Abstract:
A method of classifying a cancerous tumor is described and comprises the steps of: screening a set of targetable events within a tumor, determining a profile for tumor, and classifying the tumor based on the variant profile of the tumor. More specifically, the tumor is defined and classified based on targetable events; histology and disease stage are not considered. The method will result in greater numbers of samples for clinical studies and better, more accurate combinatorial approaches for treatment. This method overcomes the biases of traditional cancer classification schemes, and advances personalized medicine in solid tumor cancers.

Description:
RELATED U.S. APPLICATIONS 
       [0001]    The present application claims priority under U.S. Code Section 119(e) from a provisional patent application, U.S. Patent Application No. 61/496,003, filed on 12 Jun. 2011 and entitled “METHOD FOR TARGET BASED CANCER CLASSIFICATION, TREATMENT, DRUG DEVELOPMENT”. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    Not Applicable. 
       REFERENCE TO MICROFICHE APPENDIX 
       [0003]    Not Applicable. 
       BACKGROUND OF THE INVENTION 
       [0004]    1. Field of the Invention
       The present invention is in the field of solid tumor cancers. More particularly, the invention relates to methods of classifying solid tumors based on the presence of targetable events, validating the resulting classifications, and applying treatment regimens based on classifications of the solid tumors. Methods for determining the profile of targetable events and determining a classification for a cancer are provided.       
 
