Patent Publication Number: US-2016224739-A1

Title: System, Method and Software for Predicting Clinical Outcome of a Drug Treatment of Breast Cancer in a Patient

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to systems and methods of analysis of gene signaling pathways, and more specifically to systems and methods for using historic patient databases to predict drug efficacy in a patient with breast cancer. 
     BACKGROUND OF THE INVENTION 
     In the twentieth century, enormous studies were made in combatting infectious diseases, in their detection and drugs to treat them. The major problem in the medical world has thus shifted from treating acute diseases to treating chronic diseases. Over the last few decades, with the advent of genetic engineering, much research and funding has been invested in genomics and gene-based personalized medicine. A need has arisen to develop diagnostic tools for use in the characterization of personalized aspects of chronic diseases. 
     There are many known molecular pathways in a mammalian body. The molecular pathways include signaling pathways, metabolic pathways and others. 
     Intracellular signaling pathways (SPs) regulate numerous processes involved in normal and pathological conditions including development, growth, aging and cancer. Many bioinformatic tools have been developed, which analyze SPs. 
     The information relating to signaling pathway activation (SPA) can be obtained from the massive proteomic or transcriptomic data. Although the proteomic level may be somewhat closer to the biological function of SPA, the transcriptomic level of studies today is far more feasible in terms of performing experimental tests and analyzing the data. 
     US2008254497A provides a method of determining whether tumor cells or tissue is responsive to treatment with an ErbB pathway-specific drug. In accordance with the invention, measurements are made on such cells or tissues to determine values for total ErbB receptors of one or more types, ErbB receptor dimers of one or more types and their phosphorylation states, and/or one or more ErbB signaling pathway effector proteins and their phosphorylation states. These quantities, or a response index based on them, are positively or negatively correlated with cell or tissue responsiveness to treatment with an ErbB pathway-specific drug. In one aspect, such correlations are determined from a model of the mechanism of action of a ErbB pathway-specific drug on an ErbB pathway. Preferably, methods of the invention are implemented by using sets of binding compounds having releasable molecular tags that are specific for multiple components of one or more complexes formed in ErbB pathway activation. After binding, molecular tags are released and separated from the assay mixture for analysis. 
     U.S. Pat. No. 8,623,592 discloses methods for treating patients which methods comprise methods for predicting responses of cells, such as tumor cells, to treatment with therapeutic agents. These methods involve measuring, in a sample of the cells, levels of one or more components of a cellular network and then computing a Network Activation State (NAS) or a Network Inhibition State (NIS) for the cells using a computational model of the cellular network. The response of the cells to treatment is then predicted based on the NAS or NIS value that has been computed. The invention also comprises predictive methods for cellular responsiveness in which computation of a NAS or NIS value for the cells (e.g., tumor cells) is combined with use of a statistical classification algorithm Biomarkers for predicting responsiveness to treatment with a therapeutic agent that targets a component within the ErbB signaling pathway are also provided. 
     Cancer drugs are extremely expensive and should not be given to patients who will not respond thereto. There thus remains a need for systems and methods, which can predict drug efficacy in a patient. 
     SUMMARY OF THE INVENTION 
     It is an object of some aspects of the present invention to provide systems and methods, which use historic patient databases to predict anticancer therapy efficacy in a patient. 
     It is a further object of some aspects of the present invention to provide systems and methods, which provide statistical predictions to provide an indication if a therapy is likely to be effective in a patient. 
     Some of the objects of the present invention are to provide novel systems and methods for predicting drug efficacy on breast cancer in a patient. 
     Some further objects of the present invention are to provide novel systems and methods for predicting drug combination efficacy on breast cancer in a patient. 
     It is an object of some aspects of the present invention to provide systems and methods, which use historic patient databases to predict drug efficacy on breast cancer in a patient. 
     It is a further object of some aspects of the present invention to provide systems and methods, which provide statistical predictions to provide an indication if a drug is likely to be effective in a patient, who suffers from breast cancer. 
     It is another further object of some aspects of the present invention to provide systems and methods, which provide a medical practitioner with a decision on drug treatment economy for a specific patient suffering from breast cancer, which saves the use of the drug in the case where the patient is statistically likely not to respond to the drug. 
     It is an object of some aspects of the present invention to provide systems and methods, which use historic patient databases to predict drug efficacy in a patient. 
     It is a further object of some aspects of the present invention to provide systems and methods, which provide statistical predictions to provide an indication if a drug is likely to be effective in a patient, suffering from breast cancer. 
     It is another further object of some aspects of the present invention to provide systems and methods, which provide a medical practitioner with a decision on drug treatment economy for a specific patient, which saves the use of the drug in the case where the patient is statistically likely not to respond to the drug. 
     A primary object of the present invention is to provide a prediction of the clinical efficacy of anticancer therapies for treatment of patients with breast cancer using BreastCancerTreatment module of the OncoFinder tool. BreastCancerTreatment uses OncoFinder databases of signaling and metabolic pathways. It provides the probability of being a responder/a non-responder for an individual patient on the basis of a combination of marker signaling and marker metabolic pathways activation/inhibition. 
     The present invention provides systems, methods and software predicting a clinical outcome of a patient having a disease or disorder, the method including the steps of providing a drug score database (DSD) based on pathway activation strengths (PASs) for a plurality of biological pathways associated with the drug in the treatment of the breast cancer and comparing the pathway activation strengths of the plurality of biological pathways of the patient with the drug score database to provide a predictive indication if the patient is a responder or non-responder to the drug; and repeating these steps for a plurality of drugs thereby predicting a clinical outcome to the plurality of drugs of the patient to the breast cancer. 
     The biological or molecular pathways include signaling pathways, metabolic pathways and others. 
     The invention of this patent is to provide a way to estimate possible effectiveness of anticancer treatment for an individual patient. We invented a BreastCancerTreatment module of OncoFinder that provides an opportunity to check in advance if 15 common anticancer therapies may be helpful in treatment of particular patient with breast cancer. This module of OncoFinder systems is able to predict if a patient is a responder or non-responder to 15 anticancer therapies in case of breast cancer. BreastCancerTreatment module has a database of marker signaling and metabolic pathways (marker pathways—pathways that are activated or inhibited significantly different in responders compared to non-responders among patients with breast cancer). 
     The present invention provides systems, methods and software predicting a clinical outcome of a patient having breast cancer, the method including the steps of providing a drug score database (DSD) based on pathway activation strengths (PASs) for a plurality of biological pathways associated with the drug in the treatment of the breast cancer and comparing the pathway activation strengths of the plurality of biological pathways of the patient with the drug score database to provide a predictive indication if the patient is a responder or non-responder to the drug; and repeating these steps for a plurality of drugs thereby predicting a clinical outcome to the plurality of drugs of the patient to the breast cancer. 
     The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings. 
     There is thus provided according to an embodiment of the present invention, a method for predicting a clinical outcome of a patient having breast cancer, the method comprising:
         a) providing a drug score database (DSD) based on pathway activation strengths (PASs) for a plurality of biological pathways associated with the drug in the treatment of the breast cancer; and   b) comparing the pathway activation strengths of the plurality of biological pathways of the patient with the drug score database to provide a predictive indication if the patient is a responder or non-responder to the drug;   c) repeating the above steps for a plurality of drugs thereby predicting a clinical outcome to the plurality of drugs of the patient to the breast cancer.       

     According to an embodiment of the present invention, the providing a drug score database (DSD) step comprises:
         i. obtaining proliferative bodily samples and healthy bodily samples from patients;   ii. applying said drug to said patients;   iii. determining responder and non-responder patients to said drug; and   iv. repeating steps i to iii for said plurality of drugs.       

     According to another embodiment of the present invention, the determining step comprises comparing gene expression in at least one of a signaling pathway and a metabolic pathway. 
     Furthermore, according to an embodiment of the present invention, the determining step includes comparing gene expression in selected signaling pathways. 
     Further, according to an embodiment of the present invention, the selected signaling pathways are associated with the drug. 
     Yet further, according to an embodiment of the present invention, the determining step further includes determining a drug score at least one pathway activation strength (PAS) value for each pathway in the responder and the non-responder patients. 
     Moreover, according to an embodiment of the present invention, the determining step further includes determining a drug score for the drug based on the at least one pathway activation strength (PAS) value. 
     Additionally, according to an embodiment of the present invention, the bodily samples are selected from the group consisting of a tissue sample, a cell culture, an individual single cell, a bodily sample, an organism sample and a microorganism sample. 
     According to an embodiment of the present invention, the biological pathways are signaling pathways. 
     Further, according to an embodiment of the present invention, the biological pathways are metabolic pathways. 
     Moreover, according to an embodiment of the present invention, the gene expression includes quantifying expression of plurality of gene products. 
     Additionally, according to an embodiment of the present invention the gene products includes a set of at least five gene products. 
     Furthermore, according to an embodiment of the present invention, the method further includes calculating a pathway activation strength (PAS), indicative of the pathway activation of each of the biological pathways. 
     Additionally, according to an embodiment of the present invention, the calculating step includes adding concentrations of the set of the at least five gene products of the sample and comparing to a same set in the at least one control sample. 
     Furthermore, according to an embodiment of the present invention, the gene products provide at least one function in the biological pathway. 
     Further, according to an embodiment of the present invention, the at least one function includes an activation function and a suppressor function. 
     Yet further, according to an embodiment of the present invention, the at least one function includes an up-regulating function and a down-regulating function. 
     Additionally, according to an embodiment of the present invention, the determining step includes at least one of profiling gene expression, RNA profiling, RNA sequencing, DNA profiling, DNA sequencing, protein profiling, amino acid sequencing, at least one immunochemical methodology, a mass spectrometry analysis, a microarray technology, a quantitative PCR methodology and combinations thereof. 
     Additionally, according to an embodiment of the present invention, the method is quantitative. 
     Additionally or alternatively, the method is qualitative. 
     Furthermore, according to an embodiment of the present invention the patients are sick. 
     Additionally, according to an embodiment of the present invention, the sick subject suffers from a proliferative disease or disorder. 
     Moreover, according to an embodiment of the present invention, the proliferative disease or disorder is cancer. 
     Additionally, according to an embodiment of the present invention, the proliferative disease or disorder is breast cancer. 
     Moreover, according to an embodiment of the present invention, the pathway is selected from the group consisting of a Caspase Cascade pathway; a CREB pathway; a GPCR pathway; a CSK3 pathway; an HIF1Alpha Pathway; a VEGF pathway; an ILK pathway; an IP3 pathway; a PPAR pathway; and combinations thereof. 
     There is thus provided according to another embodiment of the present invention, a computer software product, the product configured for predicting drug efficacy for treating breast cancer in a patient, the product including a computer-readable medium in which program instructions are stored, which instructions, when read by a computer, cause the computer to;
         a. provide a drug score database (DSD) based on pathway activation strengths (PASs) for a plurality of biological pathways associated with the drug in the treatment of the breast cancer; and   b. compare said pathway activation strengths of said plurality of biological pathways of said patient with said drug score database to provide a predictive indication if said patient is a responder or non-responder to said drug;   c. repeat steps i) and ii) for a plurality of drugs thereby predicting a clinical outcome to said plurality of drugs of said patient to said breast cancer.       

