title: Predicting response to multidrug regimens in cancer patients using cell line experiments and regularised regression models.
abstract: BACKGROUND
  Patients suffering from cancer are often treated with a range of chemotherapeutic agents, but the treatment efficacy varies greatly between patients. Based on recent popularisation of regularised regression models the goal of this study was to establish workflows for pharmacogenomic predictors of response to standard multidrug regimens using baseline gene expression data and origin specific cell lines. The proposed workflows are tested on diffuse large B-cell lymphoma treated with R-CHOP first-line therapy.
  
  
  METHODS
  First, B-cell cancer cell lines were tested successively for resistance towards the chemotherapeutic components of R-CHOP: cyclophosphamide (C), doxorubicin (H), and vincristine (O). Second, baseline gene expression data were obtained for each cell line before treatment. Third, regularised multivariate regression models with cross-validated tuning parameters were used to generate classifier and predictor based resistance gene signatures (REGS) for the combination and individual chemotherapeutic drugs C, H, and O. Fourth, each developed REGS was used to assign resistance levels to individual patients in three clinical cohorts.
  
  
  RESULTS
  Both classifier and predictor based REGS, for the combination CHO, were of prognostic value. For patients classified as resistant towards CHO the risk of progression was 2.33 (95% CI: 1.6, 3.3) times greater than for those classified as sensitive. Similarly, an increase in the predicted CHO resistance index of 10 was related to a 22% (9%, 36%) increased risk of progression. Furthermore, the REGS classifier performed significantly better than the REGS predictor.
  
  
  CONCLUSIONS
  The regularised multivariate regression models provide a flexible workflow for drug resistance studies with promising potential. However, the gene expressions defining the REGSs should be functionally validated and correlated to known biomarkers to improve understanding of molecular mechanisms of drug resistance.
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. sfl@rn.dk.
authors.forename: Steffen
authors.initials: S
authors.lastname: Falgreen
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. k.dybkaer@rn.dk.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. k.dybkaer@rn.dk.|Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark. k.dybkaer@rn.dk.
authors.forename: Karen
authors.initials: K
authors.lastname: Dybkær
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. khyoung@mdanderson.org.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. zxu3@mdanderson.org.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. tarec.galaly@gmail.com.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. tarec.galaly@gmail.com.
authors.forename: Tarec C
authors.initials: TC
authors.lastname: El-Galaly
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. mabala@rn.dk.
authors.forename: Maria Bach
authors.initials: MB
authors.lastname: Laursen
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. j.boedker@rn.dk.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Bødker
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. makrp@rn.dk.
authors.forename: Malene K
authors.initials: MK
authors.lastname: Kjeldsen
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. alex.schmitz@rn.dk.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmitz
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. nyegaard@hum-gen.au.dk.|Department of Biomedicine, Aarhus University, Aarhus, Denmark. nyegaard@hum-gen.au.dk.
authors.forename: Mette
authors.initials: M
authors.lastname: Nyegaard
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. haej@rn.dk.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. haej@rn.dk.|Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark. haej@rn.dk.
authors.forename: Hans Erik
authors.initials: HE
authors.lastname: Johnsen
authors.affiliation: Department of Haematology, Research Section, Aalborg University Hospital, Sdr. Skovvej 15, 9000, Aalborg, Denmark. martin.boegsted@rn.dk.|Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. martin.boegsted@rn.dk.|Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark. martin.boegsted@rn.dk.
authors.forename: Martin
authors.initials: M
authors.lastname: Bøgsted
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy; D015233:Models, Statistical; D015999:Multivariate Analysis; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D011241:Prednisone / Q000627:therapeutic use; D011379:Prognosis; D012372:ROC Curve; D012044:Regression Analysis; D015203:Reproducibility of Results; D000069283:Rituximab; D012680:Sensitivity and Specificity; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone