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 - 43 . (canceled) 
     
     
         44 . 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 at least one of HER2 or p95 in the biological sample;   (c) determining whether the amount of at least one of HER2 or p95 protein in the subject's sample is above a HER2 cutoff or a p95 cutoff; and   (d) indicating that the subject should be screened for brain metastasis if the amount of at least one of HER2 or p95 is above the HER2 cutoff or the p95 cutoff.   
     
     
         45 . The method of  claim 44 , 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. 
     
     
         46 . The method of  claim 44 , wherein the subject's cancer comprises breast cancer. 
     
     
         47 . The method of  claim 46 , wherein the subject's cancer comprises primary breast cancer. 
     
     
         48 . The method of  claim 44 , wherein the subject has undergone treatment with a HER2 acting agent that does not cross the blood-brain barrier. 
     
     
         49 . The method of  claim 48 , wherein the HER2-acting agent is a monoclonal antibody. 
     
     
         50 . The method of  claim 49 , wherein the monoclonal antibody is trastuzumab. 
     
     
         51 . The method of  claim 44 , wherein the HER2 cutoff comprises at least one of:
 (i) a median amount of HER2 determined in a reference population of subjects with HER2-positive breast cancer, or   (ii) an optimized amount of HER2 as determined in a reference population of subjects with HER2-positive breast cancer.   
     
     
         52 . The method of  claim 51 , wherein the reference population of subjects with HER2-positive breast cancer have undergone treatment with a HER2-acting agent that does not cross the blood-brain barrier. 
     
     
         53 . The method of  claim 44 , wherein the p95 cutoff comprises at least one of:
 (i) a median amount of p95 determined in a reference population of subjects with HER2-positive breast cancer; or   (ii) an optimized amount of p95 as determined in a reference population of subjects with HER2-positive breast cancer.   
     
     
         54 . The method of  claim 53 , wherein the reference population of subjects with HER2-positive breast cancer have undergone treatment with a HER2-acting agent that does not cross the blood-brain barrier. 
     
     
         55 . A method of identifying subjects with HER2 positive cancer that should receive treatment with a HER2-acting agent and a second form of cancer treatment, comprising:
 (a) obtaining a biological sample of a tumor from the subject's cancer;   (b) measuring the amount of at least one of HER2 or p95 in the biological sample;   (c) determining whether the amount of at least one of HER2 or p95 protein in the subject's sample is above a HER2 cutoff or a p95 cutoff; and   (d) indicating that the subject should receive treatment with a HER2-acting agent and a second form of cancer treatment if the amount of at least one of HER2 or p95 is above the HER2 cutoff or the p95 cutoff.   
     
     
         56 . The method of  claim 55 , 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. 
     
     
         57 . The method of  claim 55 , wherein the subject's cancer comprises breast cancer. 
     
     
         58 . The method of  claim 57 , wherein the subject's cancer comprises primary breast cancer. 
     
     
         59 . The method of  claim 55 , wherein the subject has undergone treatment with a HER2 acting agent. 
     
     
         60 . The method of  claim 55 , wherein the HER2 acting agent does not cross the blood-brain barrier. 
     
     
         61 . The method of  claim 59 , wherein the HER2 acting agent does not cross the blood-brain barrier. 
     
     
         62 . The method of  claim 59 , wherein the HER2-acting agent is a monoclonal antibody. 
     
     
         63 . The method of  claim 55 , wherein the second form of cancer treatment comprises a HER2-targeted small molecule drug, chemotherapy and/or radiation therapy. 
     
     
         64 . The method of  claim 55 , wherein the HER2 cutoff comprises at least one of:
 (i) a median amount of HER2 determined in a reference population of subjects with HER2-positive breast cancer, or   (ii) an optimized amount of HER2 as determined in a reference population of subjects with HER2-positive breast cancer.   
     
     
         65 . The method of  claim 64 , wherein the reference population of subjects with HER2-positive breast cancer have undergone treatment with a HER2-acting agent that does not cross the blood-brain barrier. 
     
     
         66 . The method of  claim 55 , wherein the p95 cutoff comprises at least one of:
 (i) a median amount of p95 determined in a reference population of subjects with HER2-positive breast cancer, or   (ii) an optimized amount of p95 as determined in a reference population of subjects with HER2-positive breast cancer.   
     
     
         67 . The method of  claim 66 , wherein the reference population of subjects with HER2-positive breast cancer have undergone treatment with a HER2-acting agent that does not cross the blood-brain barrier. 
     
