Methods for Determining the Likelihood of Survival and for Predicting Likelihood of Metastasis in Cancer Patients

Abstract

The present invention relates generally to methods of accurately quantifying HER2 and/or p95 expression in subjects with a HER2 positive cancer and indicating the risk of brain relapse in such patients.

1 - 39 . (canceled) 
     
     
         40 . A method of identifying subjects with HER2-positive cancer that should be screened for brain metastasis, comprising:
 (a) obtaining a biological sample of a tumor from the subject's cancer;   (b) measuring the amount of p95-HER2 in the biological sample, wherein the measuring comprises incubating the biological sample with a p95-HER2 monoclonal antibody produced by a hybridoma cell line having ATCC accession number PTA-9740 (p95.D9.1), PTA-9738 (p95.D3.4), or PTA-9739 (p95.D8.2);   (c) selecting the subject based on the amount of p95-HER2 protein in the subject's sample being above-a p95-HER2 cutoff, wherein (i) the p95-HER2 cutoff is the median amount of p95-HER2 in a reference population with HER2 positive cancer or (ii) the p95-HER2 cutoff comprises at least one of   (i) a level of p95-HER2 protein expression at least two-fold greater than a control cancer cell line having a basal level of p95-HER2 expression, or   (ii) a level of p95-HER2 protein expression corresponding to at least a top 30th percentile of p95-HER2 protein expression in a reference cohort of subjects having the HER2-positive cancer; and   (d) indicating that the selected subject should be screened for brain metastasis.   
     
     
         41 . The method of  claim 40 , wherein measuring the amount of p95-HER2 in the biological sample comprises
 (i) incubating the biological sample with a p95-HER2 monoclonal antibody produced by a hybridoma cell line having ATCC accession number PTA-9740 (p95.D9.1), PTA-9738 (p95.D3.4), or PTA-9739 (p95.D8.2) and a binding compound that binds to the p95-HER2 monoclonal antibody, wherein the binding compound comprises a molecular tag covalently attached thereto via a cleavable linkage,   (ii) treating the biological sample with a cleaving agent to release the molecular tag from the binding compound, and   (iii) measuring the amount of released molecular tag as indicative of p95-HER2 levels in the sample to determine the amount of p95-HER2 protein in the biological sample,   wherein the p95-HER2 protein has a first amino acid corresponding to methionine 611 of HER2 protein.   
     
     
         42 . The method of  claim 40 , wherein the subject's cancer has been characterized as HER2-positive based on elevated levels of HER2 gene expression, HER2 protein level, or HER2 gene amplification. 
     
     
         43 . The method of  claim 40 , wherein the subject's cancer comprises breast cancer. 
     
     
         44 . The method of  claim 43 , wherein the subject's cancer comprises primary breast cancer. 
     
     
         45 . The method of  claim 43 , wherein the subject's cancer comprises metastatic breast cancer. 
     
     
         46 . The method of  claim 40 , wherein the subject has undergone treatment with a HER2 acting agent that does not cross the blood-brain barrier. 
     
     
         47 . The method of  claim 40 , wherein the HER2 acting agent does not cross the blood-brain barrier. 
     
     
         48 . The method of  claim 46 , wherein the HER2 acting agent is at least one of trastuzumab, pertuzumab, ertumaxomab, tratuzumab emtansine, or MM-111. 
     
     
         49 . The method of  claim 46 , wherein the HER2 acting agent is trastuzumab. 
     
     
         50 . The method of  claim 40 , further comprising indicating that the selected subject should be treated with a second form of cancer treatment. 
     
     
         51 . The method of  claim 50 , wherein the second form of cancer treatment comprises at least one of a HER2-targeted small molecule drug, chemotherapy, or radiation therapy. 
     
     
         52 . The method of  claim 50 , wherein the second form of cancer treatment comprises a tyrosine kinase inhibitor. 
     
     
         53 . The method of  claim 50 , wherein the second form of cancer treatment comprises a protease inhibitor. 
     
     
         54 . The method of  claim 50 , wherein the second form of cancer treatment comprises at least one of lapatinib, neratinib, AZD8931, ARRY-380, PF299, afatinib, pelitinib, S-222611, or AEE-788. 
     
     
         55 . The method of  claim 50 , further comprising indicating that the selected subject also be treated with a HER2 acting agent that is a monoclonal antibody. 
     
     
         56 . The method of  claim 55 , wherein the HER2 acting agent that is a monoclonal antibody is at least one of trastuzumab, pertuzumab, ertumaxomab, trastuzumab emtansine, or MM-111.