Biomarker profiles for predicting outcomes of cancer therapy with erbb3 inhibitors and/or chemotherapies

Abstract

Provided are methods for optimizing therapy of, treating a patient having, or selecting (identifying) patients who will benefit from treatment for, a cancer (e.g., a non-hematological cancer; e.g., a gynecological cancer). The methods comprise determining whether the patient will benefit from treatment with an ErbB3 inhibitor (e.g., an anti-ErbB3 antibody), with or without either a taxane or an aromatase inhibitor, or with a taxane or an aromatase inhibitor in the absence of an ErbB3 inhibitor, based on levels of particular biomarkers and combinations of biomarkers measured in a biological sample obtained from the patient. The methods further comprise optimizing the patient's therapy, selecting the patient for treatment, or treating the patient accordingly. In various aspects the biological samples are sections of a biopsy (e.g., a formalin fixed paraffin embedded biopsy). In other aspects the biomarkers are proteins and/or nucleic acids. In other aspects the biomarkers function in ErbB-mediated signal transduction.

1 - 56 . (canceled) 
     
     
         57 . A method of treating a human patient having lung cancer with a heregulin RNA in situ hybridization (RNA-ISH) score of 1+ or higher measured in a biological sample from the patient, the method comprising administering to the patient an effective amount of:
 1) a first agent that is an anti-ErbB3 antibody, wherein the anti-ErbB3 antibody comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 3 (CDRH1), SEQ ID NO: 4 (CDRH2), and SEQ ID NO: 5 (CDRH3), respectively, and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 6 (CDRL1), SEQ ID NO: 7 (CDRL2), and SEQ ID NO: 8 (CDRL3), respectively; and   2) a second agent that is an anticancer agent,   
       wherein the RNA-ISH uses one or more probes comprising:
 a) an 18- to 25-nucleotide region that is complementary to the target RNA, 
 b) a spacer sequence; and 
 c) a 14-nucleotide tail sequence. 
 
     
     
         58 . The method of  claim 57 , wherein the anti-ErbB3 antibody comprises V H  and V L  amino acid sequences set for the in SEQ ID NO:1 and SEQ ID NO:2, respectively. 
     
     
         59 . The method of  claim 57 , wherein the second anticancer agent is a taxane. 
     
     
         60 . The method of  claim 59 , wherein the second anticancer agent is paclitaxel. 
     
     
         61 . The method of  claim 59 , wherein the second anticancer agent is docetaxel. 
     
     
         62 . The method of  claim 57 , wherein the one or more probes comprise a pool of oligonucleotides that hybridize to a select region of the heregulin mRNA. 
     
     
         63 . The method of  claim 57 , wherein the probes specifically hybridize to heregulin mRNAs that encode each of heregulin isoforms α, β1, β1b, β1c, β1d, β2, β2b, β3, β3b, γ, γ2, γ3, ndf43, ndf43b, and GGF2. 
     
     
         64 . The method of  claim 57 , wherein the probes hybridize in pairs to multiple adjacent sequences on the heregulin mRNA. 
     
     
         65 . The method of  claim 64 , wherein the pairs of probes have different tail sequences which form a 28-base hybridization site for a preamplifier oligo. 
     
     
         66 . The method of  claim 57 , wherein the probes span about 1 kb of the heregulin mRNA and comprise about 20 oligonucleotide hybridization pairs. 
     
     
         67 . The method of  claim 57 , wherein the sample is a microtome section of a biopsy. 
     
     
         68 . The method of  claim 67 , wherein the biopsy is a formalin fixed and paraffin embedded biopsy. 
     
     
         69 . The method of  claim 57 , wherein the sample was taken from the patient within 90 days prior to treating the patient. 
     
     
         70 . The method of  claim 57 , wherein the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, or a pathologic complete response. 
     
     
         71 . The method of  claim 57 , wherein the lung cancer is NSCLC. 
     
     
         72 . A method of treating a human patient having lung cancer comprising:
 1) selecting a human lung cancer patient having a heregulin RNA in situ hybridization (RNA-ISH) score of 1+ or higher measured in a biological sample from the patient, and   2) administering to the patient (a) an effective amount of a first agent that is an anti-ErbB3 antibody, wherein the anti-ErbB3 antibody comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 3 (CDRH1), SEQ ID NO: 4 (CDRH2), and SEQ ID NO: 5 (CDRH3), respectively, and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 6 (CDRL1), SEQ ID NO: 7 (CDRL2), and SEQ ID NO: 8 (CDRL3), respectively; and (b) a second agent that is an anticancer agent,   
       wherein the RNA-ISH uses one or more probes comprising:
 a) an 18- to 25-nucleotide region that is complementary to the target RNA, 
 b) a spacer sequence; and 
 c) a 14-nucleotide tail sequence. 
 