         [0006]    2. Description of Related Art Including Information Disclosed Under 37 C.F.R. 1.97 and C.F.R. 1.98. 
         [0007]    Prior technology in the field of solid cancer tumors relies upon a classification of the cancer based on histology and tissue of origin (e.g., colon cancer, small cell lung cancer, etc.). These histological classifications can then be further refined using the degree, or stage, of differentiation and invasiveness into other tissues (e.g., Stage  1 I colon cancer). Treatment regimens are often prescribed using this overly simple classification scheme. 
         [0008]    With the elucidation of the human genome, genetic variants contributing to cancer phenotypes have been identified and validated as contributoring elements in cancer etiology. Treatment regimens have been designed, evaluated in clinical studies, and are now prescribed after screening a cancerous tissue sample for the genetic variant of interest. The most successful and well-publicized example of this targeted therapy is the approval of Imantinib (Gleevec) for treatment of Chronic Myeloid Leukemia (CML) in 2001. However, CML is a very unique cancer because it is driven by a single translocation (bcr-abl), and the one-hit/one-cancer type is not a successful approach to designing treatment regimens for more complex cancer genotypes. 
         [0009]    Most cancers are driven by multiple genetic variants or mutations and epigenetic changes. With few exceptions, the two-hit hypothesis is an accurate description of cancer etiology. Essentially, the two-hit hypothesis posits that at a minimum two driving events are needed for tumor development. The etiologically important “two hits” are often single nucleotide polymorphisms (SNP) or other genetic variants that may result in an abnormal cellular state and tumor generation. Further accumulated genetic changes drive invasiveness and resistance to anticancer agents. 
         [0010]    Many pharmaceuticals are being developed to target variants that contribute to certain cancers, but they are often limited to particular tissue type cancers. “Dirty kinases” that hit several targets show partial success in some cancers, specifically Renal Cell Carcinoma. However, many Renal Cell Carcinoma patients are refractory to these pharmaceutical agents, while other patients have only modest responses such as partial tumor shrinkage or a prolonged stable disease-state or remission that eventually relapses. 
         [0011]    Some pharmaceuticals or other treatment regimens are designed specifically for subpopulations of a particular tissue-type cancer. For example, BRAF inhibitors are selectively used in BRAF-positive melanomas because 70-80% of melanomas are BRAF-positive. There is evidence of a lack of BRAF-inhibitor activity in BRAF-positive tumors, presumably due to the concomitant PI3K pathway activation in these tumors. Relatedly, many BRAF-positive melanoma patients do not respond to BRAF inhibitors presumably because of compensatory mechanisms or other mutations in alternative pathways. However, some patients who would benefit from BRAF inhibitor treatment are often excluded from such treatments because based on the histology of the tumor, the patients are excluded from such treatment protocols. For example, BRAF inhibitors are seldom used in colon cancer (5-7% BRAF-positive rate) or other tissue-specific cancers with small incidence rates. 
         [0012]    Incremental, slow progress is being made toward better and more specific therapies and personalized medicine (e.g., BRAF and MEK inhibitors in BRAF-positive melanomas and PARP inhibitors in variant BRCA1 breast cancer and ovarian cancer). Unfortunately, advancing treatment regimens are limited by the current cancer classification scheme (i.e., stage/tissue type) and management of the disease. Targeting one out of several driving mutations can only benefit a small subset of patients, resulting mostly in modest responses and clinical benefit, but targeting smaller subsets of cancer patients with combination targeted therapies will yield a population of patients too small for meaningful and decisive clinical studies. For example, targeting melanoma patients with BRAF and PI3K mutations with a combination of BRAF/MEK pathway inhibitor and a PI3K/mTOR pathway inhibitor, will most likely yield a study population size too small to generate the statistically significant results for safety and effectiveness, as required for FDA approval of the treatment regimen. 
         [0013]    An alternative approach may be to use the BRAF/MEK pathway inhibitor and a PI3K/mTOR pathway inhibitor cocktail in all melanoma patients as the population size may achieve statistically significant differences between the treatment and placebo populations. The likelihood in such an approach is that only a very small percentage of patients will receive a benefit for the treatment as this “targeted treatment” is not actually being applied in a targeted manner. Rather, a large number of patients will be treated unnecessarily because their cancer will be non-responsive to the treatment. Non-melanoma cancer patients whose tumors are driven mostly by mutations in these two pathways will be completely ignored. 
         [0014]    There are many examples of genetic factors contributing to cancer. Microsatellite Instability (MSI) from deficiencies in mismatch DNA repair (MMR) is an initiating factor and a predictive factor in several cancers including colorectal, endometrial, ovarian, and gastric cancers. BRAF mutations are present in 80% of melanomas, 1-3% of lung cancer, and approximately 5% of colorectal cancer. KRAS mutations are implicated in lung adenocarcinoma, ductal carcinoma of the pancreas, and colorectal carcinoma. Thus, common targetable events found in multiple tissue type tumors can lead new combinatorial treatment regimens independent of any histological or disease progression classifications. 
         [0015]    The prior art contains methods for classifying cancers, but these methods typically involve a tissue dependent approach. Essentially, the methods described are specialized methods directed towards tumors of specific tissues of origin. U.S. Pat. No. 7,781,179 describes screening for genetic abnormalities that can be causative, disease susceptibility, or drug responsiveness variants or otherwise linked to bladder cancer. The screening for bladder cancer variation is performed in a tissue specific manner, specifically a subpopulation of urothelial basal cells. The inventors hypothesize that these particular larger cells preferentially accumulate genetic and epigenetic variation that is caused by physical or chemical assault. 
         [0016]    Prior art methods of characterizing cancers often involve gene expression profiles. Expression profiles are compiled for cancerous tumors and compared to wildtype or noncancerous expression profiles to identify those expression profiles associated with the particular cancer. U.S. Patent Application No. 2012/0064520 also involves bladder cancer and is a method of classification based on gene expression profiles. U.S. Pat. No. 7,943,306 involves detecting core serum response (CSR) profiles. Induced CSR signatures are suggested to indicate a higher probability of metastasis. Classification according to CSR response profiles allows optimization of treatment protocols. 
         [0017]    Methods for testing selected compounds against cancerous tumors can also be found in the prior art. U.S. Pat. No. 7,118,853 explains a method for utilizing expression profiles in identified genes and gene subsets that are useful for classifying breast cancer. These genes and gene subsets are probable contributors to breast cancer development, progression, and response to therapy. 
         [0018]    A method of characterizing and classifying solid tumor cancers that is independent of tissue type or stage of disease is desired. Such a method will allow researchers to include greater numbers of samples to achieve statistical significance in drug development and clinical trials of treatment regimens. Furthermore, such a method will advance the principle of personalized medicine in that a patient&#39;s cancer will be characterized based on targetable events, and presence of targetable events will result in tailored therapies for the individual. 
       SUMMARY OF THE INVENTION 
       [0019]    The present invention relates to the classification of cancers based on the presence of genetic and epigenetic predictive events. In particular, the present invention relates to classifying cancers based on profiles of a cancer generated by screening for targetable events that contribute to the cancer with no regard to the tissue of origin or to the particular stage of the disease. The classifications of the present invention are useful for prognostic evaluation of patients; for developing, testing, and validating proposed treatment regimens; and for predicting a patient&#39;s responsiveness to treatment regimens. 
         [0020]    It is an object of the present invention to provide a method capable of characterizing and classifying a solid cancer tumor, regardless of the tissue of origin of the cancer. 
         [0021]    It is a further object of the present invention to provide a method of characterizing and classifying a solid cancer tumor that enables researchers to enhance the sample size in laboratory and clinical trials for statistical validation of associating classifications and treatment regimens. 
         [0022]    It is a further object of the invention to provide a method of characterizing and classifying a solid cancer tumor that will fulfill the potential of personalized medicine. 
         [0023]    It is a further object of the invention to provide a method of characterizing and classifying a solid cancer tumor that is applicable in defining what treatment regimen to use and matching the patient with the right combination of targeted therapies. 
         [0024]    It is a further purpose of the invention to provide a method of characterizing and classifying a solid cancer tumor that provides a new and applicable path of developing cancer therapies across all tumor histologies based on the genetic make-up of the tumor. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0025]      FIG. 1  is a diagram of one embodiment of the method. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0026]    A method of classifying a cancerous tumor is described and comprises the steps of: screening a set of targetable events within a tumor, determining a profile for tumor, and classifying the tumor based on the variant profile of the tumor. A tumor classification in the present invention consists of a profile is defined by at least two targetable events. In general, targetable events will be a suspected direct or indirect contributor to a solid tumor cancer and can be detected by screening for the targetable events either directly or indirectly. 
         [0027]    The present invention is based on the realization that the current approach to defining cancers is myopic and rigid. Defining a cancer type based on tissue type gives researchers little incentive to discover common underlying events that cancers possess, even in different tissue types. Defining a cancer by factors other than tissue type, and therefore not constrained histologically, will allow researchers to increase the number of samples studied for statistical purposes. 
         [0028]    The first step in the method of classifying a solid cancer tumor is to identify genes that may contribute to the disease state. The disease state can be any stage of cancer progression. Contributing to a disease state may refer to a causative event, a modest modifier of the disease phenotype, or any other event that can potentially affect the disease. This compilation is usually accomplished by thoroughly reviewing the literature and identifying those genes, genetic variants, epigenetic modifications, and other potentially causative contributors. While this “candidate” approach may not include every possible contributor, it will eliminate much of the noise seen in whole genome approaches where thousands of potential contributors are assayed. 
         [0029]    TABLE 1 is a list of genes that may harbor potential targetable events that contribute to solid cancer tumors. Each gene in the list has been correlated with cancer in previous studies. While this list is a preferred set of genes to screen for targetable events that potentially contribute to solid cancer tumors, it is not an exhaustive list. Screening these genes for targetable events tissues taken from solid tumors, regardless of tissue or stage classification, will increase the probability of finding statistically significant profiles for further study. Furthermore, some genetic variation occurs at the epigenetic level (e.g., methylation) and can be included in the list of contributors that will be screened. As technological advances improve the sensitivity and reliability of high-throughput assays such as microarrays, these genome-wide assays may be utilized in lieu of the candidate approach. 
         [0030]    Anaplastic Lymphoma Kinase (ALK) is included in the list of genes to be screened because it has been validated by the development of crizotinib for ALK+ non-small cell lung cancer lung cancer. 
         [0031]    B-Cell CLL/Lymphoma 2 (Bcl-2) is included in the list of genes to be screened because it has been validated in phase I and phase II clinical studies of obatoclax in small cell lung cancer. 
         [0032]    (BRAF) is included in the list of genes to be screened because it has been validated by the clinical studies and development of vemurafenib in BRAF mutation positive melanoma. 
         [0033]    Breast Cancer 1 and 2 Gene (BRCA1 and BRCA2) are included in the list of genes to be screened because they have been validated in several phase II studies to predict response to PARP inhibitors (olaparib, veliparib, iniparib) in breast and ovarian cancer. 