     There is thus provided according to an additional embodiment of the present invention, a system for predicting drug efficacy for treating breast cancer in a patient the system including; 
     a. a processor adapted to activate a computer-readable medium in which program instructions are stored, which instructions, when read by a computer, cause the processor to:
         i. provide a drug score database (DSD) based on pathway activation strengths (PASs) for a plurality of biological pathways associated with the drug in the treatment of the breast cancer; and   ii. compare said pathway activation strengths of said plurality of biological pathways of said patient with said drug score database to provide a predictive indication if said patient is a responder or non-responder to said drug;   iii. repeat steps i) and ii) for a plurality of drugs thereby predicting a clinical outcome to said plurality of drugs of said patient to said disorder;       

     b. a memory for storing said drug score database (DSD); and 
     c. a display for displaying data associated with said predictive clinical outcome of said patient. 
     There is thus provided according to another embodiment of the present invention, a computer software product, the product configured for defining a best treatment therapy for a patient having breast cancer, the product including a computer-readable medium in which program instructions are stored, which instructions, when read by a computer, cause the computer to;
         i. provide a drug score database (DSD) based on pathway activation strengths (PASs) for a plurality of biological pathways associated with the therapy including at least one drug in the treatment of the breast cancer;   ii. compare the pathway activation strengths of the plurality of biological pathways of the patient with the drug score database to provide a predictive indication if the patient is a responder or non-responder to the drug;   iii. repeat steps i) and ii) for a plurality of drugs thereby predicting a clinical outcome to the plurality of drugs of the patient to the breast cancer; and   iv. output predictive results from step iii to provide a ranking table of best to worst therapies including at least one of the plurality of drugs, predicted for the patient for the cancer.       

     Additionally, according to another embodiment of the present invention, wherein the therapies are selected from the group appearing in Table 3. 
     Furthermore, according to another embodiment of the present invention, the predictive indication has an accuracy of at least 0.6. 
     Additionally, according to another embodiment of the present invention, the predictive indication has an accuracy of at least 0.7. 
     Moreover, according to another embodiment of the present invention, the predictive indication has an accuracy of at least 0.8. 
     Furthermore, according to another embodiment of the present invention, A the patient has a response score of more than 0.5. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention will now be described in connection with certain preferred embodiments with reference to the following illustrative figures so that it may be more fully understood. 
       With specific reference now to the figures in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice. 
       In the drawings: 
         FIG. 1  is a simplified schematic illustration of a system for predicting drug efficacy in a patient, in accordance with an embodiment of the present invention; 
         FIG. 2  is a simplified flowchart of a method for determining activation to mitosis conversion factors (AMCFs), in accordance with an embodiment of the present invention; 
         FIG. 3  is a simplified flowchart of a method for predicting drug efficacy in a patient, suffering from breast cancer, in accordance with an embodiment of the present invention; 
         FIG. 4  is a simplified flowchart of a method for predicting drug efficacy in a patient, suffering from breast cancer, in accordance with an embodiment of the present invention; 
         FIG. 5  is a graph of density of normally distributed x values; and 
         FIG. 6  is a histogram of responders and non-responders demonstrating the distribution of drug scores within the treatment method, in accordance with an embodiment of the present invention. 
     
    
    
     In all the figures similar reference numerals identify similar parts. 
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     In the detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that these are specific embodiments and that the present invention may be practiced also in different ways that embody the characterizing features of the invention as described and claimed herein. 
     Reference is now made to  FIG. 1 , which is a simplified schematic illustration of a system for predicting drug efficacy in a patient, suffering from breast cancer, in accordance with an embodiment of the present invention. 
     System  100  typically includes a server utility  110 , which may include one or a plurality of servers and one or more control computer terminals  112 l for programming, trouble-shooting servicing and other functions. Server utility  110  includes a system engine  111  and database,  191 . Database  191  comprises a user profile database  125 , a pathway cloud database  123  and a drug profile database  180 . Typically, the database comprises biological pathway databases  170 , including gene expression data ( 179 , not shown), metabolic pathway data ( 178 , not shown) and signaling pathway data ( 178 , not shown). 
     Depending on the capabilities of a mobile device, system  100  may also be incorporated on a mobile device that synchronizes data with a cloud-based platform. 
     The drug profile database comprises data relating to a large number of drugs for controlling and treating cancer. For each type of drug, the dosage values, pharmo-kinetic data and profile, pharmodynamic data and profiles are included. 
     The drug profile database further comprises data of drug combinations, including dosage values pharmo-kinetic data and profile, pharmodynamic data and profiles. 
     A medical professional, research personnel or patient assistant/helper/carer  141  is connected via his/her mobile device  140  to server utility  110 . The patient, subject or child  143  is also connected via his/her mobile device  142  to server utility  110 . In some cases, the subject may be a mammalian subject, such as a mouse, rat, hamster, monkey, cat or dog, used in research and development. In other cases, the subject may be a vertebrate subject, such as a frog, fish or lizard. The patient or child&#39;s is monitored using a sample analyzer  199 . Sample analyzer  199 , may be associated with one or more computers  130  and with server utility  110 . Computer  130  and/or sample analyzer  199  may have software therein for predicting drug efficacy in a patient, as will be described in further details hereinbelow. 
     Typically, gene expression data  123  ( FIG. 1 ), generated by the software of the present invention, is stored locally and/or in cloud  120  and/or on server  110 . 
     The sample analyzer may be constructed and configured to receive a solid sample  190 , such as a biopsy, a hair sample or other solid sample from patient  143 , and/or a liquid sample  195 , such as, but not limited to, urine, blood or saliva sample. The sample may be extracted by any suitable means, such as by a syringe  197 . 
     The patient, subject or child  143  may be provided with a drug (not shown) by health professional/research/doctor  141 . 
     System  100  further comprises an outputting module  185  for outputting data from the database via tweets, emails, voicemails and computer-generated spoken messages to the user, carers or doctors, via the Internet  120  (constituting a computer network), SMS, Instant Messaging, Fax through link  122 . 
     Users, patients, health care professionals or customers  141 ,  143  may communicate with server  110  through a plurality of user computers  130 ,  131 , or user devices  140 ,  142 , which may be mainframe computers with terminals that permit individual to access a network, personal computers, portable computers, small hand-held computers and other, that are linked to the Internet  120  through a plurality of links  124 . The Internet link of each of computers  130 ,  131 , may be direct through a landline or a wireless line, or may be indirect, for example through an intranet that is linked through an appropriate server to the Internet. System  100  may also operate through communication protocols between computers over the Internet which technique is known to a person versed in the art and will not be elaborated herein. 
     Users may also communicate with the system through portable communication devices such as mobile phones  140 , communicating with the Internet through a corresponding communication system (e.g. cellular system)  150  connectable to the Internet through link  152 . As will readily be appreciated, this is a very simplified description, although the details should be clear to the artisan. Also, it should be noted that the invention is not limited to the user-associated communication devices—computers and portable and mobile communication devices—and a variety of others such as an interactive television system may also be used. 
     The system  100  also typically includes at least one call and/or user support and/or tele-health center  160 . The service center typically provides both on-line and off-line services to users. The server system  110  is configured according to the invention to carry out the methods of the present invention described herein. 
     It should be understood that many variations to system  100  are envisaged, and this embodiment should not be construed as limiting. For example, a facsimile system or a phone device (wired telephone or mobile phone) may be designed to be connectable to a computer network (e.g. the Internet). Interactive televisions may be used for inputting and receiving data from the Internet. Future devices for communications via new communication networks are also deemed to be part of system  100 . Memories may be on a physical server and/or in a virtual cloud. 
     A mobile computing device may also embody a non-synced or offline copy of memories, copies of pathway cloud data, user profiles database, drug profiles database and execute the system, engine locally. 
     Reference is now made to  FIG. 2 , which is simplified flowchart of a method for determining activation to mitosis conversion factors (AMCFs), in accordance with an embodiment of the present invention. 
     There are three basic steps for determining activation to mitosis conversion factors (AMCFs). First, a mapping step  202  is performed to map molecular pathways for a target drug. Thereafter, the genes in each molecular pathway are defined in a gene determining step  204 . Thereafter, the activation to mitosis conversion factor (AMCF) is determined in an AMCF determining step  206 . 
     Though this figure refers to signaling pathways, the method is deemed to include any biological pathway, molecular pathway, such as, but not limited to, a metabolic pathway and a signaling pathway. 
       FIG. 3  is a simplified flowchart  300  of a method for determining predicting drug efficacy in a patient, suffering from breast cancer, in accordance with an embodiment of the present invention. 
     In a first obtaining step  302 , bodily samples are collected from healthy and sick (tumor samples) patients and are stored (such as by refrigeration or freezing). 
     In an applying drug step  304 , a potential drug is applied to the samples in vitro. 
     In an evaluating step  306 , the responder and non-responder samples to the drug are defined. 
     Thereafter, in a gene expression definition step  308 , the gene expression of the responder and non-responder populations are compared. 
     Thereafter, in a determining pathway manifestation strength (PMS) for each pathway in responders and non-responders is determined in a PMS determining step  310 . 
     In a determining drug score for each patient step  312 , the drug scores based on the previous steps are calculated for each patient. The patient drug scores are used to form a drug score database. 
     Thereafter, the drug score database can be used for each new patient in a prediction step  314  to predict a new patient drug score. A patient will not be treated with the drug if he/she is predicted to be a non responder but will be treated with the drug if he/she is predicted to be a responder. 
     A primary object of the present invention is to provide a prediction of the clinical efficacy of anticancer therapies for treatment of patients with breast cancer using BreastCancerTreatment module of the OncoFinder tool. BreastCancerTreatment uses OncoFinder databases of signaling and metabolic pathways. It provides the probability of being a responder/a non-responder for an individual patient on the basis of a combination of marker signaling and marker metabolic pathways activation/inhibition. 
     OncoFinder 
     OncoFinder system designed to advise oncologists conducting treatment of patients with malignant tumors. This computer system is a knowledge base that is used to support decisions regarding treatment of individual cancer patients by targeted anticancer drugs—monoclonal antibodies (mabs), kinase inhibitors (nibs), some hormones and stimulants. 
     OncoFinder knowledgebase operates basic data, which are the results of microarray analysis of the transcriptome cell biopsy as malignant tumors and healthy tissue of similar organs. Result of the system is evaluation of the degree of pathological changes in the pro- and anti-mitotic signaling pathways and the ability of targeted anticancer drugs to compensate for these changes. 
     This information can be used to forecast the clinical efficacy of drugs for individual patients with cancer and hematologic lesion. The OncoFinder system&#39;s knowledgebase based on database of targeted anticancer drugs and pro- and anti-mitotic signaling pathways, which contains information about the interaction of proteins and their corresponding genes. The system is implemented in the form of a cloud online software on “Amazon” web platform at http://aws.amazon.com/. 
     When calculating the quantitative indicators of pathological changes in pro and anti-mitotic signaling pathways for individual cancer patients, as well as the ability of anticancer drugs to compensate for these changes, OncoFinder system uses 20 the following assumptions. First, graph of protein-protein interactions in each signaling pathway is considered as two parallel chains of events: one leads to activation of signaling pathways, other—to inhibition of this pathway. Second, the expression level of signal transducer protein in each pathway is considered in dormant state much smaller than in activation state (thereby each signal transducer protein in 25 dormant state has deeply unsaturated state). 
     Thus, the OncoFinder system considers signal transducer protein of each pathway as having equal opportunities cause the activation/inhibition of pathway. Under these assumptions, based on the law of mass action next assessment of pathological changes in the signal pathway (signal outcome, SO) can be proposed, 
     
       
         
           
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     In this equation the multiplication is performed over all the genes of activators and inhibitors of the signal present in the pathway, [AGEL] i  (activator gene expression level) and [RGEL] j  (repressor gene expression level) are expression level of activators gene No i and No j, correspondingly. 
     TThe logarithm for the transition from multiplicative value to additive relative mitogenic significance of cascade (pathway mitogenic strength), which serves to evaluate the degree of pathological changes in the signal pathway: 
       PAS=AMCF p* Σ n NIInp*ARRnp*BTIFn*lg(CNRn)
 
     Here CNRn (cancer(case)-to-normal ratio) is the ratio of expression levels of a gene, encoding a protein n, from individual patient to norm (mean value of the control group). Discrete value BTIF (beyond tolerance interval flag) is calculated as: 
     
       
         
           
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     Discrete value ARR (activator/repressor role) is defined as follows and stored in the database mitogenetic pathways: 
     
       
         
           
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                          
                         pathway 
                          
                         
                             
                         
                          
                         p 
                       
                     
                   
                 
               
             
           
         
       
     
     Discrete value AMCF (activation-to-mitosis conversion factor): 
     