     
     
         73 . The method of  claim 72 , wherein the anti-ErbB3 antibody comprises V H  and V L  amino acid sequences set for the in SEQ ID NO:1 and SEQ ID NO:2, respectively. 
     
     
         74 . The method of  claim 72 , wherein the second anticancer agent is a taxane. 
     
     
         75 . The method of  claim 74 , wherein the second anticancer agent is paclitaxel. 
     
     
         76 . The method of  claim 74 , wherein the second anticancer agent is docetaxel. 
     
     
         77 . The method of  claim 72 , wherein the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, or a pathologic complete response. 
     
     
         78 . The method of  claim 72 , wherein the lung cancer is NSCLC. 
     
     
         79 . A method of treating a human patient having lung cancer with a positive heregulin RNA in situ hybridization (RNA-ISH) score measured in a biological sample from the patient, wherein the positive score is at least 1 dot/cell in at least 10% of tumor cells from the biological sample, and wherein the method comprises administering to the patient an effective amount of:
 1) a first agent that is an anti-ErbB3 antibody, wherein the anti-ErbB3 antibody comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 3 (CDRH1), SEQ ID NO: 4 (CDRH2), and SEQ ID NO: 5 (CDRH3), respectively, and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 6 (CDRL1), SEQ ID NO: 7 (CDRL2), and SEQ ID NO: 8 (CDRL3), respectively; and   2) a second agent that is an anticancer agent.   
     
     
         80 . The method of  claim 79 , wherein the anti-ErbB3 antibody comprises V H  and V L  amino acid sequences set for the in SEQ ID NO:1 and SEQ ID NO:2, respectively. 
     
     
         81 . The method of  claim 79 , wherein the second anticancer agent is a taxane. 
     
     
         82 . The method of  claim 81 , wherein the second anticancer agent is paclitaxel. 
     
     
         83 . The method of  claim 81 , wherein the second anticancer agent is docetaxel. 
     
     
         84 . The method of  claim 79 , wherein the positive score is at least 1-3 dots/cell in at least 10% of tumor cells. 
     
     
         85 . The method of  claim 79 , wherein the positive score is at least 4 dots/cell in at least 10% of tumor cells. 
     
     
         86 . The method of  claim 79 , wherein the biological sample comprises at least 50 tumor cells. 
     
     
         87 . The method of  claim 79 , wherein the sample is a microtome section of a biopsy. 
     
     
         88 . The method of  claim 87 , wherein the biopsy is a formalin fixed and paraffin embedded biopsy. 
     
     
         89 . The method of  claim 79 , wherein the sample was taken from the patient within 90 days prior to treating the patient. 
     
     
         90 . The method of  claim 79 , wherein the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, or a pathologic complete response. 
     
     
         91 . The method of  claim 79 , wherein the lung cancer is NSCLC. 
     
     
         92 . A method of treating a human patient having lung cancer comprising:
 1) selecting a human lung cancer patient having a positive RNA in situ hybridization (RNA-ISH) score measured in a biological sample from the patient, wherein the positive score is at least 1 dot/cell in at least 10% of tumor cells from the biological sample, and   2) administering to the patient (a) an effective amount of a first agent that is an anti-ErbB3 antibody, wherein the anti-ErbB3 antibody comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 3 (CDRH1), SEQ ID NO: 4 (CDRH2), and SEQ ID NO: 5 (CDRH3), respectively, and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO: 6 (CDRL1), SEQ ID NO: 7 (CDRL2), and SEQ ID NO: 8 (CDRL3), respectively;   and (b) a second agent that is an anticancer agent.   
     
     
         93 . The method of  claim 92 , wherein the anti-ErbB3 antibody comprises V H  and V L  amino acid sequences set for the in SEQ ID NO:1 and SEQ ID NO:2, respectively. 
     
     
         94 . The method of  claim 92 , wherein the second anticancer agent is a taxane. 
     
     
         95 . The method of  claim 92 , wherein the second anticancer agent is paclitaxel. 
     
     
         96 . The method of  claim 92 , wherein the second anticancer agent is docetaxel. 
     
     
         97 . The method of  claim 92 , wherein the treatment produces at least one therapeutic effect selected from the group consisting of reduction in size of a tumor, reduction in number of metastatic lesions over time, complete response, partial response, stable disease, or a pathologic complete response. 
     
     
         98 . The method of  claim 92 , wherein the lung cancer is NSCLC.