         [0034]    v-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene (Kit) is included in the list of genes to be screed because it has been validated as a driver for some tumors like gastrointestinal stromal tumor (GIST) and tyrosine kinase inhibitors that inhibit Kit demonstrated activity in several phase II studies, and the FDA approved this treatment regiment for patients with GIST. 
         [0035]    Met Protooncogene (Met) is included in the list of genes to be screened because Met has been established in preclinical studies as a driver for certain tumor development, invasiveness and metastasis. Phase I studies of Met inhibitors like ARQ 197 demonstrated clinical activity in subgroups of colorectal cancer and lung cancer. 
         [0036]    Epidermal Growth Factor Receptor (EGFR) is included in the list of genes to be screened because EGFR expression correlated with response to EGFR inhibitors like Cetuximab in head and neck, colorectal, and lung cancer. 
         [0037]    Focal Adhesion Kinase (FAK) is included in the list of genes to be screened because FAK has been recently established as a contributor in cancer progression and inhibitors of FAK like PF-00562271 demonstrated clinical activity in subset of advanced cancer patients. 
         [0038]    V-ERB-B2 Avian Erthyroblastic Leukemia Viral Oncogene Homolog 2 (HER-2) is included in the list of genes to be screened because it has been validated to predict response to anti-HER2 antibody trastuzumab and HER2 inhibitor lapatinib. 
         [0039]    V-KI-Ras 2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is included in the list of genes to be screened because it has been established to predict response to panitumumab in colorectal cancer patients and also established as a contributor in cancer development and is of prognostic value. 
         [0040]    FKBP12—Rapamycin Complex-Associated Protein (mTOR) is included in the list of genes to be screened because the PI3K-AKT-mTOR has been well established as a pathway for tumorigenesis and mTOR inhibition demonstrated clinical activity in several tumors and is approved for renal cell carcinoma. 
         [0041]    Phosphatidylinositol 3-Kinase, Catalytic, Alpha (PI3KCA) is included in the list of genes to be screened because as the PI3K-AKT-mTOR has been well established as a pathway for tumorigenesis and recent clinical data demonstrated promising activity for PI3K inhibitors and correlation with PI3KCA mutations. 
         [0042]    Rearranged During Transfection Protooncogene (RET) is included in the list of genes to be screened because activating mutations in RET are associated with cancer development specially thyroid cancer and various endocrine cancer. Recently, RET inhibitors like XL-184 and vandetanib demonstrated activity in tumors with high incidence of RET mutation, and vandetanib was recently approved as a pharmaceutical treatment for medullary thyroid cancer. 
         [0043]    Vascular Endothelial Growth Factor A (VEGF) is included in the list of genes to be, screened because anti VEGF (Bevacizumab) and anti-VEGFR (Sorafenib, sunitinib, Tivozanib) demonstrated activity in tumors known to have high levels of VEGF and VEGFR. 
         [0044]    Additional genes that may harbor targetable events are abundant and can be included in the screening process. Additional genes may be studied pre-clinically, in tumor samples, or otherwise followed to assess the effectiveness of targeting these additional events with small molecules or biological to evaluate their possible addition to the preferred fifteen targetable events. 
         [0045]    Table 2 is a list of additional genes that may harbor targetable events that may play an etiological role in solid tumor cancer. One skilled in the art would recognize that the list of genes that harbor targetable events that contribute to cancer expands well beyond this list and that this list is a preferred, but not exhaustive, list of genes to be screened. Each of the genes listed has been linked to cancer in previous studies, but additional targetable events need not be just genes or variants therein. Epigenetic modifications, translocations, insertions, deletions as well as environmental inputs (e.g., carcinogen exposure) can be targetable events as well. 
         [0046]    Signal Transducer and Activator of Transposition 3 (STAT3) is included in, the list of additional targetable events because it has been established player in tumorigenesis and several inhibitors are now in preclinical and early clinical investigation. 
         [0047]    Fibroblast Activation Protein, Alpha (FAP) is included in the list of additional targetable events because it has been identified as a substantial contributor to tumor progression and metastasis and several targeting modalities are under investigation. 
         [0048]    Fibroblast Growth Factor Receptors 1-4 (EGFR 1-4) are included in the list of additional targetable events because they have been implicated in breast, hepatic and lung cancer and inhibitors of FGFRs are in preclinical and early clinical development. 
         [0049]    PIM Oncogene (PIM) is included in the list of additional targetable events because it has been discovered to play a prominent role in development of sarcoma and metastasis. PIM inhibitor studies are ongoing. 
         [0050]    Insulin-like Growth Factor 1 Receptor (IGF1R) is included in the list of additional targetable events because it has been implicated in cancer development and phase I/II studies of targeting inhibitors are enrolling patients. 
         [0051]    Neuroblastoma Ras Viral Oncogene Homolog (NRAS) is included in the list of additional targetable events because preclinical data shows possible predicative value for NRAS mutation in regards to inhibitors of downstream MEK. Clinical studies with molecular screening for NRAS, MEK and BRAF mutations are ongoing. 
         [0052]    A set of genes will be screened for targetable events to determine a profile for a sample. A sample can be material obtained in a biopsy, a tissue bank or other repository, a blood draw, or any other material that may be used to generate useful information concerning targetable events or cancerous or normal states. The material can be in any form including genetic material, tissue samples, proteins, or any other material that may be used to generate useful information regarding targetable events or cancerous or normal states. While screening is a required step for the method, no particular screening method is required. For instance, detecting genetic variation in a gene can be accomplished by sequencing the gene but particular single nucleotide polymorphisms (SNPs) can be screened for directly using microarray analysisor other commercially available or proprietary methods. In some embodiments of the invention, genes are screened for targetable events, but in alternative embodiments, known targetable events are screened for directly in samples. In one embodiment of the invention, screening a set of genes for targetable events will consist of amplifying the exonic, and adjacent, regions of the genes by polymerase chain reaction (PCR) or other amplification means. The amplified regions of interest will then be used as templates in sequencing reactions to determine the sequence of the regions of interest. Known genetic variants can be detected while unknown variants, such as rare variants that have not been discussed in the literature, can be detected by comparing the sample&#39;s sequence to a wildtype, or reference, sequence. 
         [0053]    In another embodiment of the invention, the regions of interest will not be sequenced, but rather, known genetic variation such as deletions, insertions, single nucleotide polymorphisms (SNPs), and rare variants will be screened directly. 
         [0054]    Many of the embodiments described above utilize nucleotide resolution detection methods for detecting genetic variation, one skilled in the art will understand that the methods used to screen for targetable events can result in nucleotide resolution, but lower resolution methods, as well as non-genetic methods, can be used as well. For example, in one embodiment, translocations can be screened for using karyotype analysis. Furthermore, the material used for screening can be any material which can be used to characterize a tumor. For instance, deoxyribonucleic acid isolated from a tumor biopsy sample could be used to screen for targetable events such as genetic variants. Isolated ribonucleic acid (RNA) could be used to determine an expression profile that could aid in classifying a tumor. Also, whole blood samples could be used to screen for targetable events such as aberrant protein levels caused by a tumor. 
         [0055]    In another embodiment of the invention, the targetable events screened for may include epigenetic variation such as methylation. There are numerous categories of epigenetic variation and one skilled in the art would recognize the invention is not limited to any particular type of epigenetic variation to provide the data necessary to classify a cancerous tumor. 
         [0056]    Results of screening for targetable events are used to assemble a profile for the sample. A profile can consist of the entire screening results or a subset of the results. A preferred profile would consist of each gene screened being characterized as positive or negative for targetable events. For example, if FAP, Bcl-2, and ALK are screened, and three SNPs are detected in FAP, a deletion is detected in BLC-2, and no targetable events are detected in ALK, the profile of the three screened genes could be FAP+/Bcl-2+/ALK. Alternative profile reporting is available, such as including in the profile only those genes screened that contain targetable events. Using such a profile reporting scheme for the example above would result in the following profile: FAP/Bcl-2. One skilled in the art will recognize that a profile can take any number of forms so long as it is descriptive of the samples screened. Individual targetable events, such as a known disease-associated SNP, can also be included in the profile. Including such information can aid in discerning a proper treatment course for a patient or designing a proper clinical trial. 
         [0057]    Once a profile has been assembled for a sample, classifications can be assigned. A classification will consist of at least two targetable events. The incidence of each profile can be determined prior to assigning classifications, and in such an embodiment, a cut-off incidence rate would be established and only those profiles with an incidence rater greater than the cut-off incidence rate would be assigned a classification. This would be an efficient means of identifying only those profiles that would allow researchers to conduct statistically significant clinical studies. Lower incidence rate profiles would not yield statistically significant results, and any proposed treatment regimen could not be validated due to low statistical power. Alternatively, every profile can be assigned a classification, and then the incidence of the classification can be determined. 
         [0058]    Table 3 is a partial list of classifications based on the detection of targetable events in the gene set listed in Table 1. Table 3 illustrates that a single profile may have multiple classifications.  FIG. 1  illustrates the method described herein. The sample screened for the preferred set of genes in Table 1 has a targetable event 4 in the FAK gene 1, a targetable event 5 in the KRAS gene 2, and a targetable event 6 in the RET gene 3. The resulting profile 7 may be written as FAK/KRAS/RET to indicate that targetable events were detected in these three genes. Based on this profile 7, the tumor classification 8 will be Cancer Type 417. The same sample can also be classified as Cancer Type 61 (targetable events detected in FAK and KRAS), Cancer Type 64 (targetable events detected in FAK and RET), and Cancer Type 73 (targetable events detected in KRAS and RET). 
         [0059]    As the frequency of any given targetable event is less than 1.0, each additional targetable event will cause the frequency of the profile (Cancer Type) to decrease (with the exception of complete linkage of targetable events, in which case the frequency would remain the same). As the frequency decreases, greater numbers of samples will be required to reach statistical significance. Assigning multiple classifications can allow a researcher to identify those classifications that have a sufficient number of samples to achieve statistical significance. 
         [0060]    There are approximately ten million patients afflicted with some form of solid cancer tumor. If the frequency, or prevalence, of one of the Cancer Types listed in Table 3 is 1 in 1000, then there would be approximately ten thousand patients with that particular Cancer Type. This is a large enough number of patients to develop a treatment modality. It is expected that all Cancer Types would meet the Orphan disease status based on the number of patients (i.e., &lt;200,000 patients). 
         [0061]    In one embodiment of the invention, an individual patient&#39;s tumor sample will be screened for diagnostic and therapeutic purposes. The classification of the tumor will aid the caregiver in determining the proper therapeutic approach. A combination of pharmaceuticals may likely be prescribed because the tumor will have at least two targetable events. In a clinical setting, determination of the incidence rate may not be necessary. An individual patient&#39;s profile could be immediately assigned a classification and a treatment regimen assigned based on the profile. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 NCBI Accession No. 
                 Event 
                 Description 
               