       
         
           
             AMCF 
             = 
             
               { 
               
                 
                   
                     
                       
                         - 
                         1 
                       
                       , 
                       
                         activation 
                          
                         
                             
                         
                          
                         prevents 
                          
                         
                             
                         
                          
                         mitosis 
                       
                     
                   
                 
                 
                   
                     
                       1 
                       , 
                       
                         activation 
                          
                         
                             
                         
                          
                         activates 
                          
                         
                             
                         
                          
                         mitosis 
                       
                     
                   
                 
               
             
           
         
       
     
     Discrete value node involvement index: 
     
       
         
           
             NH 
             = 
             
               { 
               
                 
                   
                     
                       0 
                       , 
                       
                         there 
                          
                         
                             
                         
                          
                         is 
                          
                         
                             
                         
                          
                         no 
                          
                         
                             
                         
                          
                         protein 
                          
                         
                             
                         
                          
                         t 
                          
                         
                             
                         
                          
                         in 
                          
                         
                             
                         
                          
                         the 
                          
                         
                             
                         
                          
                         pathway 
                          
                         
                             
                         
                          
                         p 
                       
                     
                   
                 
                 
                   
                     
                       1 
                       , 
                       
                         there 
                          
                         
                             
                         
                          
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                          
                         
                             
                         
                          
                         protein 
                          
                         
                             
                         
                          
                         t 
                          
                         
                             
                         
                          
                         in 
                          
                         
                             
                         
                          
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                          
                         
                             
                         
                          
                         pathway 
                          
                         
                             
                         
                          
                         p 
                       
                     
                   
                 
               
             
           
         
       
     
     Medical Database Building 
     Data Preparation and Analysis 
     Datasets expression files were downloaded from GEO database. All datasets were required to have information about clinical response of patients to anticancer therapy such as complete response, partial response, no response, stable disease, progressive disease etc. Samples failed to provide this information were excluded from further analyses. For each dataset a table of gene expression profiles of tumor and normal samples was built by R and Bioconductor (www.bioconductor.org/). 
     First step is to quantile normalize the gene expression data by R and Bioconductor. 
     Second step is to put the normalized data to OncoFinder tool and process it with the default OncoFinder parameters: Sigma=2, CNR (cancer/normal ratio of gene expression level) lower limit=0.67, CNR upper limit=1.5. These parameters are used to determine differentially expressed genes in tumor samples compared to normal samples. 
     OncoFinder algorithm: 
     1) counts CNRs to all genes and determines differentially expressed genes
 
2) evaluates the degree of pathological changes in the signaling pathways (PAS)
 
3) evaluates the degree of pathological changes in the metabolic pathways (PAS)
 
     Third step is to divide all samples of patients into two groups: responders and non-responders according to given information in datasets description. 
     Final step is to compare PAS values of responders against PAS values of non-responders. R was used to count correlation test and AUC values. Thresholds for p-value of correlation test and AUC values were p-value &lt;=0.05 and AUC &gt;=0.7. 
     Pathways which passed threshold filters are called marker pathways that significantly differ in responders in comparison to non-responders samples. These marker pathways are used to predict the effectiveness of anticancer therapy for each sample in chosen datasets. 
     Thus, medical database of marker signaling and metabolic pathways for breast cancer is built for 15 anticancer therapies (Table 1 [appended] and table 2). 
     Probability 
     Probabilities of being a responder and a non-responder are built for an individual patient on the basis of PAS values of each marker pathway. 
     Assumption: PAS values of signaling and metabolic pathways are normally distributed. 
     Probability (P) is built as a cumulative density function or distribution function. It returns the area below the given value of “x” or for x=−1, the shaded region in  FIG. 5 . If the given value of “x”&gt;=mean then probability is built as (1−P). Thus, the range of probability is 0 to 0.5. 
     Responsescore 
     At this stage probabilities of being a responder and a non-responder are built for all patients for all marker pathways separately. To arrive to a decision if a patient is a responder or non-responder the ResponseScore is counted. 
     
       
         
           
             ResponseScore 
             = 
             
               
                 
                   
                     
                       Number 
                        
                       
                           
                       
                        
                       of 
                        
                       
                           
                       
                        
                       marker 
                        
                       
                           
                       
                        
                       
                         pathways 
                         · 
                       
                     
                   
                 
                 
                   
                     
                       { 
                       
                         
                           P 
                            
                           
                             ( 
                             responder 
                             ) 
                           
                         
                         &gt; 
                         
                           P 
                            
                           
                             ( 
                             
                               non 
                                
                               
                                 - 
                               
                                
                               responder 
                             
                             ) 
                           
                         
                       
                       } 
                     
                   
                 
               
               
                 Number 
                  
                 
                     
                 
                  
                 of 
                  
                 
                     
                 
                  
                 all 
                  
                 
                     
                 
                  
                 marker 
                  
                 
                     
                 
                  
                 pathways 
               
             
           
         
       
     
     P (responder)—probability of being a responder, P (non-responder)—probability of being a non-responder. 
     If ResponseScore &gt;0.5 a patient is considered to be a responder, otherwise a non-responder. 
     Response Scores for all samples are in supplementary materials. 
     PAS values of marker metabolic pathways are shown in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Datasets characteristics. For each dataset anticancer therapy is presented. For all marker 
               
               
                 signaling pathways AUC values, PAS threshold and Fisher test p-values are counted when a group 
               
               
                 of responders and a group of non-responders to the anticancer therapy are compared. 
               
            
           
           
               
               
               
               
               
               
            
               
                 GEO 
                   
                   
                   
                 PAS 
                 Fisher 
               
               
                 Series ID 
                 Anticancer therapy 
                 Marker pathways 
                 AUC 
                 threshold 
                 test p-value 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 GSE48905 
                 fulvestrant 
                 Cellular Anti Apoptosis Pathway 
                 0.70 
                 −0.64 
                 0.0086 
               
               
                   
                   
                 (Depolarization) 
               
               
                   
                   
                 Estrogen Main Pathway 
                 0.72 
                 −0.66 
                 0.0005 
               
               
                   
                   
                 GPCR Main Pathway 
                 0.70 
                 −3.96 
                 0.0009 
               
               
                   
                   
                 Hedgehog Main Pathway 
                 0.73 
                 4.74 
                 0.0051 
               
               
                   
                   
                 HIF1Alpha Pathway (VEGF pathway) 
                 0.70 
                 0.68 
                 0.0028 
               
               
                   
                   
                 DDR Pathway (NER) 
                 0.71 
                 1.60 
                 0.0128 
               
               
                   
                   
                 Cell Cycle Pathway (End of S-phase) 
                 0.71 
                 2.76 
                 0.0052 
               
               
                 GSE50948 
                 doxorubicin/paclitaxel 
                 HIF1Alpha Pathway (p53 Hypoxia 
                 0.70 
                 −1.06 
                 0.0008 
               
               
                   
                 (AT) followed by 
                 pathway) 
               
               
                   
                 cyclophosphamide/ 
                 JNK Pathway (Apoptosis Inflammation 
                 0.73 
                 1.20 
                 0.0002 
               
               
                   
                 methotrexate/ 
                 Tumorigenesis Cell Migration) 
               
               
                   
                 fluorouracil (CMF) 
               
               
                 GSE22358 
                 docetaxel- 
                 AKT Pathway (ERK Pathway) 
                 0.77 
                 −0.12 
                 0.0052 
               
               
                   
                 capecitabine 
                 AKT Pathway (p53 Degradation) 
                 0.83 
                 −0.92 
                 0.0014 
               
               
                   
                   
                 AKT Pathway (Protein Synthesis) 
                 0.87 
                 0.05 
                 0.0003 
               
               
                   
                   
                 Androgen Receptor Pathway 
                 0.84 
                 −0.55 
                 0.0006 
               
               
                   
                   
                 (Degradation) 
               
               
                   
                   
                 BRCA1 Main Pathway 
                 0.78 
                 0.86 
                 0.0104 
               
               
                   
                   
                 cAMP Pathway (Degradation of Cell 
                 0.72 
                 1.44 
                 0.0195 
               
               
                   
                   
                 Cycle Regulators) 
               
               
                   
                   
                 Caspase Cascade (Apoptosis) 
                 0.80 
                 −0.33 
                 0.0055 
               
               
                   
                   
                 Cellular Anti Apoptosis Pathway 
                 0.81 
                 0.16 
                 0.0060 
               
               
                   
                   
                 (Apoptosis) 
               
               
                   
                   
                 Chemokine Main Pathway 
                 0.75 
                 2.17 
                 0.0134 
               
               
                   
                   
                 EGFR Main Pathway 
                 0.72 
                 0.53 
                 0.0325 
               
               
                   
                   
                 ErbB Family Pathway (Anti-Apoptosis) 
                 0.76 
                 −1.00 
                 0.0098 
               
               
                   
                   
                 Fas Signaling Pathway (Negative) 
                 0.81 
                 2.28 
                 0.0038 
               
               
                   
                   
                 Fas Signaling Pathway (Positive) 
                 0.75 
                 −1.56 
                 0.0308 
               
               
                   
                   
                 GPCR Pathway (Gene expression) 
                 0.78 
                 1.04 
                 0.0096 
               
               
                   
                   
                 GSK3 Main Pathway 
                 0.78 
                 −5.93 
                 0.0265 
               
               
                   
                   
                 GSK3 Pathway (Degradation) 
                 0.85 
                 3.35 
                 0.0001 
               
               
                   
                   
                 HIF1Alpha Pathway (p53 Hypoxia 
                 0.79 
                 0.48 
                 0.0067 
               
               
                   
                   
                 pathway) 
               
               
                   
                   
                 IL-2 Main Pathway 
                 0.79 
                 −0.24 
                 0.0010 
               
               
                   
                   
                 IL-2 Pathway (Actin reorganization) 
                 0.75 
                 0.45 
                 0.0269 
               
               
                   
                   
                 IL-2 Pathway (Protein synthesis) 
                 0.79 
                 0.45 
                 0.0124 
               
               
                   
                   
                 JAK-STAT Main Pathway 
                 0.75 
                 −2.22 
                 0.0055 
               
               
                   
                   
                 Mitochondrial Apoptosis Main Pathway 
                 0.78 
                 7.51 
                 0.0134 
               
               
                   
                   
                 NGF (Positive) Main Pathway 
                 0.77 
                 0.56 
                 0.0094 
               
               
                   
                   
                 p53 (Negative) Main Pathway 
                 0.78 
                 1.10 
                 0.0108 
               
               
                   
                   
                 Telomere Main Pathway 
                 0.89 
                 0.07 
                 0.0001 
               
               
                   
                   
                 Cell Cycle Pathway (SCC during S- 
                 0.79 
                 2.13 
                 0.0094 
               
               
                   
                   
                 phase) 
               
               
                   
                   
                 SMAD (Negative) Main Pathway 
                 0.79 
                 −6.28 
                 0.0081 
               
               
                   
                   
                 SMAD (Positive) Main Pathway 
                 0.79 
                 −6.28 
                 0.0081 
               
               
                   
                   
                 TNF (Negative) Main Pathway 
                 0.80 
                 1.96 
                 0.0094 
               
               
                   
                   
                 TNF (Positive) Main Pathway 
                 0.78 
                 −0.37 
                 0.0108 
               
               
                   
                   
                 TRAF (Positive) Main Pathway 
                 0.82 
                 2.33 
                 0.0044 
               
               
                   
                   
                 Cell Cycle Pathway (End of S-phase) 
                 0.84 
                 −0.67 
                 0.0006 
               
               
                   
                   
                 Ubiquitin Proteasome Main Pathway 
                 0.85 
                 −0.09 
                 0.0007 
               
               
                 GSE23988 
                 5-fluorouracil, 
                 AKT Pathway (Protein Synthesis) 
                 0.71 
                 −2.09 
                 0.0023 
               
               
                   
                 doxorubicin and 
                 ATM Pathway (G2 Mitosis Progression) 
                 0.77 
                 −3.03 
                 0.0003 
               