     
         68 . A method for determining an expected time to brain metastasis (TTBM) in a subject with a HER2-positive cancer comprising:
 (a) obtaining a biological sample of a tumor from the subject's cancer;   (b) measuring the amount of at least one of HER2 or p95 in the biological sample;   (c) determining whether the amount of at least one of HER2 or p95 protein in the subject's sample is above a HER2 cutoff or a p95 cutoff; and   (d) indicating the subject's expected TTBM based on the incidence of brain metastasis over time in a reference population having HER2 or p95 levels above or below the HER2 cutoff or p95 cutoff.   
     
     
         69 . The method of  claim 68 , 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. 
     
     
         70 . The method of  claim 68 , wherein the subject's cancer comprises breast cancer. 
     
     
         71 . The method of  claim 70 , wherein the subject's cancer comprises primary breast cancer. 
     
     
         72 . The method of  claim 68 , wherein the subject has undergone treatment with a HER2 acting agent that does not cross the blood-brain barrier. 
     
     
         73 . The method of  claim 72 , wherein the HER2-acting agent is a monoclonal antibody. 
     
     
         74 . The method of  claim 68 , wherein if the amount of HER2 in the biological sample is above the HER2 cutoff the subject's chance of being free of brain metastasis is about 73% at about 1 year, about 61% at about 2 years, and about 37% at about 3 years. 
     
     
         75 . The method of  claim 68 , wherein if the amount of HER2 in the biological sample is below the HER2 cutoff the subject's chance of being free of brain metastasis is about 89% at about 1 year, about 78% at about 2 years, and about 69% at about 3 years. 
     
     
         76 . The method of  claim 68 , wherein if the amount of p95 in the biological sample is above the p95 cutoff the subject's chance of being free of brain metastasis is about 77% at about 1 year, about 63% at about 2 years, and about 40% at about 3 years. 
     
     
         77 . The method of  claim 68 , wherein if the amount of p95 in the biological sample is below the p95 cutoff the subject's chance of being free of brain metastasis is about 85% at about 1 year, about 77% at about 2 years, and about 67% at about 3 years. 
     
     
         78 . The method of  claim 68 , wherein if the amount of HER2 in the biological sample is below the HER2 cutoff and the amount of p95 is above the p95 cutoff the subject's chance of being free of brain metastasis is about 80% at about 1 year, about 66% at about 2 years, and about 50% at about 3 years. 
     
     
         79 . The method of  claim 68 , wherein if the amount of HER2 in the biological sample is below the HER2 cutoff and the amount of p95 is below the p95 cutoff the subject's chance of being free of brain metastasis is about 94% at about 1 year, about 86% at about 2 years, and about 80% at about 3 years. 
     
     
         80 . The method of  claim 68 , wherein the subject has about a 2.6 fold increased risk of brain metastasis if the amount of HER2 in the biological sample is above the HER2 cutoff as compared to if the amount is below the HER2 cutoff. 
     
     
         81 . The method of  claim 68 , wherein the subject has about a 2 fold increased risk of brain metastasis if the amount of p95 in the biological sample is above the p95 cutoff as compared to if the amount is below the p95 cutoff. 
     
     
         82 . The method of  claim 68 , wherein the subject has about a 5.7 fold decreased risk of brain metastasis if the subject's cancer is Grade 1 or 2 and the amount of HER2 in the biological sample is below the HER2 cutoff as compared to if the subject's cancer was Grade 3 or if the subject's cancer was Grade 1 or 2 and the amount of the amount of HER2 in the biological sample is above the HER2 cutoff. 
     
     
         83 . The method of  claim 68 , wherein the HER2 cutoff comprises at least one of:
 (i) a median amount of HER2 determined in a reference population of subjects with HER2-positive breast cancer, or   (ii) an optimized amount of HER2 as determined in a reference population of subjects with HER2-positive breast cancer.   
     
     
         84 . The method of  claim 83 , wherein the reference population of subjects with HER2-positive breast cancer have undergone treatment with a HER2-acting agent that does not cross the blood-brain barrier. 
     
     
         85 . The method of  claim 68 , wherein the p95 cutoff comprises at least one of:
 (i) a median amount of p95 determined in a reference population of subjects with HER2-positive breast cancer, or   (ii) an optimized amount of p95 as determined in a reference population of subjects with HER2-positive breast cancer.   
     
     
         86 . The method of  claim 85 , wherein the reference population of subjects with HER2-positive breast cancer have undergone treatment with a HER2-acting agent that does not cross the blood-brain barrier.