               
                   
               
             
             
               
                 NG_009445.1 
                 ALK 
                 Anaplastic Lymphoma Kinas mutations e.g., EML4-ALK 
               
               
                 NG_009361.1 
                 Bcl-2 
                 B-cell lymphoma 2 family including BCL-2 and BCLXL over 
               
               
                   
                   
                 expression and BAX mutation 
               
               
                 NG_007873.2 
                 BRAF 
                 Proto-oncogene B-Raf activating mutation; e.g., V600E; other 
               
               
                   
                   
                 mutations include: R461I, I462S, G463E, G463V, G465A, 
               
               
                   
                   
                 G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, 
               
               
                   
                   
                 G595R, L596V, T598I, V599D, V599E, V599K, V599R, K600E, 
               
               
                   
                   
                 A727V 
               
               
                 NG_005905.2 
                 BRCA 
                 Inactivating mutations in tumor suppressor Breast Cancer 
               
               
                 (BRCA1) 
                   
                 Gene 1 (BRCA1) or 2 (BRCA2); e.g., Frameshift mutations 
               
               
                 NG_012772.3 
                   
                 that prevent translation of functional protein 
               
               
                 (BRCA2) 
               
               
                 NG_007456.1 
                 cKit 
                 Activating mutations in Mast/stem cell growth factor 
               
               
                   
                   
                 receptor (SCFR), also known as proto-oncogene c-Kit or 
               
               
                   
                   
                 tyrosine-protein kinase Kit or CD117; e.g., activating 
               
               
                   
                   
                 mutations in exon 17 
               
               
                 NG_008996.1 
                 cMet 
                 Overexpression of Proto-oncogene that encodes a protein 
               
               
                   
                   
                 known as hepatocyte growth factor receptor (HGFR), also 
               
               
                   
                   
                 known as MET 
               
               
                 NG_007726.2 
                 EGFR 
                 Overexpression or activating mutation in Epidermal Growth 
               
               
                   
                   
                 Factor Receptor; e.g., EGFRvIII mutation, EGFR upregulation 
               
               
                 NG_029467.1 
                 FAK 
                 Overexpression of Focal Adhesion Kinase (FAK) 
               
               
                 NG_007503.1 
                 HER2 
                 Amplification/over-expression of HER2: Human Epidermal 
               
               
                   
                   
                 Growth Factor Receptor 2, also known as Neu, ErbB-2, 
               
               
                   
                   
                 CD340 or p185 
               
               
                 NG_007524.1 
                 KRAS 
                 Activating mutations in Kirsten rat sarcoma viral oncogene 
               
               
                   
                   
                 homolog or KRAS; e.g., Activating KRAS mutations include 
               
               
                   
                   
                 codons 12, 13, 59, 61 
               
               
                 NM_004958 
                 mTOR 
                 Loss of PTEN (negative regulator of mTOR), activating 
               
               
                   
                   
                 mutations in AKT1, activating mutations in mTOR, 
               
               
                   
                   
                 hyperphosphorylation of S6K and S6 
               
               
                 NG_012113.2 
                 PI3K 
                 Activating mutations in p110α (PIK3CA) exons 9 and 20 
               
               
                   
                   
                 [codons 532-554 of exon 9 (helical domain) and 
               
               
                   
                   
                 codons1011-1062 of exon 20 (kinase domain)], or amplified 
               
               
                   
                   
                 PIK3CA 
               
               
                 NG_007489.1 
                 RET 
                 Chromosomal rearrangements resulting in Oncoptotein 
               
               
                   
                   
                 RET/PTC or point mutations activating RET like M918T 
               
               
                 NG_008732.1 
                 VEGF 
                 Overexpression of VEGF, VEGFR-1, or VEGFR-2 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 NCBI Accession No. 
                 Event 
                 Description 
               
               
                   
               
             
             
               
                 NG_007370.1 
                 STAT3 
                 Signal transducer and activator 
               
               
                   
                   
                 of transcription 3 
               
               
                 NG_027991.1 
                 FAP 
                 Fibroblast activation, protein 
               
               
                 NG_007729.1 
                 FGFR 
                 Fibroblast growth factor receptors 
               
               
                 (FGFR1) 
                   
                 (1-4) 
               
               
                 NG_012449.1 
               
               
                 (FGFR2) 
               
               
                 NG_012632.1 
               
               
                 (FGFR3) 
               
               
                 NG_012067.1 
               
               
                 (FGFR4) 
               
               
                 NG_029601.1 
                 PIM 
                 PIM oncogenes 1-3; serine/threonine 
               
               
                 (PIM1) 
                   
                 protein kinases of the Pim (proviral 
               
               
                 NG_016262.1 
                   
                 integration of Moloney virus) 
               
               
                 (PIM2) 
               
               
                 NM_001001852 
               
               
                 (PIM3) 
               
               
                 NG_009492.1 
                 IGF-1R 
                 Insulin-like growth factor type I 
               
               
                   
                   
                 receptor e.g., IR-A fetal splice variant 
               
               
                 NG_007572.1 
                 NRAS 
                 Neuroblastoma RAS 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Cancer Type 
                 Event 1 
                 Event 2 
                 Event 3 
                 Event 4 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 ALK 
                 Bcl-2 
                   
               
               