               
                   
                 cyclophosphamide 
                 ATM Pathway (G2/M Checkpoint 
                 0.72 
                 −1.61 
                 0.0025 
               
               
                   
                 followed by 
                 Arrest) 
               
               
                   
                 4 additional 
                 ATM Pathway (S-Phase Progression) 
                 0.72 
                 −1.07 
                 0.0011 
               
               
                   
                 courses of weekly 
                 Caspase Cascade (Apoptosis) 
                 0.74 
                 −7.37 
                 0.0010 
               
               
                   
                 docetaxel and 
                 DDR pathway Apoptosis 
                 0.74 
                 3.22 
                 0.0010 
               
               
                   
                 capecitabine 
                 G-protein Pathway (Ras family 
                 0.75 
                 3.10 
                 0.0000 
               
               
                   
                   
                 GTPases) 
               
               
                   
                   
                 Mismatch Repair Main Pathway 
                 0.74 
                 8.33 
                 0.0001 
               
               
                   
                   
                 PTEN Main Pathway 
                 0.72 
                 −6.26 
                 0.0009 
               
               
                   
                   
                 Cell Cycle Pathway (Origin of S-phase) 
                 0.77 
                 7.06 
                 0.0009 
               
               
                   
                   
                 Cell Cycle Pathway (End of S-phase) 
                 0.75 
                 3.57 
                 0.0017 
               
               
                 GSE21974 
                 epirubicine 
                 AKT Pathway (Cell Survival) 
                 0.81 
                 −0.33 
                 0.0017 
               
               
                   
                 cyclophosphamide 
                 AKT Pathway (Genetic Stability) 
                 0.76 
                 −10.02 
                 0.0126 
               
               
                   
                 followed by 
                 AKT Pathway (Survival Genes) 
                 0.71 
                 9.80 
                 0.0557 
               
               
                   
                 4 cycles of 
                 ATM Pathway (Cell Survival) 
                 0.71 
                 11.29 
                 0.0058 
               
               
                   
                 docetaxel 
                 ATM Pathway (G2 Mitosis Progression) 
                 0.71 
                 −5.63 
                 0.0063 
               
               
                   
                   
                 ATM Pathway (S-Phase Progression) 
                 0.71 
                 −1.21 
                 0.0237 
               
               
                   
                   
                 cAMP Pathway (Cell Proliferation) 
                 0.74 
                 −0.96 
                 0.0060 
               
               
                   
                   
                 Cellular Anti Apoptosis Pathway 
                 0.85 
                 5.12 
                 0.0006 
               
               
                   
                   
                 (Depolarization) 
               
               
                   
                   
                 Chemokine Main Pathway 
                 0.74 
                 87.18 
                 0.0014 
               
               
                   
                   
                 Cytokine Main Pathway 
                 0.79 
                 7.85 
                 0.0030 
               
               
                   
                   
                 G-protein Pathway (Ras family 
                 0.74 
                 8.76 
                 0.0128 
               
               
                   
                   
                 GTPases) 
               
               
                   
                   
                 Glucocorticoid Receptor Main Pathway 
                 0.76 
                 114.32 
                 0.0010 
               
               
                   
                   
                 Glucocorticoid Receptor Pathway 
                 0.76 
                 84.01 
                 0.0187 
               
               
                   
                   
                 (Inflammatory cytokines) 
               
               
                   
                   
                 IL-2 Main Pathway 
                 0.74 
                 71.81 
                 0.0237 
               
               
                   
                   
                 IL-2 Pathway (Actin reorganization) 
                 0.76 
                 9.39 
                 0.0051 
               
               
                   
                   
                 IL-2 Pathway (Protein synthesis) 
                 0.74 
                 5.80 
                 0.0049 
               
               
                   
                   
                 IL-6 Main Pathway 
                 0.79 
                 60.10 
                 0.0013 
               
               
                   
                   
                 MAPK Family Main Pathway 
                 0.75 
                 168.39 
                 0.0063 
               
               
                   
                   
                 PAK Main Pathway 
                 0.75 
                 140.87 
                 0.0187 
               
               
                   
                   
                 PTEN Main Pathway 
                 0.75 
                 −16.15 
                 0.0128 
               
               
                   
                   
                 STAT3 Main Pathway 
                 0.75 
                 145.49 
                 0.0014 
               
               
                   
                   
                 TRAF (Negative) Main Pathway 
                 0.75 
                 8.97 
                 0.0303 
               
               
                 GSE18728 
                 docetaxel (T) and 
                 AKT Pathway (Cell Cycle Progression) 
                 0.76 
                 4.52 
                 0.0877 
               
               
                   
                 capecitabine (X) 
                 AKT Pathway (Genetic Stability) 
                 0.83 
                 1.52 
                 0.0181 
               
               
                   
                   
                 ATM Pathway (G2 Mitosis Progression) 
                 0.84 
                 0.00 
                 0.0436 
               
               
                   
                   
                 ErbB Family Pathway (Anti-Apoptosis) 
                 0.76 
                 1.37 
                 0.0206 
               
               
                   
                   
                 GSK3 Pathway (Degradation) 
                 0.77 
                 −2.23 
                 0.0573 
               
               
                   
                   
                 HGF Pathway (Cell cycle progression) 
                 0.77 
                 0.68 
                 0.0460 
               
               
                   
                   
                 Notch Main Pathway 
                 0.86 
                 2.12 
                 0.0031 
               
               
                 GSE8465 
                 gemcitabine plus 
                 Cellular Anti Apoptosis Pathway 
                 0.77 
                 −1.79 
                 0.0181 
               
               
                   
                 doxorubicin + 
                 (Apoptosis) 
               
               
                   
                 gemcitabine plus 
                 HGF Main Pathway 
                 0.75 
                 −1.01 
                 0.0181 
               
               
                   
                 cisplatin 
                 IGF1R Pathway (Glucose uptake) 
                 0.80 
                 0.44 
                 0.0063 
               
               
                   
                   
                 Translation Pathway (Regulation of 
                 0.76 
                 0.49 
                 0.0445 
               
               
                   
                   
                 EIF4F activity) 
               
               
                 GSE33658 
                 anastrozole (A), 
                 DDR Pathway (BRCA1-induced 
                 0.97 
                 0.97 
                 0.0152 
               
               
                   
                 fulvestrant (F)/ 
                 responses) 
               
               
                   
                 and gefitinib 
                 Glucocorticoid Receptor Pathway 
                 0.87 
                 5.97 
                 0.0606 
               
               
                   
                   
                 (Inflammatory cytokines) 
               
               
                   
                   
                 IL-2 Pathway (Apoptosis inhibition) 
                 0.80 
                 1.72 
                 0.0606 
               
               
                 GSE37946 
                 trastuzumab 
                 IGF1R Pathway (Glucose uptake) 
                 0.72 
                 −0.63 
                 0.0054 
               
               
                 GSE42822 
                 fluorouracil/epirubicin/ 
                 AKT Pathway (Protein Synthesis) 
                 0.72 
                 −2.16 
                 0.0003 
               
               
                   
                 cyclophosphamide 
                 ATM Pathway (G2 Mitosis Progression) 
                 0.74 
                 −2.51 
                 0.0002 
               
               
                   
                 (FEC) followed by 
                 ATM Pathway (G2/M Checkpoint 
                 0.71 
                 −1.80 
                 0.0005 
               
               
                   
                 four cycles of 
                 Arrest) 
               
               
                   
                 docetaxel/capecitabine 
                 ATM Pathway (S-Phase Progression) 
                 0.71 
                 −1.02 
                 0.0002 
               
               
                   
                   
                 DDR pathway Apoptosis 
                 0.71 
                 4.15 
                 0.0020 
               
               
                   
                   
                 HIF1-Alpha Main Pathway 
                 0.71 
                 12.33 
                 0.0019 
               
               
                   
                   
                 Cell Cycle Pathway (Origin of S-phase) 
                 0.72 
                 3.46 
                 0.0015 
               
               
                 GSE42822 
                 fluorouracil/epirubicin/ 
                 AHR Pathway (AHR Degradation) 
                 0.78 
                 3.05 
                 0.0052 
               
               
                   
                 cyclophosphamide 
                 cAMP Pathway (Axonal Growth) 
                 0.76 
                 −1.53 
                 0.0154 
               
               
                   
                 (FEC) followed by 
                 cAMP Pathway (Glycolysis) 
                 0.76 
                 1.12 
                 0.0048 
               
               
                   
                 four cycles of 
                 CD40 Pathway (Cell Survival) 
                 0.76 
                 −0.27 
                 0.0112 
               
               
                   
                 docetaxel/capecitabine, 
                 Glucocorticoid Receptor Pathway 
                 0.73 
                 3.50 
                 0.0112 
               
               
                   
                 her2+ patients received 
                 (SMAD signaling) 
               
               
                   
                 trastuzumab 
                 IL-2 Pathway (Apoptosis inhibition) 
                 0.74 
                 −4.90 
                 0.0391 
               
               
                   
                   
                 Interferon Main Pathway 
                 0.74 
                 −2.05 
                 0.0149 
               
               
                 GSE41998 
                 cyclophosphamide/ 
                 cAMP Pathway (Myocardial 
                 0.70 
                 8.10 
                 0.0000 
               
               
                   
                 doxorubicin+ 
                 Contraction) 
               
               
                   
                 Ixabepilone 
                 Chemokine Main Pathway 
                 0.74 
                 48.90 
                 0.0000 
               
               
                   
                   
                 Glucocorticoid Receptor Pathway 
                 0.70 
                 24.12 
                 0.0000 
               
               
                   
                   
                 (Inflammatory cytokines) 
               
               
                   
                   
                 IL-2 Main Pathway 
                 0.71 
                 40.09 
                 0.0002 
               
               
                   
                   
                 IL-2 Pathway (Apoptosis inhibition) 
                 0.70 
                 2.60 
                 0.0000 
               
               
                   
                   
                 IL-6 Main Pathway 
                 0.73 
                 40.71 
                 0.0000 
               
               
                   
                   
                 p38 (Negative) Main Pathway 
                 0.71 
                 103.28 
                 0.0001 
               
               
                   
                   
                 p38 (Positive) Main Pathway 
                 0.71 
                 103.28 
                 0.0001 
               
               
                   
                   
                 STAT3 Main Pathway 
                 0.72 
                 46.10 
                 0.0000 
               
               
                   
                   
                 TNF (Negative) Main Pathway 
                 0.74 
                 5.48 
                 0.0000 
               
               
                 GSE32646 
                 paclitaxel 
                 DDR Pathway (BRCA1-induced 
                 0.72 
                 2.94 
                 0.0003 
               
               
                   
                 followed by 5- 
                 responses) 
               
               
                   
                 fluorouracil/epirubicin/ 
                 Chemokine Main Pathway 
                 0.78 
                 30.69 
                 0.0000 
               
               
                   
                 cyclophosphamide 
                 Chemokine Pathway (Internalization 
                 0.71 
                 1.79 
                 0.0001 
               
               
                   
                   
                 Degradation Recycling) 
               
               
                   
                   
                 Fas Signaling Pathway (Negative) 
                 0.71 
                 15.74 
                 0.0002 
               
               
                   
                   
                 Glucocorticoid Receptor Main Pathway 
                 0.74 
                 65.39 
                 0.0000 
               
               
                   
                   
                 IL-2 Main Pathway 
                 0.72 
                 42.76 
                 0.0009 
               
               
                   
                   
                 PTEN Main Pathway 
                 0.70 
                 −19.79 
                 0.0000 
               
               
                   
                   
                 STAT3 Main Pathway 
                 0.71 
                 38.74 
                 0.0008 
               
               
                 GSE22513 
                 paclitaxel/radiation 
                 AKT Main Pathway 
                 0.71 
                 77.60 
                 0.0299 
               
               
                   
                 treatment 
                 AKT Pathway (Genetic Stability) 
                 0.81 
                 0.84 
                 0.0019 
               
