointestinal cancer patient is likely responsive to therapy comprising the administration of anti-VEGF antibody and anti-EGFR antibody based therapy, comprising screening a suitable cell or tissue sample isolated from said patient for at least one genetic marker of the group:
 (i) TGF-β (T29C);   (ii) FCGRIIIA (V158F);   (iii) XPD (A751C);   (iv) HIF1-α (C1772T);   (v) OATPC (A388G); or   (vi) FCGRIIB (T232C),   wherein for the genetic marker screened, the presence of at least one genetic marker of the group:   (i) (C/C or T/T) for TGF-β (T29C);   (ii) (F/F or V/F) for FCGRIIIA (V158F);   (iii) (A/A or A/C) for XPD (A751C);   (iv) (C/T or T/T) for HIF1-α (C1772T);   (v) (A/A) for OATPC (A388G); or   (vi) (T/T or T/C) for FCGRIIB (T232C),   indicates the patient will likely be responsive to the therapy.   
     
     
         2 . A method for determining if a human gastrointestinal cancer patient is likely responsive to therapy comprising the administration of anti-VEGF antibody, anti-EGFR antibody and topoisomerase I inhibitor based therapy, comprising screening a suitable cell or tissue sample isolated from said patient for at least one genetic marker of the group:
 (i) TGF-β (T29C);   (ii) Cyclin D1 (A870G);   (iii) UGT1A1 (UGT1A1*28);   (iv) EGFR (G497A);   (v) ERCC1 (C-118T);   (vi) GSTP (V105I);   (vii) VEGFR2 expression and NRP1 expression;   (viii) NRP1 expression and ERCC1 expression;   (ix) EGFR expression; or   (x) EGFR expression and VEGFR2 expression,   wherein for the genetic marker screened, the presence of at least one genetic marker of the group:   (i) (C/C or T/T) for TGF-β (T29C);   (ii) (A/A or G/G) for Cyclin D1 (A870G);   (iii) (6/6, 6/7, or 8) for UGT1A1 (UGT1A1*28);   (iv) (G/G or G/A) for EGFR (G497A);   (v) (C/C or T/T) for ERCC1 (C-118T);   (vi) (V/I or I/I) for GSTP (V105I);   (vii) high VEGFR2 expression and low NRP1 expression;   (viii) high NRP 1 expression and low ERCC 1 expression;   (ix) high EGFR expression; or   (x) low EGFR expression and high VEGFR2 expression,   indicates the patient is likely responsive to said therapy.   
     
     
         3 . The method of  claim 1  or  2 , wherein the gastrointestinal cancer is a metastatic or non-metastatic gastrointestinal cancer selected from the group consisting of rectal cancer, colorectal cancer, colon cancer, gastric cancer, lung cancer, non-small cell lung cancer and esophageal cancer. 
     
     
         4 . The method of  claim 1  or  2 , wherein the gastrointestinal cancer is colorectal cancer. 
     
     
         5 . The method of  claim 1  or  2 , wherein the gastrointestinal cancer is metastatic colorectal cancer. 
     
     
         6 . The method of  claim 1  or  2 , wherein the suitable cell or tissue sample is a tumor cell or tissue sample. 
     
     
         7 . The method of  claim 1  or  2 , wherein the suitable cell or tissue sample is a metastatic colorectal tumor cell or tissue sample. 
     
     
         8 . The method of  claim 1  or  2 , wherein the suitable cell or tissue sample is a normal cell or tissue sample. 
     
     
         9 . The method of  claim 1  or  2 , wherein the suitable cell or tissue sample is peripheral blood lymphocytes. 
     
     
         10 . A method for treating a human gastrointestinal patient comprising administering an effective amount of an anti-VEGF antibody and anti-EGFR antibody based therapy, to a human gastrointestinal patient selected for said therapy based on having at least one genetic marker of the group:
 (i) (C/C or T/T) for TGF-β (T29C);   (ii) (F/F or V/F) for FCGRIIIA (V158F);   (iii) (A/A or A/C) for XPD (A751C);   (iv) (C/T or T/T) for HIF1-α (C1772T);   (v) (A/A) for OATPC (A388G);   (vi) (T/T or T/C) for FCGRIIB (T232C),   thereby treating said patient.   
     
     
         11 . A method for treating a human gastrointestinal patient comprising administering an effective amount of a therapy comprising administration of an effective amount of an anti-VEGF antibody, anti-EGFR antibody and topoisomerase I inhibitor based therapy, to a human gastrointestinal patient selected for said therapy based on having at least one genetic marker of the group:
 (i) (C/C or T/T) for TGF-β (T29C);   (ii) (A/A or G/G) for Cyclin D1 (A870G);   (iii) (6/6, 6/7, or 8) for UGT1A1 (UGT1A1*28);   (iv) (G/G or G/A) for EGFR (G497A);   (v) (C/C or T/T) for ERCC1 (C-118T);   (vi) (V/I or I/I) for GSTP (V105I);   (vii) high VEGFR2 expression and low NRP1 expression;   (viii) high NRP1 expression and low ERCC1 expression;   (ix) high EGFR expression; or   (x) low EGFR expression and high VEGFR2 expression,   thereby treating said patient.   
     
     
         12 . The method of  claim 10  or  11 , wherein the gastrointestinal cancer is a metastatic or non-metastatic gastrointestinal cancer selected from the group consisting of rectal cancer, colorectal cancer, colon cancer, gastric cancer, lung cancer, non-small cell lung cancer and esophageal cancer. 
     
     
         13 . A panel of genetic markers for determining whether a patient is likely responsive to anti-VEGF antibody and anti-EGFR antibody based therapy, the panel comprising a group of primers and/or a probes that identify the genetic markers:
 (i) TGF-β (T29C);   (ii) FCGRIIIA (V158F);   (iii) XPD (A751C);   (iv) HIF1-α (C1772T);   (v) OATPC (A388G); and   (vi) FCGRIIB (T232C).   
     
     
         14 . A panel of genetic markers for determining whether a patient is likely responsive to anti-VEGF antibody, anti-EGFR antibody and topoisomerase I inhibitor based therapy, the panel comprising a group of primers or probes that identify the genetic markers:
 (i) TGF-β (T29C);   (ii) Cyclin D1 (A870G);   (iii) UGT1A1 (UGT1A1*28);   (iv) EGFR (G497A);   (v) ERCC1 (C-118T);   (vi) GSTP (V105I);   (vii) VEGFR2 expression;   (viii) NRP1 expression;   (ix) ERCC1 expression; and   (x) EGFR expression.