                 2 
                 ALK 
                 BRAF 
               
               
                 3 
                 ALK 
                 BRCA 
               
               
                 4 
                 ALK 
                 cKit 
               
               
                 5 
                 ALK 
                 cMet 
               
               
                 6 
                 ALK 
                 EGFR 
               
               
                 7 
                 ALK 
                 FAK 
               
               
                 8 
                 ALK 
                 HER2 
               
               
                 9 
                 ALK 
                 KRAS 
               
               
                 10 
                 ALK 
                 mTOR 
               
               
                 11 
                 ALK 
                 PI3K 
               
               
                 12 
                 ALK 
                 RET 
               
               
                 13 
                 ALK 
                 VEGF 
               
               
                 14 
                 Bcl-2 
                 BRAF 
               
               
                 15 
                 Bcl-2 
                 BRCA 
               
               
                 16 
                 Bcl-2 
                 cKit 
               
               
                 17 
                 Bcl-2 
                 cMet 
               
               
                 18 
                 Bcl-2 
                 EGFR 
               
               
                 19 
                 Bcl-2 
                 FAK 
               
               
                 20 
                 Bcl-2 
                 HER2 
               
               
                 21 
                 Bcl-2 
                 KRAS 
               
               
                 22 
                 Bcl-2 
                 mTOR 
               
               
                 23 
                 Bcl-2 
                 PI3K 
               
               
                 24 
                 Bcl-2 
                 RET 
               
               
                 25 
                 Bcl-2 
                 VEGF 
               
               
                 26 
                 BRCA 
                 cKit 
               
               
                 27 
                 BRCA 
                 cMet 
               
               
                 28 
                 BRCA 
                 EGFR 
               
               
                 29 
                 BRCA 
                 FAK 
               
               
                 30 
                 BRCA 
                 HER2 
               
               
                 31 
                 BRCA 
                 KRAS 
               
               
                 32 
                 BRCA 
                 mTOR 
               
               
                 33 
                 BRCA 
                 PI3K 
               
               
                 34 
                 BRCA 
                 RET 
               
               
                 35 
                 BRCA 
                 VEGF 
               
               
                 36 
                 cKit 
                 cMet 
               
               
                 37 
                 cKit 
                 EGFR 
               
               
                 38 
                 cKit 
                 FAK 
               
               
                 39 
                 cKit 
                 HER2 
               
               
                 40 
                 cKit 
                 KRAS 
               
               
                 41 
                 cKit 
                 mTOR 
               
               
                 42 
                 cKit 
                 PI3K 
               
               
                 43 
                 cKit 
                 RET 
               
               
                 44 
                 cKit 
                 VEGF 
               
               
                 45 
                 cMet 
                 EGFR 
               
               
                 46 
                 cMet 
                 FAK 
               
               
                 47 
                 cMet 
                 HER2 
               
               
                 48 
                 cMet 
                 KRAS 
               
               
                 49 
                 cMet 
                 mTOR 
               
               
                 50 
                 cMet 
                 PI3K 
               
               
                 51 
                 cMet 
                 RET 
               
               
                 52 
                 cMet 
                 VEGF 
               
               
                 53 
                 EGFR 
                 FAK 
               
               
                 54 
                 EGFR 
                 HER2 
               
               
                 55 
                 EGFR 
                 KRAS 
               
               
                 56 
                 EGFR 
                 mTOR 
               
               
                 57 
                 EGFR 
                 PI3K 
               
               
                 58 
                 EGFR 
                 RET 
               
               
                 59 
                 EGFR 
                 VEGF 
               
               
                 60 
                 FAK 
                 HER2 
               
               
                 61 
                 FAK 
                 KRAS 
               
               
                 62 
                 FAK 
                 mTOR 
               
               
                 63 
                 FAK 
                 PI3K 
               
               
                 64 
                 FAK 
                 RET 
               
               
                 65 
                 FAK 
                 VEGF 
               
               
                 66 
                 HER2 
                 KRAS 
               
               
                 67 
                 HER2 
                 mTOR 
               
               
                 68 
                 HER2 
                 PI3K 
               
               
                 69 
                 HER2 
                 RET 
               
               
                 70 
                 HER2 
                 VEGF 
               
               
                 71 
                 KRAS 
                 mTOR 
               
               
                 72 
                 KRAS 
                 PI3K 
               
               
                 73 
                 KRAS 
                 RET 
               
               
                 74 
                 KRAS 
                 VEGF 
               
               
                 75 
                 mTOR 
                 PI3K 
               
               
                 76 
                 mTOR 
                 RET 
               
               
                 77 
                 mTOR 
                 VEGF 
               
               
                 78 
                 PI3K 
                 RET 
               
               
                 79 
                 PI3K 
                 VEGF 
               
               
                 80 
                 RET 
                 VEGF 
               
               
                 81 
                 ALK 
                 Bcl-2 
                 BRAF 
               
               
                 82 
                 ALK 
                 Bcl-2 
                 BRCA 
               
               
                 83 
                 ALK 
                 Bcl-2 
                 cKit 
               
               
                 84 
                 ALK 
                 Bcl-2 
                 cMet 
               
               
                 85 
                 ALK 
                 Bcl-2 
                 EGFR 
               
               
                 86 
                 ALK 
                 Bcl-2 
                 FAK 
               
               
                 87 
                 ALK 
                 Bcl-2 
                 HER2 
               
               
                 88 
                 ALK 
                 Bcl-2 
                 KRAS 
               
               
                 89 
                 ALK 
                 Bcl-2 
                 mTOR 
               
               
                 90 
                 ALK 
                 Bcl-2 
                 PI3K 
               
               
                 91 
                 ALK 
                 Bcl-2 
                 RET 
               
               
                 92 
                 ALK 
                 Bcl-2 
                 VEGF 
               
               
                 93 
                 ALK 
                 BRAF 
                 BRCA 
               
               
                 94 
                 ALK 
                 BRAF 
                 cKit 
               
               
                 95 
                 ALK 
                 BRAF 
                 cMet 
               
               
                 96 
                 ALK 
                 BRAF 
                 EGFR 
               
               
                 97 
                 ALK 
                 BRAF 
                 FAK 
               
               
                 98 
                 ALK 
                 BRAF 
                 HER2 
               
               
                 99 
                 ALK 
                 BRAF 
                 KRAS 
               
               
                 100 
                 ALK 
                 BRAF 
                 mTOR 
               
               
                 101 
                 ALK 
                 BRAF 
                 PI3K 
               
               
                 102 
                 ALK 
                 BRAF 
                 RET 
               
               
                 103 
                 ALK 
                 BRAF 
                 VEGF 
               
               
                 104 
                 ALK 
                 BRCA 
                 cKit 
               
               
                 105 
                 ALK 
                 BRCA 
                 cMet 
               
               
                 106 
                 ALK 
                 BRCA 
                 EGFR 
               
               
                 107 
                 ALK 
                 BRCA 
                 FAK 
               
               
                 108 
                 ALK 
                 BRCA 
                 HER2 
               
               
                 109 
                 ALK 
                 BRCA 
                 KRAS 
               
               
                 110 
                 ALK 
                 BRCA 
                 mTOR 
               
               
                 111 
                 ALK 
                 BRCA 
                 PI3K 
               
               
                 112 
                 ALK 
                 BRCA 
                 RET 
               
               
                 113 
                 ALK 
                 BRCA 
                 VEGF 
               
               
                 114 
                 ALK 
                 cKit 
                 cMet 
               
               
                 115 
                 ALK 
                 cKit 
                 EGFR 
               
               
                 116 
                 ALK 
                 cKit 
                 FAK 
               
               
                 117 
                 ALK 
                 cKit 
                 HER2 
               
               
                 118 
                 ALK 
                 cKit 
                 KRAS 
               
               
                 119 
                 ALK 
                 cKit 
                 mTOR 
               
               
                 120 
                 ALK 
                 cKit 
                 PI3K 
               
               
                 121 
                 ALK 
                 cKit 
                 RET 
               
               
                 122 
                 ALK 
                 cKit 
                 VEGF 
               
               
                 123 
                 ALK 
                 cMet 
                 EGFR 
               
               
                 124 
                 ALK 
                 cMet 
                 FAK 
               
               