               
                   
                   
                 Androgen Receptor Pathway (Cell 
                 0.83 
                 3.22 
                 0.0030 
               
               
                   
                   
                 Survival &amp; Cell Growth) 
               
               
                   
                   
                 ATM Pathway (S-Phase Progression) 
                 0.78 
                 0.00 
                 0.0019 
               
               
                   
                   
                 cAMP Pathway (Cell Proliferation) 
                 0.81 
                 1.83 
                 0.0095 
               
               
                   
                   
                 cAMP Pathway (Cytokines Production) 
                 0.84 
                 0.47 
                 0.0042 
               
               
                   
                   
                 Chemokine Main Pathway 
                 0.86 
                 23.11 
                 0.0002 
               
               
                   
                   
                 Circadian Main Pathway 
                 0.78 
                 −1.10 
                 0.0019 
               
               
                   
                   
                 Cytokine Main Pathway 
                 0.79 
                 3.98 
                 0.0148 
               
               
                   
                   
                 Erythropoeitin Main Pathway 
                 0.75 
                 18.27 
                 0.0292 
               
               
                   
                   
                 FLT3 Main Pathway 
                 0.77 
                 6.80 
                 0.0018 
               
               
                   
                   
                 G-protein Pathway (Ras family 
                 0.81 
                 5.17 
                 0.0084 
               
               
                   
                   
                 GTPases) 
               
               
                   
                   
                 Glucocorticoid Receptor Main Pathway 
                 0.84 
                 31.25 
                 0.0097 
               
               
                   
                   
                 Glucocorticoid Receptor Pathway 
                 0.87 
                 16.10 
                 0.0025 
               
               
                   
                   
                 (Inflammatory cytokines) 
               
               
                   
                   
                 GPCR Pathway (Gene expression) 
                 0.77 
                 9.07 
                 0.0148 
               
               
                   
                   
                 Growth Hormone Main Pathway 
                 0.79 
                 7.45 
                 0.0042 
               
               
                   
                   
                 Growth Hormone Pathway (Gene 
                 0.80 
                 4.01 
                 0.0042 
               
               
                   
                   
                 expression) 
               
               
                   
                   
                 GSK3 Pathway (Degradation) 
                 0.77 
                 −4.92 
                 0.0110 
               
               
                   
                   
                 HIF1-Alpha Main Pathway 
                 0.80 
                 8.44 
                 0.0084 
               
               
                   
                   
                 IL-10 Pathway (Gene expression) 
                 0.83 
                 1.04 
                 0.0025 
               
               
                   
                   
                 IL-10 Pathway (Translational 
                 0.80 
                 0.65 
                 0.0006 
               
               
                   
                   
                 modulation) 
               
               
                   
                   
                 IL-6 Main Pathway 
                 0.81 
                 32.49 
                 0.0034 
               
               
                   
                   
                 JNK Main Pathway 
                 0.76 
                 56.07 
                 0.0292 
               
               
                   
                   
                 MAPK Family Main Pathway 
                 0.93 
                 50.63 
                 0.0002 
               
               
                   
                   
                 DDR pathway (MMR) 
                 0.74 
                 5.75 
                 0.0048 
               
               
                   
                   
                 Mismatch Repair Main Pathway 
                 0.73 
                 14.52 
                 0.0034 
               
               
                   
                   
                 p38 (Negative) Main Pathway 
                 0.74 
                 92.89 
                 0.0148 
               
               
                   
                   
                 p38 (Positive) Main Pathway 
                 0.74 
                 92.89 
                 0.0148 
               
               
                   
                   
                 PAK Main Pathway 
                 0.80 
                 71.17 
                 0.0148 
               
               
                   
                   
                 PPAR Main Pathway 
                 0.73 
                 27.85 
                 0.0581 
               
               
                   
                   
                 STAT3 Main Pathway 
                 0.88 
                 49.96 
                 0.0005 
               
               
                   
                   
                 TGF-beta Main Pathway 
                 0.76 
                 54.16 
                 0.0095 
               
               
                   
                   
                 TRAF (Positive) Main Pathway 
                 0.86 
                 10.89 
                 0.0025 
               
               
                   
                   
                 VEGF Main Pathway 
                 0.84 
                 8.41 
                 0.0019 
               
               
                   
                   
                 Wnt Main Pathway 
                 0.81 
                 37.47 
                 0.0097 
               
               
                 GSE5462 
                 letrozole 
                 Androgen Receptor Pathway (Cell 
                 0.70 
                 2.06 
                 0.0057 
               
               
                   
                   
                 Survival &amp; Cell Growth) 
               
               
                   
                   
                 BRCA1 Main Pathway 
                 0.72 
                 1.13 
                 0.0045 
               
               
                   
               
            
           
         
       
     
     Prediction System Validation 
     Cross validation was done to estimate the accuracy of prediction of ResponseScore value for 15 therapies. 
     The following was done for all samples in analyzed datasets: 
     Each sample was excluded out of analysis one by one; the rest were analyzed as described in data preparation and analysis section. Thus, all samples were predicted to be a responder or non-responder. Given the datasets information (real clinical outcomes) it is easy to detect the accuracy of the prediction system for particular anticancer therapy (Table 3 and table 4). AUC was also counted between real clinical outcomes and predicted clinical outcomes (Table 3 and table 4). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Results of BreastCancerTreatment module&#39;s ability to predict the 
               
               
                 clinical outcome of patients with the use of signaling pathways 
               
            
           
           
               
               
               
               
            
               
                 GEO 
                   
                   
                   
               
               
                 Series ID 
                 Anticancer therapy 
                 AUC 
                 Accuracy 
               
               
                   
               
               
                 GSE18728 
                 docetaxel (T) and capecitabine (X) 
                 0.91 
                 0.83 
               
               
                 GSE21974 
                 epirubicine cyclophosphamide 
                 0.83 
                 0.77 
               
               
                   
                 followed by 4 cycles of docetaxel 
               
               
                 GSE22358 
                 docetaxel-capecitabine 
                 0.89 
                 0.84 
               
               
                 GSE22513 
                 paclitaxel/radiation treatment 
                 0.90 
                 0.81 
               
               
                 GSE23988 
                 5-fluorouracil, doxorubicin and 
                 0.79 
                 0.72 
               
               
                   
                 cyclophosphamide follwed by 
               
               
                   
                 4 additional courses of weekly 
               
               
                   
                 docetaxel and capecitabine 
               
               
                 GSE32646 
                 paclitaxel followed by 5- 
                 0.78 
                 0.69 
               
               
                   
                 fluorouracil/epirubicin/cyclo- 
               
               
                   
                 phosphamide 
               
               
                 GSE33658 
                 anastrozole (A), fulvestrant 
                 0.88 
                 0.80 
               
               
                   
                 (F)/and gefitinib 
               
               
                 GSE37946 
                 Trastuzumab 
                 0.65 
                 0.65 
               
               
                 GSE41998 
                 cyclophosphamide/ 
                 0.75 
                 0.70 
               
               
                   
                 doxorubicin + Ixabepilone 
               
               
                 GSE42822 
                 fluorouracil/epirubicin/cyclo- 
                 0.73 
                 0.69 
               
               
                   
                 phosphamide (FEC) followed 
               
               
                   
                 by four cycles of docetaxel/ 
               
               
                   
                 capecitabine 
               
               
                 GSE42822 
                 fluorouracil/epirubicin/cyclo- 
                 0.89 
                 0.83 
               
               
                   
                 phosphamide (FEC) followed 
               
               
                   
                 by four cycles of docetaxel/ 
               
               
                   
                 capecitabine, her2+ patients 
               
               
                   
                 received trastuzumab 
               
               
                 GSE48905 
                 Fulvestrant 
                 0.72 
                 0.68 
               
               
                 GSE50948 
                 doxorubicin/paclitaxel (AT) 
                 0.77 
                 0.78 
               
               
                   
                 followed by cyclophosphamide/ 
               
               
                   
                 methotrexate/fluorouracil (CMF) 
               
               
                 GSE5462 
                 Letrozole 
                 0.71 
                 0.67 
               
               
                 GSE8465 
                 gemcitabine plus doxorubicin + 
                 0.86 
                 0.83 
               
               
                   
                 gemcitabine plus cisplatin 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Results of BreastCancerTreatment module&#39;s ability 
               
               
                 to predict the clinical outcome of patients with 
               
               
                 the use of signaling and metabolic pathways 
               
            
           
           
               
               
               
               
            
               
                 GEO 
                   
                   
                   
               
               
                 Series ID 
                 Anticancer therapy 
                 AUC 
                 Accuracy 
               
               
                   
               
               
                 GSE23988 
                 5-fluorouracil, doxorubicin and 
                 0.83 
                 0.73 
               
               
                   
                 cyclophosphamide follwed by 4 
               
               
                   
                 additional courses of weekly 
               
               
                   
                 docetaxel and capecitabine 
               
               
                 GSE32646 
                 paclitaxel followed by 5- 
                 0.73 
                 0.81 
               
               
                   
                 fluorouracil/epirubicin/ 
               
               
                   
                 cyclophosphamide 
               
               
                 GSE41998 
                 cyclophosphamide/doxorubicin + 
                 0.73 
                 0.71 
               
               
                   
                 Ixabepilone 
               
               
                 GSE42822 
                 fluorouracil/epirubicin/ 
                 0.81 
                 0.74 
               
               
                   
                 cyclophosphamide (FEC) followed 
               
               
                   
                 by four cycles of docetaxel/ 
               
               
                   
                 capecitabine 
               
               
                 GSE48905 
                 Fulvestrant 
                 0.70 
                 0.70 
               
               
                 GSE5462 
                 Letrozole 
                 0.76 
                 0.61 
               
               
                   
               
            
           
         
       
     
     It is intended to add new, edit and delete unnecessary items in databases. One can edit the contents of a signaling pathways database, genes in signaling pathways, nodes of their graphs, activating and inhibitory connections between them, components of nodes of the signaling pathways graph, as well as anticancer drugs. 
     Reference is now made to  FIG. 4 , which is a simplified flowchart  400  of a method for predicting drug efficacy in a patient, in accordance with an embodiment of the present invention. 
     In a first data obtaining step  402  data is obtained relating to patient responders/non-responders to one or more drugs. Data preparation and analysis—for example, datasets expression files were downloaded from GEO database. All datasets were required to have information about clinical response of patients to anticancer therapy such as complete response, partial response, no response, stable disease, progressive disease etc. Samples failed to provide this information were excluded from further analyses. 
     For each dataset, a table of gene expression profiles of tumor and normal samples is built in a gene expression profile definition step  404 , using any one or more suitable mathematical tool, such as by R and Bioconductor (www.bioconductor.org/). 
     In a normalizing data step  406 , the gene expression profile data from the profile definition step  404  is normalized. 
     Thereafter, the normalized gene profile data is inputted into the OncoFinder tool in a data processing step  408 . The data is processed using, for example, default OncoFinder parameters: Sigma=2, CNR (cancer/normal ratio of gene expression level) lower limit=0.67, CNR upper limit=1.5. These parameters are used to determine differentially expressed genes in tumor samples compared to normal samples. 
     OncoFinder algorithm:
         counts CNRs to all genes and determines differentially expressed genes   evaluates the degree of pathological changes in the signaling pathways (PAS)   evaluates the degree of pathological changes in the metabolic pathways (PAS)       

     Thereafter in a patient dividing step  410 , all samples of patients are divided into two groups: responders and non-responders according to given information in datasets description. 
     In a drug efficacy predication step  412 , the PAS values of responders to PAS values of non-responders are compared. R is used to count correlation test and AUC values. Thresholds for p-value of correlation test and AUC values were p-value&lt;=0.05 and AUC&gt;=0.7. Pathways which pass threshold filters are called marker pathways that significantly differ in responders in comparison to non-responders samples. These marker pathways are used to predict the effectiveness of each drug (such as an anticancer therapy) for each sample in chosen datasets. 
     Final step is to compare PAS values of responders against PAS values of non-responders. AUC was used to detect how well the Oncofinder algorithms separate the group being tested into those who are responders and those who are not. R was used to count correlation test and AUC values. Cut-off values for p-value of correlation test and AUC values were p-value&lt;=0.05 and AUC&gt;=0.7. Pathways which passed threshold filters are called marker pathways that significantly differ in responders in comparison to non-responders samples. These marker pathways are used to predict the effectiveness of anticancer therapy for each sample in chosen datasets. PAS threshold of each marker pathway was detected by Fisher test. PAS threshold of a marker pathway shows the cut-off value such as if PAS value is higher than the threshold a patient is likely to be a responder and vice versa when PAS values of responders of a particular marker pathway is higher compared to non-responders&#39; PAS values. 
     Thus, medical database of marker signaling and metabolic pathways for breast cancer is built for 15 anticancer therapies (Table 1 and table 2). 
     Probability 
     Assumption: PAS values of signaling and metabolic pathways are normally distributed. 
     Probability (P) is built as a cumulative density function or distribution function. It returns the area below the given value of “x” or for x=-1, the shaded region in  FIG. 5 . If the given value of “x” &gt;=mean then probability is built as (1−P). Thus, the range of probability is 0 to 0.5. 
     ResponseScore 
     At this stage probabilities of being a responder and a non-responder are built for all patients for all marker pathways separately. To arrive to a decision if a patient is a responder or non-responder the ResponseScore is counted. 
     
