title: Strategies to design clinical studies to identify predictive biomarkers in cancer research.
abstract: The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field.
authors.affiliation: Department of Oncology, University Clinic of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IDISNA), Pamplona, Spain. Electronic address: jlgracia@unav.es.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Perez-Gracia
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Sanmamed
authors.affiliation: Division of Oncology and Pathology Department of Clinical Sciences, Lund University, Sweden.
authors.forename: Ana
authors.initials: A
authors.lastname: Bosch
authors.affiliation: Department of Pediatrics and CIMA LAB Diagnostics, University Clinic of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Patiño-Garcia
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: IDISNA and Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martín
authors.affiliation: Department of Oncology, University Clinic of Navarra, Pamplona, Spain.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Fusco
authors.affiliation: Department of Oncology, University Clinic of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Maria Esperanza
authors.initials: ME
authors.lastname: Rodriguez-Ruiz
authors.affiliation: Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.affiliation: Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Prior
authors.affiliation: Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Program in Solid Tumors and Biomarkers, CIMA, University of Navarra, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
authors.affiliation: Department of Hematology and Medical Oncology, Hospital Universitario Morales Meseguer, Universidad Católica San Antonio de Murcia, Murcia, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Gonzalez-Billalabeitia
authors.affiliation: Department of Biochemistry, University Clinic of Navarra, Pamplona, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gonzalez Hernandez
authors.affiliation: Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Páez
authors.affiliation: Department of Medical Oncology, Institut Català d'Oncologia, Barcelona, Spain.
authors.forename: Jose María
authors.initials: JM
authors.lastname: Piulats
authors.affiliation: Department of Oncology, University Clinic of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IDISNA), Pamplona, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gurpide
authors.affiliation: Department of Oncology, University Clinic of Navarra, Pamplona, Spain.
authors.forename: Mapi
authors.initials: M
authors.lastname: Andueza
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: de Velasco
authors.affiliation: Department of Medical Oncology, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pazo
authors.affiliation: Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Grande
authors.affiliation: Chair in Law and the Human Genome, University of the Basque Country, Bizkaia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Nicolas
authors.affiliation: Clinical Pharmacology Service, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, University Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria la Princesa (IP), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Abad-Santos
authors.affiliation: Department of Medical Oncology, HM Hospitales - Centro Integral Oncológico HM Clara Campal, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Garcia-Donas
authors.affiliation: Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain; Program in Solid Tumors and Biomarkers, CIMA, University of Navarra, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Suarez
authors.affiliation: Department of Oncology, Hospital Universitario de la Princesa, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Colomer
authors.affiliation: Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Navarra, Spain; Program in Solid Tumors and Biomarkers, CIMA, University of Navarra, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.affiliation: Department of Oncology, University Clinic of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IDISNA), Pamplona, Spain; Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D035843:Biomedical Research / Q000379:methods* / Q000592:standards; D000068456:Clinical Studies as Topic; D002986:Clinical Trials as Topic; D066246:ErbB Receptors / Q000235:genetics; D006801:Humans; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human
keywords: Biomarkers; Clinical trial design; Extreme phenotypes; Mutation; Rearrangement