                 125 
                 ALK 
                 cMet 
                 HER2 
               
               
                 126 
                 ALK 
                 cMet 
                 KRAS 
               
               
                 127 
                 ALK 
                 cMet 
                 mTOR 
               
               
                 128 
                 ALK 
                 cMet 
                 PI3K 
               
               
                 129 
                 ALK 
                 cMet 
                 RET 
               
               
                 130 
                 ALK 
                 cMet 
                 VEGF 
               
               
                 131 
                 ALK 
                 EGFR 
                 FAK 
               
               
                 132 
                 ALK 
                 EGFR 
                 HER2 
               
               
                 133 
                 ALK 
                 EGFR 
                 KRAS 
               
               
                 134 
                 ALK 
                 EGFR 
                 mTOR 
               
               
                 135 
                 ALK 
                 EGFR 
                 PI3K 
               
               
                 136 
                 ALK 
                 EGFR 
                 RET 
               
               
                 137 
                 ALK 
                 EGFR 
                 VEGF 
               
               
                 138 
                 ALK 
                 FAK 
                 HER2 
               
               
                 139 
                 ALK 
                 FAK 
                 KRAS 
               
               
                 140 
                 ALK 
                 FAK 
                 mTOR 
               
               
                 141 
                 ALK 
                 FAK 
                 PI3K 
               
               
                 142 
                 ALK 
                 FAK 
                 RET 
               
               
                 143 
                 ALK 
                 FAK 
                 VEGF 
               
               
                 144 
                 ALK 
                 HER2 
                 KRAS 
               
               
                 145 
                 ALK 
                 HER2 
                 mTOR 
               
               
                 146 
                 ALK 
                 HER2 
                 PI3K 
               
               
                 147 
                 ALK 
                 HER2 
                 RET 
               
               
                 148 
                 ALK 
                 HER2 
                 VEGF 
               
               
                 149 
                 ALK 
                 KRAS 
                 mTOR 
               
               
                 150 
                 ALK 
                 KRAS 
                 PI3K 
               
               
                 151 
                 ALK 
                 KRAS 
                 RET 
               
               
                 152 
                 ALK 
                 KRAS 
                 VEGF 
               
               
                 153 
                 ALK 
                 mTOR 
                 PI3K 
               
               
                 154 
                 ALK 
                 mTOR 
                 RET 
               
               
                 155 
                 ALK 
                 mTOR 
                 VEGF 
               
               
                 156 
                 ALK 
                 PI3K 
                 RET 
               
               
                 157 
                 ALK 
                 PI3K 
                 VEGF 
               
               
                 158 
                 ALK 
                 RET 
                 VEGF 
               
               
                 159 
                 Bcl-2 
                 BRAF 
                 BRCA 
               
               
                 160 
                 Bcl-2 
                 BRAF 
                 cKit 
               
               
                 161 
                 Bcl-2 
                 BRAF 
                 cMet 
               
               
                 162 
                 Bcl-2 
                 BRAF 
                 EGFR 
               
               
                 163 
                 Bcl-2 
                 BRAF 
                 FAK 
               
               
                 164 
                 Bcl-2 
                 BRAF 
                 HER2 
               
               
                 165 
                 Bcl-2 
                 BRAF 
                 KRAS 
               
               
                 166 
                 Bcl-2 
                 BRAF 
                 mTOR 
               
               
                 167 
                 Bcl-2 
                 BRAF 
                 PI3K 
               
               
                 168 
                 Bcl-2 
                 BRAF 
                 RET 
               
               
                 169 
                 Bcl-2 
                 BRAF 
                 VEGF 
               
               
                 170 
                 Bcl-2 
                 BRCA 
                 cKit 
               
               
                 171 
                 Bcl-2 
                 BRCA 
                 cMet 
               
               
                 172 
                 Bcl-2 
                 BRCA 
                 EGFR 
               
               
                 173 
                 Bcl-2 
                 BRCA 
                 FAK 
               
               
                 174 
                 Bcl-2 
                 BRCA 
                 HER2 
               
               
                 175 
                 Bcl-2 
                 BRCA 
                 KRAS 
               
               
                 176 
                 Bcl-2 
                 BRCA 
                 mTOR 
               
               
                 177 
                 Bcl-2 
                 BRCA 
                 PI3K 
               
               
                 178 
                 Bcl-2 
                 BRCA 
                 RET 
               
               
                 179 
                 Bcl-2 
                 BRCA 
                 VEGF 
               
               
                 180 
                 Bcl-2 
                 cKit 
                 cMet 
               
               
                 181 
                 Bcl-2 
                 cKit 
                 EGFR 
               
               
                 182 
                 Bcl-2 
                 cKit 
                 FAK 
               
               
                 183 
                 Bcl-2 
                 cKit 
                 HER2 
               
               
                 184 
                 Bcl-2 
                 cKit 
                 KRAS 
               
               
                 185 
                 Bcl-2 
                 cKit 
                 mTOR 
               
               
                 186 
                 Bcl-2 
                 cKit 
                 PI3K 
               
               
                 187 
                 Bcl-2 
                 cKit 
                 RET 
               
               
                 188 
                 Bcl-2 
                 cKit 
                 VEGF 
               
               
                 189 
                 Bcl-2 
                 cMet 
                 EGFR 
               
               
                 190 
                 Bcl-2 
                 cMet 
                 FAK 
               
               
                 191 
                 Bcl-2 
                 cMet 
                 HER2 
               
               
                 192 
                 Bcl-2 
                 cMet 
                 KRAS 
               
               
                 193 
                 Bcl-2 
                 cMet 
                 mTOR 
               
               
                 194 
                 Bcl-2 
                 cMet 
                 PI3K 
               
               
                 195 
                 Bcl-2 
                 cMet 
                 RET 
               
               
                 196 
                 Bcl-2 
                 cMet 
                 VEGF 
               
               
                 197 
                 Bcl-2 
                 EGFR 
                 FAK 
               
               
                 198 
                 Bcl-2 
                 EGFR 
                 HER2 
               
               
                 199 
                 Bcl-2 
                 EGFR 
                 KRAS 
               
               
                 200 
                 Bcl-2 
                 EGFR 
                 mTOR 
               
               
                 201 
                 Bcl-2 
                 EGFR 
                 PI3K 
               
               
                 202 
                 Bcl-2 
                 EGFR 
                 RET 
               
               
                 203 
                 Bcl-2 
                 EGFR 
                 VEGF 
               
               
                 204 
                 Bcl-2 
                 FAK 
                 HER2 
               
               
                 205 
                 Bcl-2 
                 FAK 
                 KRAS 
               
               
                 206 
                 Bcl-2 
                 FAK 
                 mTOR 
               
               
                 207 
                 Bcl-2 
                 FAK 
                 PI3K 
               
               
                 208 
                 Bcl-2 
                 FAK 
                 RET 
               
               
                 209 
                 Bcl-2 
                 FAK 
                 VEGF 
               
               
                 210 
                 Bcl-2 
                 HER2 
                 KRAS 
               
               
                 211 
                 Bcl-2 
                 HER2 
                 mTOR 
               
               
                 212 
                 Bcl-2 
                 HER2 
                 PI3K 
               
               
                 213 
                 Bcl-2 
                 HER2 
                 RET 
               
               
                 214 
                 Bcl-2 
                 HER2 
                 VEGF 
               
               
                 215 
                 Bcl-2 
                 KRAS 
                 mTOR 
               
               
                 216 
                 Bcl-2 
                 KRAS 
                 PI3K 
               
               
                 217 
                 Bcl-2 
                 KRAS 
                 RET 
               
               
                 218 
                 Bcl-2 
                 KRAS 
                 VEGF 
               
               
                 219 
                 Bcl-2 
                 mTOR 
                 PI3K 
               
               
                 220 
                 Bcl-2 
                 mTOR 
                 RET 
               
               
                 221 
                 Bcl-2 
                 mTOR 
                 VEGF 
               
               
                 222 
                 Bcl-2 
                 PI3K 
                 RET 
               
               
                 223 
                 Bcl-2 
                 PI3K 
                 VEGF 
               
               
                 224 
                 Bcl-2 
                 RET 
                 VEGF 
               
               
                 225 
                 BRAF 
                 BRCA 
                 cKit 
               
               
                 226 
                 BRAF 
                 BRCA 
                 cMet 
               
               
                 227 
                 BRAF 
                 BRCA 
                 EGFR 
               
               
                 228 
                 BRAF 
                 BRCA 
                 FAK 
               
               
                 229 
                 BRAF 
                 BRCA 
                 HER2 
               
               
                 230 
                 BRAF 
                 BRCA 
                 KRAS 
               
               
                 231 
                 BRAF 
                 BRCA 
                 mTOR 
               
               
