title: Assessment of a HER2 scoring system for colorectal cancer: results from a validation study.
abstract: We sought to develop criteria for ERBB2-positivity (HER2) in colorectal cancer to ensure accurate identification of ERBB2-amplified metastatic colorectal cancer patients suitable for enrollment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2-positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test (N=256) and clinical validation (N=830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2-positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2-positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2-positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.affiliation: Istituto di Candiolo, FPO-IRCCS, Candiolo, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Martino
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.affiliation: Centre Jean Perrin, University of Auvergne, Clermont-Ferrand, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penaullt-Llorca
authors.affiliation: Istituto Europeo Oncologia, Milano, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Istituto di Candiolo, FPO-IRCCS, Candiolo, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Risio
authors.affiliation: Anatomia Patologica, Azienda Ospedale-Università di Padova, Padova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Grigioni
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Bencardino
authors.affiliation: Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Oncologia Medica 1, Istituto Oncologico Veneto - IRCCS, Padova, Italy.
authors.forename: Vittorina
authors.initials: V
authors.lastname: Zagonel
authors.affiliation: Istituto di Candiolo, FPO-IRCCS, Candiolo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Leone
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Noe
authors.affiliation: Seconda Università di Napoli, Napoli, Italy.
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Pinto
authors.affiliation: Ospedale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Labianca
authors.affiliation: Ospedale Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mosconi
authors.affiliation: Ospedale di Bolzano Via Boehler, Bolzano, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Graiff
authors.affiliation: Ospedale Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia, Udine, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Aprile
authors.affiliation: Policlinico Universitario di Cagliari, Monserrato, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Frau
authors.affiliation: Istituto Nazionale Tumori Regina Elena, Roma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Garufi
authors.affiliation: Azienda Ospedaliero-Universitaria Pisana Via Roma, Pisa, Italy.
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.affiliation: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Racca
authors.affiliation: Policlinico Universitario Campus Biomedico, Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Calogero
authors.initials: C
authors.lastname: Lauricella
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Truini
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.|Università degli Studi di Milano, Milano, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.affiliation: Istituto di Candiolo, FPO-IRCCS, Candiolo, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.affiliation: Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milano, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Gambacorta
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000032:analysis; D015179:Colorectal Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods* / Q000592:standards; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D011799:Quinazolines; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D000068878:Trastuzumab
chemical_list: D014408:Biomarkers, Tumor; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human