       
         
           
             ResponseScore 
             = 
             
               
                 
                   
                     
                       Number 
                        
                       
                           
                       
                        
                       of 
                        
                       
                           
                       
                        
                       marker 
                        
                       
                           
                       
                        
                       
                         pathways 
                         · 
                       
                     
                   
                 
                 
                   
                     
                       { 
                       
                         
                           P 
                            
                           
                             ( 
                             responder 
                             ) 
                           
                         
                         &gt; 
                         
                           P 
                            
                           
                             ( 
                             
                               non 
                                
                               
                                 - 
                               
                                
                               responder 
                             
                             ) 
                           
                         
                       
                       } 
                     
                   
                 
               
               
                 Number 
                  
                 
                     
                 
                  
                 of 
                  
                 
                     
                 
                  
                 all 
                  
                 
                     
                 
                  
                 marker 
                  
                 
                     
                 
                  
                 pathways 
               
             
           
         
       
     
     P (responder)—probability of being a responder, P (non-responder)—probability of being a non-responder. 
     If ResponseScore&gt;0.5 a patient is considered to be a responder, otherwise a non-responder. 
     Response Scores data for provided examples are in supplementary materials. 
     To improve the prediction power PAS values of marker metabolic pathways were included to analyses (Table 2). 
     Prediction System Validation 
     Cross validation was done to estimate the accuracy of prediction of Response Score value for 15 therapies. 
     The following was done for all samples in analyzed datasets: 
     Each sample was excluded out of analysis one by one; the rest were analyzed as described in data preparation and analysis section. Thus, all samples were predicted to be a responder or non-responder. Given the datasets information (real clinical outcomes) it is easy to detect the accuracy of the prediction system for particular anticancer therapy (Table 3 and table 4). AUC was also counted between real clinical outcomes and predicted clinical outcomes (Table 3 and table 4). 
     EXAMPLES 
     The description for methods of prediction of drug efficacy in a responder/non-responder patient shown in  FIGS. 3-4  are used to in the examples hereinbelow for various non-limiting examples. 
     Structure of Medical Database of Oncofinder 
     1. Nosology 
     1.1. Breast cancer
         1.1.1. Treatment methods
           1.1.1.1. Probability Table
               Table 1. Structure of probability table   No Probability Table   col   1 Sample (data from GEO datasets)   2 Group (Responder or Non-responder)   3 Marker Pathway 1 (probability of being a responder or non-responder)   4 Marker Pathway 2   . . . Marker Pathway N   
               1.1.1.2. PAS1 Table
               Table 2. Structure of PAS1 table   No PAS1 Table   col   1 Marker Pathway   2 Sample 1   3 Sample N   
               1.1.1.3. Graphic Scheme (Responders-nonresponders histogram)   
               

     The Main Menu of Oncofinder System 
     OncoFinder system consists of two main parts - the client and the administrative. 
     For all users personal accounts are created. Profile information is provided by clients. 
     The Client Part of the Breastcancertreatment Module 
     The client part contains menu options &lt;&lt;Biochem Database&gt;&gt;, &lt;&lt;Drugs Database&gt;&gt;, &lt;&lt;Medical Database&gt;&gt;. All clients have their project directories. To work within Medical database project type must be chosen as medical. Within a project one can upload new documents with expression profiles data. 
     File format requirements:
         Accepted file formats are: CSV, TXT, XLS, XLSX with delimeters \t,;   Files must have names in English letters only!   Columns with gene names should be called “SYMBOL”   Columns with Samples must contain “Tumour” in it&#39;s name   Columns with Norms mustt contain “Norm” in it&#39;s name       

     One can add useful information about the data in a description field. 
     All uploaded documents (input) have informational fields:
         Document (document name)   Type (input or output)   Information (Number of samples, number of norms, number of genes(Rows))   Date (Create date, Last calculated at, Last calculated by “User_name”)   Description       

     Processed documents (output) have the same information fields except “Information” field: it contains applied parameters of Oncofinder:
         Pathway DataBase (Human, Mouse, Metabolism)   Normal algorithm (Geometric, Arithmetic)   Use sigma: True (Sigma amount)   Use CNR: True (CNR lower, CNR upper)       

     Treatment methods: 
     1) Letrozole (2.5mg/day per oral) for three months in the neoadjuvant setting
 
2) FEC—DtxCap: neoadjuvant four courses of 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2), given once every 21 days, followed by 12 weeks of docetaxel (35 mg/m2), given once weekly concomitant with capecitabine (850 mg/m2 given twice daily for 14 days, repeated every 21 days)
 
3) Gem+A—Gem+Cis: 4 cycles of gemcitabine 1200 mg/m2 plus doxorubicin 60 mg/m2 (Gem+Dox), then 4 cycles of gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 (Gem+Cis)
 
4) DtxCap: neoadjuvant docetaxel (75 mg/m2 intravenous) on day 1 and capecitabine (1,000 mg/m2 per oral) twice daily on days 2-15 every 21 days for four cycles
 
5) EC—Dtx: 4 cycles of neoadjuvant chemotherapy with epirubicine 90 mg/m2 and cyclophosphamide 600mg/m2 every 3 weeks, followed by 4 cycles of docetaxel 100mg/m2
 
6) DtxCap: neoadjuvant therapy for four 21-day cycles with capecitabine 825 mg/m(2) plus docetaxel 75 mg/m(2)
 
7) Ptx: three cycles of paclitaxel (175 mg/m2 every 3 wk), followed by twice weekly paclitaxel (30 mg/m2) and concurrent radiation.
 
8) Ptx—FEC: paclitaxel (80 mg/m2) weekly for 12 cycles followed by 5-fluorouracil (500 mg/m2), epirubicin (75 mg/m2) and cyclophosphamide (500 mg/m2) every 3 weeks for four cycles
 
9) AFG: neoadjuvant anastrozole 1 mg per oral daily, and fulvestrant 250 mg intramuscular monthly (AF group), or anastrozole 1 mg per oral daily, and fulvestrant 250 mg intramuscular monthly and gefitinib 250 mg per oral daily (AFG group). All patients then received the three drugs (AFG) to complete a total of 4 months from the time of enrollment.
 
10) Neoadjuvant FE+trastuzumab or AC-T+trastuzumab (fluorouracil/epirubicin or Adriamycin/cyclophosphamide-taxol) plus trastuzumab
 
11) AC—Ixabepilone: neoadjuvant therapy with 4 cycles of AC (doxorubicin 60 mg/m2 intravenously and cyclophosphamide 600 mg/m2 intravenously) given every 3 weeks, followed by 4 cycles of ixabepilone (40 mg/m2 3-hour infusion) given every 3 weeks
 
12) FEC—DtxCap: four cycles of 5-fluorouracil/epirubicin/cyclophosphamide followed by four cycles of docetaxel/capecitabine
 
13) FEC—DtxCap+trastuzumab: four cycles of 5-fluorouracil/epirubicin/cyclophosphamide followed by four cycles of docetaxel/capecitabine+trastuzumab
 
14) Fulvestrant 500 mg or 250 mg in the neoadjuvant setting
 
15) AT—CMF: neoadjuvant doxorubicin (60 mg/m2) and paclitaxel (150 mg/m2, every 3 weeks) ×3, followed by cyclophosphamide (600 mg/m2, every 4 weeks), methotrexate (40 mg/m2, every 4 weeks), and fluorouracil (600 mg/m2, every 4 weeks) on days 1 and 8 x3.
 
     Output
         Information (description of the dataset)
           1) Name   2) Number of patients   3) Histological type   4) Grade   5) Hormone receptor status   6) HER2 status   7) Stage   8) Treatment   9) Citation(s)   10) Organization name   
           Probability table
           1) Sample   2) Group (Responder or Non-responder)   3) Marker Pathways   
           PAS 1 Table (PAS values)   Histogram ( FIG. 2 )       

     The Administrative Part of the Breastcancertreatment Module 
     It is intended to add new, edit and delete unnecessary items in databases. You can edit the contents of a signaling pathways database, genes in signaling pathways, nodes of their graphs, activating and inhibitory connections between them, components of nodes of the signaling pathways graph, as well as anticancer drugs. 
     The references cited herein teach many principles that are applicable to the present invention. Therefore the full contents of these publications are incorporated by reference herein where appropriate for teachings of additional or alternative details, features and/or technical background. 
     It is to be understood that the invention is not limited in its application to the details set forth in the description contained herein or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Those skilled in the art will readily appreciate that various modifications and changes can be applied to the embodiments of the invention as hereinbefore described without departing from its scope, defined in and by the appended claims. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Datasets characteristics. For each dataset anticancer therapy is presented. For all 
               
               
                 marker signaling pathways mean PAS values and sd of PAS values are counted for a group of 
               
               
                 responders and a group of non-responders to the anticancer therapy 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 GEO 
                   
                   
                   
                   
                 Non- 
                 Non- 
               
               
                 Series 
                 Anticancer 
                   
                 Responders 
                 Responders 
                 responders 
                 responders 
               
               
                 ID 
                 therapy 
                 Marker pathways 
                 mean 
                 sd 
                 mean 
                 sd 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 GSE48905 
                 fulvestrant 
                 Cellular Anti Apoptosis Pathway (Depolarization) 
                 −0.64 
                 0.58 
                 −0.23 
                 0.48 
               
               
                   
                   
                 Estrogen Main Pathway 
                 3.47 
                 9.72 
                 8.91 
                 5.90 
               
               
                   
                   
                 GPCR Main Pathway 
                 1.56 
                 13.06 
                 10.04 
                 7.36 
               
               
                   
                   
                 Hedgehog Main Pathway 
                 4.17 
                 1.15 
                 3.24 
                 1.06 
               
               
                   
                   
                 HIF1Alpha Pathway (VEGF pathway) 
                 0.45 
                 1.29 
                 1.25 
                 0.92 
               
               
                   
                   
                 DDR Pathway (NER) 
                 4.59 
                 1.72 
                 3.18 
                 2.40 
               
               
                   
                   
                 Cell Cycle Pathway (End of S-phase) 
                 3.24 
                 1.88 
                 1.80 
                 1.86 
               
               
                 GSE50948 
                 doxorubicin/ 
                 HIF1Alpha Pathway (p53 Hypoxia pathway) 
                 −0.89 
                 0.68 
                 −0.30 
                 1.30 
               
               
                   
                 paclitaxel 
                 JNK Pathway (Apoptosis Inflammation 
                 0.83 
                 1.58 
                 1.77 
                 1.42 
               
               
                   
                 (AT) 
                 Tumorigenesis Cell Migration) 
               
               
                   
                 followed by 
               
               
                   
                 cyclophosphamide/ 
               
               
                   
                 methotrexate/ 
               
               
                   
                 fluorouracil 
               
               
                   
                 (CMF) 
               
               
                 GSE22358 
                 docetaxel- 
                 AKT Pathway (ERK Pathway) 
                 0.35 
                 1.60 
                 −1.05 
                 0.95 
               
               
                   
                 capecitabine 
                 AKT Pathway (p53 Degradation) 
                 1.22 
                 1.26 
                 −0.34 
                 1.21 
               
               
                   
                   
                 AKT Pathway (Protein Synthesis) 
                 −0.32 
                 0.57 
                 0.24 
                 0.34 
               
               
                   
                   
                 Androgen Receptor Pathway (Degradation) 
                 −5.86 
                 5.09 
                 −0.49 
                 2.16 
               
               
                   
                   
                 BRCA1 Main Pathway 
                 8.20 
                 5.78 
                 2.94 
                 3.68 
               
               
                   
                   
                 cAMP Pathway (Degradation of Cell Cycle 
                 −0.10 
                 1.22 
                 0.96 
                 1.55 
               
               
                   
                   
                 Regulators) 
               
               
                   
                   
                 Caspase Cascade (Apoptosis) 
                 −1.98 
                 2.25 
                 0.08 
                 1.21 
               
               
                   
                   
                 Cellular Anti Apoptosis Pathway (Apoptosis) 
                 0.52 
                 2.32 
                 −2.13 
                 2.49 
               
               
                   
                   
                 Chemokine Main Pathway 
                 8.25 
                 10.64 
                 −0.56 
                 3.77 
               
               
                   
                   
                 EGFR Main Pathway 
                 −0.22 
                 4.95 
                 −4.83 
                 6.27 
               
               
                   
                   
                 ErbB Family Pathway (Anti-Apoptosis) 
                 0.20 
                 0.58 
                 −0.51 
                 0.87 
               
               
                   
                   
                 Fas Signaling Pathway (Negative) 
                 3.75 
                 3.62 
                 0.15 
                 1.75 
               
               
                   
                   
                 Fas Signaling Pathway (Positive) 
                 1.53 
                 1.74 
                 −0.09 
                 1.81 
               
               
                   
                   
                 GPCR Pathway (Gene expression) 
                 3.24 
                 3.63 
                 0.19 
                 1.56 
               
               
                   
                   
                 GSK3 Main Pathway 
                 −10.51 
                 14.68 
                 2.35 
                 6.51 
               
               
                   
                   
                 GSK3 Pathway (Degradation) 
                 −2.04 
                 5.01 
                 3.98 
                 3.62 
               
               
                   
                   
                 HIF1Alpha Pathway (p53 Hypoxia pathway) 
                 1.60 
                 1.59 
                 0.10 
                 0.79 
               
               
                   
                   
                 IL-2 Main Pathway 
                 5.20 
                 9.64 
                 −2.75 
                 2.11 
               
               
                   
                   
                 IL-2 Pathway (Actin reorganization) 
                 0.51 
                 1.92 
                 −1.20 
                 1.90 
               
               
                   
                   
                 IL-2 Pathway (Protein synthesis) 
                 0.61 
                 1.10 
                 −0.73 
                 1.37 
               
               
                   
                   
                 JAK-STAT Main Pathway 
                 −0.70 
                 2.63 
                 −3.82 
                 3.77 
               
               
                   
                   
                 Mitochondrial Apoptosis Main Pathway 
                 13.60 
                 9.63 
                 4.80 
                 6.11 
               
               
                   
                   
                 NGF (Positive) Main Pathway 
                 0.99 
                 2.73 
                 −1.99 
                 2.77 
               
               
                   
                   
                 p53 (Negative) Main Pathway 
                 1.36 
                 2.94 
                 −1.52 
                 2.29 
               
               
                   
                   
                 Telomere Main Pathway 
                 1.22 
                 1.55 
                 −1.21 
                 1.64 
               
               
                   
                   
                 Cell Cycle Pathway (SCC during S-phase) 
                 2.70 
                 2.15 
                 0.63 
                 1.20 
               
               
                   
                   
                 SMAD (Negative) Main Pathway 
                 −8.57 
                 6.99 
                 −1.15 
                 5.17 
               
               
                   
                   
                 SMAD (Positive) Main Pathway 
                 −8.57 
                 6.99 
                 −1.15 
                 5.17 
               
               
                   
                   
                 TNF (Negative) Main Pathway 
                 2.33 
                 1.91 
                 0.41 
                 1.31 
               
               
                   
                   
                 TNF (Positive) Main Pathway 
                 0.68 
                 4.30 
                 −2.90 
                 1.75 
               
               
                   
                   
                 TRAF (Positive) Main Pathway 
                 4.11 
                 5.18 
                 −0.53 
                 2.05 
               
               
                   
                   
                 Cell Cycle Pathway (End of S-phase) 
                 0.99 
                 1.60 
                 −0.94 
                 1.25 
               
               
                   
                   
                 Ubiquitin Proteasome Main Pathway 
                 4.63 
                 9.53 
                 −4.48 
                 2.93 
               
               
                 GSE23988 
                 5- 
                 AKT Pathway (Protein Synthesis) 
                 −2.51 
                 1.03 
                 −1.84 
                 0.85 
               
               
                   
                 fluorouracil, 
                 ATM Pathway (G2 Mitosis Progression) 
                 −3.66 
                 1.04 
                 −2.52 
                 1.36 
               
               
                   
                 doxorubicin 
                 ATM Pathway (G2/M Checkpoint Arrest) 
                 −5.19 
                 1.68 
                 −3.30 
                 2.76 
               
               
                   
                 and 
                 ATM Pathway (S-Phase Progression) 
                 −2.07 
                 0.86 
                 −1.33 
                 1.01 
               
               
                   
                 cyclophosphamide 
                 Caspase Cascade (Apoptosis) 
                 −8.87 
                 2.70 
                 −6.48 
                 3.30 
               
               
                   
                 followed by 
                 DDR pathway Apoptosis 
                 4.76 
                 3.03 
                 2.55 
                 2.71 
               
               
                   
                 4 additional 
                 G-protein Pathway (Ras family GTPases) 
                 4.78 
                 1.59 
                 3.28 
                 2.03 
               
               
                   
                 courses of 
                 Mismatch Repair Main Pathway 
                 10.18 
                 5.20 
                 5.91 
                 4.22 
               
               
                   
                 weekly 
                 PTEN Main Pathway 
                 −8.99 
                 4.19 
                 −5.81 
                 4.13 
               
               
                   
                 docetaxel 
                 Cell Cycle Pathway (Origin of S-phase) 
                 11.12 
                 7.26 
                 4.64 
                 5.51 
               
               
                   
                 and 
                 Cell Cycle Pathway (End of S-phase) 
                 4.72 
                 3.02 
                 2.10 
                 2.66 
               
               
                   
                 capecitabine 
               
               
                 GSE21974 
                 epirubicine 
                 AKT Pathway (Cell Survival) 
                 −2.24 
                 1.23 
                 −0.33 
                 1.64 
               
               
                   
                 cyclophosphamide 
                 AKT Pathway (Genetic Stability) 
                 −10.03 
                 2.36 
                 −8.16 
                 2.28 
               
               
                   
                 followed by 
                 AKT Pathway (Survival Genes) 
                 8.73 
                 2.52 
                 10.70 
                 2.22 
               
               
                   
                 4 cycles of 
                 ATM Pathway (Cell Survival) 
                 12.18 
                 1.96 
                 13.64 
                 1.62 
               
               
                   
                 docetaxel 
                 ATM Pathway (G2 Mitosis Progression) 
                 −5.32 
                 1.39 
                 −4.23 
                 1.15 
               
               
                   
                   
                 ATM Pathway (S-Phase Progression) 
                 −2.03 
                 1.17 
                 −1.09 
                 1.02 
               
               
                   
                   
                 cAMP Pathway (Cell Proliferation) 
                 −0.11 
                 0.56 
                 −0.83 
                 0.88 
               
               
                   
                   
                 Cellular Anti Apoptosis Pathway (Depolarization) 
                 5.74 
                 0.85 
                 4.62 
                 1.08 
               
               
                   
                   
                 Chemokine Main Pathway 
                 81.89 
                 12.16 
                 71.49 
                 9.00 
               
               
                   
                   
                 Cytokine Main Pathway 
                 9.46 
                 5.83 
                 5.43 
                 4.08 
               
               
                   
                   
                 G-protein Pathway (Ras family GTPases) 
                 9.28 
                 1.73 
                 7.73 
                 1.59 
               
               
                   
                   
                 Glucocorticoid Receptor Main Pathway 
                 114.78 
                 14.66 
                 101.57 
                 9.80 
               
               
                   
                   
                 Glucocorticoid Receptor Pathway (Inflammatory 
                 77.54 
                 12.50 
                 65.46 
                 11.04 
               
               
                   
                   
                 cytokines) 
               
               
                   
                   
                 IL-2 Main Pathway 
                 87.87 
                 17.16 
                 73.52 
                 15.54 
               
               
                   
                   
                 IL-2 Pathway (Actin reorganization) 
                 9.77 
                 2.46 
                 7.54 
                 2.31 
               
               
                   
                   
                 IL-2 Pathway (Protein synthesis) 
                 5.29 
                 2.54 
                 3.55 
                 1.92 
               
               
                   
                   
                 IL-6 Main Pathway 
                 56.54 
                 16.34 
                 41.13 
                 10.78 
               
               
                   
                   
                 Mab targets 
                 34.59 
                 6.70 
                 29.78 
                 5.69 
               
               
                   
                   
                 MAPK Family Main Pathway 
                 162.06 
                 15.18 
                 147.58 
                 14.04 
               
               
                   
                   
                 PAK Main Pathway 
                 133.08 
                 15.18 
                 119.09 
                 15.10 
               
               
                   
                   
                 PTEN Main Pathway 
                 −17.15 
                 2.95 
                 −14.33 
                 3.37 
               
               
                   
                   
                 STAT3 Main Pathway 
                 142.05 
                 25.27 
                 120.57 
                 18.83 
               
               
                   
                   
                 TRAF (Negative) Main Pathway 
                 7.02 
                 1.44 
                 8.38 
                 1.41 
               
               
                 GSE18728 
                 docetaxel 
                 AKT Pathway (Cell Cycle Progression) 
                 3.17 
                 1.39 
                 1.88 
                 1.06 
               
               
                   
                 (T) and 
                 AKT Pathway (Genetic Stability) 
                 3.17 
                 1.39 
                 1.11 
                 1.89 
               
               
                   
                 capecitabine 
                 ATM Pathway (G2 Mitosis Progression) 
                 0.77 
                 0.89 
                 −0.79 
                 1.21 
               
               
                   
                 (X) 
                 ErbB Family Pathway (Anti-Apoptosis) 
                 0.88 
                 0.75 
                 0.22 
                 0.54 
               
               
                   
                   
                 GSK3 Pathway (Degradation) 
                 −4.67 
                 3.43 
                 −1.21 
                 3.18 
               
               
                   
                   
                 HGF Pathway (Cell cycle progression) 
                 0.42 
                 0.48 
                 1.33 
                 0.98 
               
               
                   
                   
                 Notch Main Pathway 
                 1.27 
                 0.76 
                 3.01 
                 1.90 
               
               
                 GSE8465 
                 gemcitabine 
                 Cellular Anti Apoptosis Pathway (Apoptosis) 
                 −1.29 
                 1.77 
                 0.18 
                 1.04 
               
               
                   
                 plus 
                 HGF Main Pathway 
                 2.18 
                 2.66 
                 −0.31 
                 2.33 
               
               
                   
                 doxorubicin + 
                 IGF1R Pathway (Glucose uptake) 
                 0.53 
                 0.39 
                 0.10 
                 0.33 
               