                 232 
                 BRAF 
                 BRCA 
                 PI3K 
               
               
                 233 
                 BRAF 
                 BRCA 
                 RET 
               
               
                 234 
                 BRAF 
                 BRCA 
                 VEGF 
               
               
                 235 
                 BRAF 
                 cKit 
                 cMet 
               
               
                 236 
                 BRAF 
                 cKit 
                 EGFR 
               
               
                 237 
                 BRAF 
                 cKit 
                 FAK 
               
               
                 238 
                 BRAF 
                 cKit 
                 HER2 
               
               
                 239 
                 BRAF 
                 cKit 
                 KRAS 
               
               
                 240 
                 BRAF 
                 cKit 
                 mTOR 
               
               
                 241 
                 BRAF 
                 cKit 
                 PI3K 
               
               
                 242 
                 BRAF 
                 cKit 
                 RET 
               
               
                 243 
                 BRAF 
                 cKit 
                 VEGF 
               
               
                 244 
                 BRAF 
                 cMet 
                 EGFR 
               
               
                 245 
                 BRAF 
                 cMet 
                 FAK 
               
               
                 246 
                 BRAF 
                 cMet 
                 HER2 
               
               
                 247 
                 BRAF 
                 cMet 
                 KRAS 
               
               
                 248 
                 BRAF 
                 cMet 
                 mTOR 
               
               
                 249 
                 BRAF 
                 cMet 
                 PI3K 
               
               
                 250 
                 BRAF 
                 cMet 
                 RET 
               
               
                 251 
                 BRAF 
                 cMet 
                 VEGF 
               
               
                 252 
                 BRAF 
                 EGFR 
                 FAK 
               
               
                 253 
                 BRAF 
                 EGFR 
                 HER2 
               
               
                 254 
                 BRAF 
                 EGFR 
                 KRAS 
               
               
                 255 
                 BRAF 
                 EGFR 
                 mTOR 
               
               
                 256 
                 BRAF 
                 EGFR 
                 PI3K 
               
               
                 257 
                 BRAF 
                 EGFR 
                 RET 
               
               
                 258 
                 BRAF 
                 EGFR 
                 VEGF 
               
               
                 259 
                 BRAF 
                 FAK 
                 HER2 
               
               
                 260 
                 BRAF 
                 FAK 
                 KRAS 
               
               
                 261 
                 BRAF 
                 FAK 
                 mTOR 
               
               
                 262 
                 BRAF 
                 FAK 
                 PI3K 
               
               
                 263 
                 BRAF 
                 FAK 
                 RET 
               
               
                 264 
                 BRAF 
                 FAK 
                 VEGF 
               
               
                 265 
                 BRAF 
                 HER2 
                 KRAS 
               
               
                 266 
                 BRAF 
                 HER2 
                 mTOR 
               
               
                 267 
                 BRAF 
                 HER2 
                 PI3K 
               
               
                 268 
                 BRAF 
                 HER2 
                 RET 
               
               
                 269 
                 BRAF 
                 HER2 
                 VEGF 
               
               
                 270 
                 BRAF 
                 KRAS 
                 mTOR 
               
               
                 271 
                 BRAF 
                 KRAS 
                 PI3K 
               
               
                 272 
                 BRAF 
                 KRAS 
                 RET 
               
               
                 273 
                 BRAF 
                 KRAS 
                 VEGF 
               
               
                 274 
                 BRAF 
                 mTOR 
                 PI3K 
               
               
                 275 
                 BRAF 
                 mTOR 
                 RET 
               
               
                 276 
                 BRAF 
                 mTOR 
                 VEGF 
               
               
                 277 
                 BRAF 
                 PI3K 
                 RET 
               
               
                 278 
                 BRAF 
                 PI3K 
                 VEGF 
               
               
                 279 
                 BRAF 
                 RET 
                 VEGF 
               
               
                 280 
                 BRCA 
                 cKit 
                 cMet 
               
               
                 281 
                 BRCA 
                 cKit 
                 EGFR 
               
               
                 282 
                 BRCA 
                 cKit 
                 FAK 
               
               
                 283 
                 BRCA 
                 cKit 
                 HER2 
               
               
                 284 
                 BRCA 
                 cKit 
                 KRAS 
               
               
                 285 
                 BRCA 
                 cKit 
                 mTOR 
               
               
                 286 
                 BRCA 
                 cKit 
                 PI3K 
               
               
                 287 
                 BRCA 
                 cKit 
                 RET 
               
               
                 288 
                 BRCA 
                 cKit 
                 VEGF 
               
               
                 289 
                 BRCA 
                 cMet 
                 EGFR 
               
               
                 290 
                 BRCA 
                 cMet 
                 FAK 
               
               
                 291 
                 BRCA 
                 cMet 
                 HER2 
               
               
                 292 
                 BRCA 
                 cMet 
                 KRAS 
               
               
                 293 
                 BRCA 
                 cMet 
                 mTOR 
               
               
                 294 
                 BRCA 
                 cMet 
                 PI3K 
               
               
                 295 
                 BRCA 
                 cMet 
                 RET 
               
               
                 296 
                 BRCA 
                 cMet 
                 VEGF 
               
               
                 297 
                 BRCA 
                 EGFR 
                 FAK 
               
               
                 298 
                 BRCA 
                 EGFR 
                 HER2 
               
               
                 299 
                 BRCA 
                 EGFR 
                 KRAS 
               
               
                 300 
                 BRCA 
                 EGFR 
                 mTOR 
               
               
                 301 
                 BRCA 
                 EGFR 
                 PI3K 
               
               
                 302 
                 BRCA 
                 EGFR 
                 RET 
               
               
                 303 
                 BRCA 
                 EGFR 
                 VEGF 
               
               
                 304 
                 BRCA 
                 FAK 
                 HER2 
               
               
                 305 
                 BRCA 
                 FAK 
                 KRAS 
               
               
                 306 
                 BRCA 
                 FAK 
                 mTOR 
               
               
                 307 
                 BRCA 
                 FAK 
                 PI3K 
               
               
                 308 
                 BRCA 
                 FAK 
                 RET 
               
               
                 309 
                 BRCA 
                 FAK 
                 VEGF 
               
               
                 310 
                 BRCA 
                 HER2 
                 KRAS 
               
               
                 311 
                 BRCA 
                 HER2 
                 mTOR 
               
               
                 312 
                 BRCA 
                 HER2 
                 PI3K 
               
               
                 313 
                 BRCA 
                 HER2 
                 RET 
               
               
                 314 
                 BRCA 
                 HER2 
                 VEGF 
               
               
                 315 
                 BRCA 
                 KRAS 
                 mTOR 
               
               
                 316 
                 BRCA 
                 KRAS 
                 PI3K 
               
               
                 317 
                 BRCA 
                 KRAS 
                 RET 
               
               
                 318 
                 BRCA 
                 KRAS 
                 VEGF 
               
               
                 319 
                 BRCA 
                 mTOR 
                 PI3K 
               
               
                 320 
                 BRCA 
                 mTOR 
                 RET 
               
               
                 321 
                 BRCA 
                 mTOR 
                 VEGF 
               
               
                 322 
                 BRCA 
                 PI3K 
                 RET 
               
               
                 323 
                 BRCA 
                 PI3K 
                 VEGF 
               
               
                 324 
                 BRCA 
                 RET 
                 VEGF 
               
               
                 325 
                 cKit 
                 cMet 
                 EGFR 
               
               
                 326 
                 cKit 
                 cMet 
                 FAK 
               
               
                 327 
                 cKit 
                 cMet 
                 HER2 
               
               
                 328 
                 cKit 
                 cMet 
                 KRAS 
               
               
                 329 
                 cKit 
                 cMet 
                 mTOR 
               
               
                 330 
                 cKit 
                 cMet 
                 PI3K 
               
               
                 331 
                 cKit 
                 cMet 
                 RET 
               
               
                 332 
                 cKit 
                 cMet 
                 VEGF 
               
               
                 333 
                 cKit 
                 EGFR 
                 FAK 
               
               
                 334 
                 cKit 
                 EGFR 
                 HER2 
               
               
                 335 
                 cKit 
                 EGFR 
                 KRAS 
               
               
                 336 
                 cKit 
                 EGFR 
                 mTOR 
               
               
                 337 
                 cKit 
                 EGFR 
                 PI3K 
               
               
                 338 
                 cKit 
                 EGFR 
                 RET 
               
               
