title: Concordance of blood- and tumor-based detection of RAS mutations to guide anti-EGFR therapy in metastatic colorectal cancer.
abstract: BACKGROUND
  Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy.
  
  
  METHODS
  A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue.
  
  
  RESULTS
  ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%.
  
  
  CONCLUSIONS
  Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona.|Department of Medical Oncology, Catalan Institute of Oncology, Universitat de Barcelona, L'Hospitalet, Barcelona.
authors.forename: J
authors.initials: J
authors.lastname: Grasselli
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona.|Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: E
authors.initials: E
authors.lastname: Elez
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona.
authors.forename: G
authors.initials: G
authors.lastname: Caratù
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona.
authors.forename: J
authors.initials: J
authors.lastname: Matito
authors.affiliation: Department of Medical Oncology, Catalan Institute of Oncology, Universitat de Barcelona, L'Hospitalet, Barcelona.
authors.forename: C
authors.initials: C
authors.lastname: Santos
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona.|Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: T
authors.initials: T
authors.lastname: Macarulla
authors.affiliation: Department of Medical Oncology, Del Mar University Hospital, Barcelona.
authors.forename: J
authors.initials: J
authors.lastname: Vidal
authors.affiliation: Department of Medical Oncology, Catalan Institute of Oncology, Universitat de Barcelona, L'Hospitalet, Barcelona.
authors.forename: M
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Department of Medical Oncology, Asturias University Hospital, Oviedo.
authors.forename: J M
authors.initials: JM
authors.lastname: Viéitez
authors.affiliation: Department of Medical Oncology, Santa Creu i Sant Pau University Hospital, Barcelona.
authors.forename: D
authors.initials: D
authors.lastname: Paéz
authors.affiliation: Department of Medical Oncology, Son Llatzer University Hospital, Palma de Mallorca.
authors.forename: E
authors.initials: E
authors.lastname: Falcó
authors.affiliation: Department of Medical Oncology, Marques de Valdecilla University Hospital, Santander.
authors.forename: C
authors.initials: C
authors.lastname: Lopez Lopez
authors.affiliation: Department of Medical Oncology, Reina Sofía University Hospital, Córdoba, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Aranda
authors.affiliation: Sysmex Inostics, Mundelein, USA.
authors.forename: F
authors.initials: F
authors.lastname: Jones
authors.affiliation: Sysmex Inostics, Mundelein, USA.
authors.forename: V
authors.initials: V
authors.lastname: Sikri
authors.affiliation: Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona.
authors.forename: P
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona.
authors.forename: R
authors.initials: R
authors.lastname: Fasani
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona.|Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona.
authors.forename: J
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Medical Oncology, Del Mar University Hospital, Barcelona.
authors.forename: C
authors.initials: C
authors.lastname: Montagut
authors.affiliation: Traslational Research Laboratory, Catalan Institute of Oncology, L'Hospitalet, Barcelona.
authors.forename: D
authors.initials: D
authors.lastname: Azuara
authors.affiliation: Department of Medical Oncology, Vall d'Hebron Institute of Oncology, Barcelona.|Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Dienstmann
authors.affiliation: Department of Medical Oncology, Catalan Institute of Oncology, Universitat de Barcelona, L'Hospitalet, Barcelona.
authors.forename: R
authors.initials: R
authors.lastname: Salazar
authors.affiliation: Cancer Genomics Group, Vall d'Hebron Institute of Oncology, Barcelona.
authors.forename: A
authors.initials: A
authors.lastname: Vivancos
mesh_terms: D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D011905:Genes, ras; D006801:Humans; D009154:Mutation; D009362:Neoplasm Metastasis
chemical_list: D066246:ErbB Receptors
keywords: RAS analysis; anti-EGFR therapy; circulating tumor DNA; metastatic colorectal cancer