               
                   
                 gemcitabine 
                 Translation Pathway (Regulation of EIF4F 
                 2.86 
                 2.01 
                 0.67 
                 2.19 
               
               
                   
                 plus 
                 activity) 
               
               
                   
                 cisplatin 
               
               
                 GSE33658 
                 anastrozole 
                 DDR Pathway (BRCA1-induced responses) 
                 3.70 
                 1.61 
                 0.51 
                 1.56 
               
               
                   
                 (A), 
                 Glucocorticoid Receptor Pathway (Inflammatory 
                 7.76 
                 3.67 
                 3.14 
                 2.45 
               
               
                   
                 fulvestrant 
                 cytokines) 
               
               
                   
                 (F)/and 
                 IL-2 Pathway (Apoptosis inhibition) 
                 2.08 
                 1.31 
                 0.60 
                 0.38 
               
               
                   
                 gefitinib 
               
               
                 GSE37946 
                 trastuzumab 
                 IGF1R Pathway (Glucose uptake) 
                 −0.82 
                 0.98 
                 −0.01 
                 1.18 
               
               
                 GSE42822 
                 fluorouracil/ 
                 AKT Pathway (Protein Synthesis) 
                 −2.44 
                 0.99 
                 −1.77 
                 0.78 
               
               
                   
                 epirubicin/cyclophosphamide 
                 ATM Pathway (G2 Mitosis Progression) 
                 −3.53 
                 0.93 
                 −2.58 
                 1.28 
               
               
                   
                 (FEC) 
                 ATM Pathway (G2/M Checkpoint Arrest) 
                 −5.09 
                 1.75 
                 −3.36 
                 2.75 
               
               
                   
                 followed by 
                 ATM Pathway (S-Phase Progression) 
                 −1.93 
                 0.80 
                 −1.27 
                 0.98 
               
               
                   
                 four cycles 
                 DDR pathway Apoptosis 
                 4.66 
                 2.73 
                 2.97 
                 2.49 
               
               
                   
                 of 
                 HIF1-Alpha Main Pathway 
                 13.16 
                 4.82 
                 9.96 
                 3.07 
               
               
                   
                 docetaxel/capecitabine 
                 Cell Cycle Pathway (Origin of S-phase) 
                 9.65 
                 6.81 
                 4.91 
                 4.82 
               
               
                 GSE42822 
                 fluorouracil/ 
                 AHR Pathway (AHR Degradation) 
                 1.37 
                 1.08 
                 2.83 
                 2.03 
               
               
                   
                 epirubicin/cyclophosphamide 
                 cAMP Pathway (Axonal Growth) 
                 −1.87 
                 0.58 
                 −1.14 
                 0.87 
               
               
                   
                 (FEC) 
                 cAMP Pathway (Glycolysis) 
                 0.55 
                 0.78 
                 1.83 
                 1.45 
               
               
                   
                 followed by 
                 CD40 Pathway (Cell Survival) 
                 −1.28 
                 1.58 
                 0.13 
                 0.94 
               
               
                   
                 four cycles 
                 Glucocorticoid Receptor Pathway (SMAD 
                 2.25 
                 1.12 
                 3.37 
                 1.32 
               
               
                   
                 of 
                 signaling) 
               
               
                   
                 docetaxel/capecitabine, her2+ 
                 IL-2 Pathway (Apoptosis inhibition) 
                 −3.99 
                 1.85 
                 −2.57 
                 1.35 
               
               
                   
                 patients 
                 Interferon Main Pathway 
                 −0.30 
                 3.56 
                 2.76 
                 3.76 
               
               
                   
                 received 
               
               
                   
                 trastuzumab 
               
               
                 GSE41998 
                 cyclophosphamide/ 
                 cAMP Pathway (Myocardial Contraction) 
                 6.29 
                 2.09 
                 8.69 
                 3.75 
               
               
                   
                 doxorubicin + 
                 Chemokine Main Pathway 
                 60.95 
                 11.54 
                 50.15 
                 13.44 
               
               
                   
                 Ixabepilone 
                 Glucocorticoid Receptor Pathway (Inflammatory 
                 32.67 
                 13.30 
                 24.20 
                 12.54 
               
               
                   
                   
                 cytokines) 
               
               
                   
                   
                 IL-2 Main Pathway 
                 42.77 
                 10.59 
                 35.00 
                 11.08 
               
               
                   
                   
                 IL-2 Pathway (Apoptosis inhibition) 
                 4.92 
                 1.43 
                 3.80 
                 1.69 
               
               
                   
                   
                 IL-6 Main Pathway 
                 48.48 
                 12.20 
                 37.79 
                 13.98 
               
               
                   
                   
                 p38 (Negative) Main Pathway 
                 121.70 
                 25.91 
                 102.32 
                 26.01 
               
               
                   
                   
                 p38 (Positive) Main Pathway 
                 121.70 
                 25.91 
                 102.32 
                 26.01 
               
               
                   
                   
                 STAT3 Main Pathway 
                 67.55 
                 21.75 
                 50.92 
                 21.28 
               
               
                   
                   
                 TNF (Negative) Main Pathway 
                 6.84 
                 2.45 
                 4.70 
                 2.52 
               
               
                 GSE32646 
                 paclitaxel 
                 DDR Pathway (BRCA1-induced responses) 
                 5.80 
                 2.93 
                 3.16 
                 3.44 
               
               
                   
                 followed by 
                 Chemokine Main Pathway 
                 38.47 
                 8.38 
                 30.20 
                 8.40 
               
               
                   
                 5- 
                 Chemokine Pathway (Internalization Degradation 
                 3.40 
                 1.72 
                 2.39 
                 1.45 
               
               
                   
                 fluorouracil/ 
                 Recycling) 
               
               
                   
                 epirubicin/cyclophosphamide 
                 Fas Signaling Pathway (Negative) 
                 17.43 
                 2.49 
                 15.47 
                 3.61 
               
               
                   
                   
                 Glucocorticoid Receptor Main Pathway 
                 64.05 
                 13.08 
                 53.80 
                 10.07 
               
               
                   
                   
                 IL-2 Main Pathway 
                 45.43 
                 12.67 
                 36.78 
                 9.30 
               
               
                   
                   
                 Mab targets 
                 12.50 
                 5.88 
                 8.06 
                 4.37 
               
               
                   
                   
                 PTEN Main Pathway 
                 −21.18 
                 3.39 
                 −18.82 
                 3.97 
               
               
                   
                   
                 STAT3 Main Pathway 
                 52.75 
                 20.87 
                 39.58 
                 14.97 
               
               
                 GSE22513 
                 paclitaxel/radiation 
                 AKT Main Pathway 
                 80.27 
                 15.77 
                 67.73 
                 13.89 
               
               
                   
                 treatment 
                 AKT Pathway (Genetic Stability) 
                 −0.26 
                 1.10 
                 1.42 
                 1.70 
               
               
                   
                   
                 Androgen Receptor Pathway (Cell Survival &amp; Cell 
                 3.71 
                 1.16 
                 2.26 
                 0.86 
               
               
                   
                   
                 Growth) 
               
               
                   
                   
                 ATM Pathway (S-Phase Progression) 
                 −1.26 
                 0.66 
                 −0.30 
                 1.24 
               
               
                   
                   
                 cAMP Pathway (Cell Proliferation) 
                 1.73 
                 0.50 
                 1.17 
                 0.65 
               
               
                   
                   
                 cAMP Pathway (Cytokines Production) 
                 1.38 
                 1.44 
                 0.20 
                 0.40 
               
               
                   
                   
                 Chemokine Main Pathway 
                 28.12 
                 3.54 
                 19.75 
                 7.02 
               
               
                   
                   
                 Circadian Main Pathway 
                 −0.76 
                 0.45 
                 −1.69 
                 1.23 
               
               
                   
                   
                 Cytokine Main Pathway 
                 4.04 
                 2.88 
                 1.64 
                 1.53 
               
               
                   
                   
                 Erythropoeitin Main Pathway 
                 24.01 
                 5.66 
                 18.77 
                 3.81 
               
               
                   
                   
                 FLT3 Main Pathway 
                 6.78 
                 2.83 
                 4.40 
                 2.06 
               
               
                   
                   
                 G-protein Pathway (Ras family GTPases) 
                 7.17 
                 2.06 
                 4.67 
                 2.16 
               
               
                   
                   
                 Glucocorticoid Receptor Main Pathway 
                 38.88 
                 5.58 
                 27.86 
                 8.70 
               
               
                   
                   
                 Glucocorticoid Receptor Pathway (Inflammatory 
                 23.25 
                 6.39 
                 12.89 
                 5.41 
               
               
                   
                   
                 cytokines) 
               
               
                   
                   
                 GPCR Pathway (Gene expression) 
                 8.87 
                 3.66 
                 5.61 
                 2.70 
               
               
                   
                   
                 Growth Hormone Main Pathway 
                 8.40 
                 1.31 
                 6.78 
                 1.86 
               
               
                   
                   
                 Growth Hormone Pathway (Gene expression) 
                 5.09 
                 1.44 
                 2.54 
                 2.58 
               
               
                   
                   
                 GSK3 Pathway (Degradation) 
                 −4.90 
                 2.96 
                 −1.31 
                 3.95 
               
               
                   
                   
                 HIF1-Alpha Main Pathway 
                 12.76 
                 3.06 
                 8.05 
                 4.75 
               
               
                   
                   
                 IL-10 Pathway (Gene expression) 
                 2.70 
                 1.26 
                 0.94 
                 1.71 
               
               
                   
                   
                 IL-10 Pathway (Translational modulation) 
                 1.03 
                 1.52 
                 −0.47 
                 0.72 
               
               
                   
                   
                 IL-6 Main Pathway 
                 27.32 
                 12.87 
                 13.19 
                 8.06 
               
               
                   
                   
                 JNK Main Pathway 
                 65.31 
                 8.49 
                 54.42 
                 10.67 
               
               
                   
                   
                 Mab targets 
                 4.90 
                 1.26 
                 2.82 
                 2.31 
               
               
                   
                   
                 MAPK Family Main Pathway 
                 57.60 
                 6.25 
                 42.53 
                 8.99 
               
               
                   
                   
                 DDR pathway (MMR) 
                 6.10 
                 2.42 
                 4.15 
                 1.87 
               
               
                   
                   
                 Mismatch Repair Main Pathway 
                 11.42 
                 4.81 
                 8.05 
                 3.31 
               
               
                   
                   
                 p38 (Negative) Main Pathway 
                 90.94 
                 17.32 
                 75.11 
                 13.82 
               
               
                   
                   
                 p38 (Positive) Main Pathway 
                 90.94 
                 17.32 
                 75.11 
                 13.82 
               
               
                   
                   
                 PAK Main Pathway 
                 70.69 
                 7.88 
                 59.42 
                 10.50 
               
               
                   
                   
                 PPAR Main Pathway 
                 26.42 
                 3.92 
                 20.75 
                 6.74 
               
               
                   
                   
                 STAT3 Main Pathway 
                 54.01 
                 9.24 
                 37.36 
                 10.65 
               
               
                   
                   
                 TGF-beta Main Pathway 
                 54.63 
                 7.92 
                 45.05 
                 10.23 
               
               
                   
                   
                 TRAF (Positive) Main Pathway 
                 14.07 
                 2.61 
                 9.72 
                 2.77 
               
               
                   
                   
                 VEGF Main Pathway 
                 10.49 
                 2.01 
                 6.36 
                 3.19 
               
               
                   
                   
                 Wnt Main Pathway 
                 44.12 
                 5.11 
                 34.66 
                 9.31 
               
               
                 GSE5462 
                 letrozole 
                 Androgen Receptor Pathway (Cell Survival &amp; 
                 1.74 
                 2.50 
                 3.36 
                 2.53 
               
               
                   
                   
                 Cell Growth) 
               
               
                   
                   
                 BRCA1 Main Pathway 
                 2.04 
                 3.83 
                 5.02 
                 4.18