                 339 
                 cKit 
                 EGFR 
                 VEGF 
               
               
                 340 
                 cKit 
                 FAK 
                 HER2 
               
               
                 341 
                 cKit 
                 FAK 
                 KRAS 
               
               
                 342 
                 cKit 
                 FAK 
                 mTOR 
               
               
                 343 
                 cKit 
                 FAK 
                 PI3K 
               
               
                 344 
                 cKit 
                 FAK 
                 RET 
               
               
                 345 
                 cKit 
                 FAK 
                 VEGF 
               
               
                 346 
                 cKit 
                 HER2 
                 KRAS 
               
               
                 347 
                 cKit 
                 HER2 
                 mTOR 
               
               
                 348 
                 cKit 
                 HER2 
                 PI3K 
               
               
                 349 
                 cKit 
                 HER2 
                 RET 
               
               
                 350 
                 cKit 
                 HER2 
                 VEGF 
               
               
                 351 
                 cKit 
                 KRAS 
                 mTOR 
               
               
                 352 
                 cKit 
                 KRAS 
                 PI3K 
               
               
                 353 
                 cKit 
                 KRAS 
                 RET 
               
               
                 354 
                 cKit 
                 KRAS 
                 VEGF 
               
               
                 355 
                 cKit 
                 mTOR 
                 PI3K 
               
               
                 356 
                 cKit 
                 mTOR 
                 RET 
               
               
                 357 
                 cKit 
                 mTOR 
                 VEGF 
               
               
                 358 
                 cKit 
                 PI3K 
                 RET 
               
               
                 359 
                 cKit 
                 PI3K 
                 VEGF 
               
               
                 360 
                 cKit 
                 RET 
                 VEGF 
               
               
                 361 
                 cMet 
                 EGFR 
                 FAK 
               
               
                 362 
                 cMet 
                 EGFR 
                 HER2 
               
               
                 363 
                 cMet 
                 EGFR 
                 KRAS 
               
               
                 364 
                 cMet 
                 EGFR 
                 mTOR 
               
               
                 365 
                 cMet 
                 EGFR 
                 PI3K 
               
               
                 366 
                 cMet 
                 EGFR 
                 RET 
               
               
                 367 
                 cMet 
                 EGFR 
                 VEGF 
               
               
                 368 
                 cMet 
                 FAK 
                 HER2 
               
               
                 369 
                 cMet 
                 FAK 
                 KRAS 
               
               
                 370 
                 cMet 
                 FAK 
                 mTOR 
               
               
                 371 
                 cMet 
                 FAK 
                 PI3K 
               
               
                 372 
                 cMet 
                 FAK 
                 RET 
               
               
                 373 
                 cMet 
                 FAK 
                 VEGF 
               
               
                 374 
                 cMet 
                 HER2 
                 KRAS 
               
               
                 375 
                 cMet 
                 HER2 
                 mTOR 
               
               
                 376 
                 cMet 
                 HER2 
                 PI3K 
               
               
                 377 
                 cMet 
                 HER2 
                 RET 
               
               
                 378 
                 cMet 
                 HER2 
                 VEGF 
               
               
                 379 
                 cMet 
                 KRAS 
                 mTOR 
               
               
                 380 
                 cMet 
                 KRAS 
                 PI3K 
               
               
                 381 
                 cMet 
                 KRAS 
                 RET 
               
               
                 382 
                 cMet 
                 KRAS 
                 VEGF 
               
               
                 383 
                 cMet 
                 mTOR 
                 PI3K 
               
               
                 384 
                 cMet 
                 mTOR 
                 RET 
               
               
                 385 
                 cMet 
                 mTOR 
                 VEGF 
               
               
                 386 
                 cMet 
                 PI3K 
                 RET 
               
               
                 387 
                 cMet 
                 PI3K 
                 VEGF 
               
               
                 388 
                 cMet 
                 RET 
                 VEGF 
               
               
                 389 
                 EGFR 
                 FAK 
                 HER2 
               
               
                 390 
                 EGFR 
                 FAK 
                 KRAS 
               
               
                 391 
                 EGFR 
                 FAK 
                 mTOR 
               
               
                 392 
                 EGFR 
                 FAK 
                 PI3K 
               
               
                 393 
                 EGFR 
                 FAK 
                 RET 
               
               
                 394 
                 EGFR 
                 FAK 
                 VEGF 
               
               
                 395 
                 EGFR 
                 HER2 
                 KRAS 
               
               
                 396 
                 EGFR 
                 HER2 
                 mTOR 
               
               
                 397 
                 EGFR 
                 HER2 
                 PI3K 
               
               
                 398 
                 EGFR 
                 HER2 
                 RET 
               
               
                 399 
                 EGFR 
                 HER2 
                 VEGF 
               
               
                 400 
                 EGFR 
                 KRAS 
                 mTOR 
               
               
                 401 
                 EGFR 
                 KRAS 
                 PI3K 
               
               
                 402 
                 EGFR 
                 KRAS 
                 RET 
               
               
                 403 
                 EGFR 
                 KRAS 
                 VEGF 
               
               
                 404 
                 EGFR 
                 mTOR 
                 PI3K 
               
               
                 405 
                 EGFR 
                 mTOR 
                 RET 
               
               
                 406 
                 EGFR 
                 mTOR 
                 VEGF 
               
               
                 407 
                 EGFR 
                 PI3K 
                 RET 
               
               
                 408 
                 EGFR 
                 PI3K 
                 VEGF 
               
               
                 409 
                 EGFR 
                 RET 
                 VEGF 
               
               
                 410 
                 FAK 
                 HER2 
                 KRAS 
               
               
                 411 
                 FAK 
                 HER2 
                 mTOR 
               
               
                 412 
                 FAK 
                 HER2 
                 PI3K 
               
               
                 413 
                 FAK 
                 HER2 
                 RET 
               
               
                 414 
                 FAK 
                 HER2 
                 VEGF 
               
               
                 415 
                 FAK 
                 KRAS 
                 mTOR 
               
               
                 416 
                 FAK 
                 KRAS 
                 PI3K 
               
               
                 417 
                 FAK 
                 KRAS 
                 RET 
               
               
                 418 
                 FAK 
                 KRAS 
                 VEGF 
               
               
                 419 
                 FAK 
                 mTOR 
                 PI3K 
               
               
                 420 
                 FAK 
                 mTOR 
                 RET 
               
               
                 421 
                 FAK 
                 mTOR 
                 VEGF 
               
               
                 422 
                 FAK 
                 PI3K 
                 RET 
               
               
                 423 
                 FAK 
                 PI3K 
                 VEGF 
               
               
                 424 
                 FAK 
                 RET 
                 VEGF 
               
               
                 425 
                 HER2 
                 KRAS 
                 mTOR 
               
               
                 426 
                 HER2 
                 KRAS 
                 PI3K 
               
               
                 427 
                 HER2 
                 KRAS 
                 RET 
               
               
                 428 
                 HER2 
                 KRAS 
                 VEGF 
               
               
                 429 
                 HER2 
                 mTOR 
                 PI3K 
               
               
                 430 
                 HER2 
                 mTOR 
                 RET 
               
               
                 431 
                 HER2 
                 mTOR 
                 VEGF 
               
               
                 432 
                 HER2 
                 PI3K 
                 RET 
               
               
                 433 
                 HER2 
                 PI3K 
                 VEGF 
               
               
                 434 
                 HER2 
                 RET 
                 VEGF 
               
               
                 435 
                 KRAS 
                 mTOR 
                 PI3K 
               
               
                 436 
                 KRAS 
                 mTOR 
                 RET 
               
               
                 437 
                 KRAS 
                 mTOR 
                 VEGF 
               
               
                 438 
                 KRAS 
                 PI3K 
                 RET 
               
               
                 439 
                 KRAS 
                 PI3K 
                 VEGF 
               
               
                 440 
                 KRAS 
                 RET 
                 VEGF 
               
               
                 441 
                 mTOR 
                 PI3K 
                 RET 
               
               
                 442 
                 mTOR 
                 PI3K 
                 VEGF 
               
               
                 443 
                 mTOR 
                 RET 
                 VEGF 
               
               
                 444 
                 PI3K 
                 RET 
                 VEGF 
               
               
                   
               
               
                 Classifications with 4 events may be added based on prevalence of 1 in 1000 or higher