title: Reaching the limits of prognostication in non-small cell lung cancer: an optimized biomarker panel fails to outperform clinical parameters.
abstract: Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.
authors.affiliation: Department of Statistics, TU Dortmund University, Dortmund, Germany.
authors.forename: Marianna
authors.initials: M
authors.lastname: Grinberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Dijana
authors.identifier: 0000-0002-1852-5409
authors.initials: D
authors.lastname: Djureinovic
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Hans Rr
authors.initials: HR
authors.lastname: Brunnström
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Johanna Sm
authors.initials: JS
authors.lastname: Mattsson
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Linnea
authors.initials: L
authors.lastname: La Fleur
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
authors.affiliation: Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden.|Centre for Research and Development, Uppsala University, County Council of Gävleborg, Gävle, Sweden.
authors.forename: Hirsh
authors.initials: H
authors.lastname: Koyi
authors.affiliation: Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden.|Centre for Research and Development, Uppsala University, County Council of Gävleborg, Gävle, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Branden
authors.affiliation: Department of Clinical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ståhle
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Oxleas NHS Foundation Trust, London, UK.|Cognition, Schizophrenia and Imaging Laboratory, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Tracy
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Botling
authors.affiliation: Department of Statistics, TU Dortmund University, Dortmund, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D000075982:Cell Adhesion Molecule-1 / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D011379:Prognosis; D000074482:Thyroid Nuclear Factor 1 / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D000075982:Cell Adhesion Molecule-1; D051272:Glucose Transporter Type 1; D047908:Intracellular Signaling Peptides and Proteins; C492406:NIFK protein, human; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; C495677:SLC2A1 protein, human; D000074482:Thyroid Nuclear Factor 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein