title: Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer.
abstract: Purpose:Even ifRAS-BRAFwild-type andHER2/MET-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence ofKRAS,NRAS, andEGFRextracellular domain mutations as well asHER2/METalterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies.Experimental design:Twenty-twoRAS-BRAFwild-type,HER2/MET-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silverin situhybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples.Results:RASmutations andHER2/METamplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand,BRAFandEGFRectodomain mutations were much rarer. Patients with acquiredMETamplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade.Conclusions:Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC.Clin Cancer Res; 23(10); 2414-22. ©2016 AACR.
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. filippo.pietrantonio@istitutotumori.mi.it.
authors: Filippo
authors: F
authors: Pietrantonio
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|Istituto FIRC di Oncologia Molecolare, Milan, Italy.
authors: Claudio
authors: C
authors: Vernieri
authors: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors: Giulia
authors: G
authors: Siravegna
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Alessia
authors: A
authors: Mennitto
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Rosa
authors: R
authors: Berenato
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Federica
authors: F
authors: Perrone
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Annunziata
authors: A
authors: Gloghini
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Elena
authors: E
authors: Tamborini
authors: Oncologia Medica 1, Istituto Oncologico Veneto-IRCCS, Padova, Italy.
authors: Sara
authors: S
authors: Lonardi
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Federica
authors: F
authors: Morano
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Benedetta
authors: B
authors: Picciani
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Adele
authors: A
authors: Busico
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Chiara Costanza
authors: CC
authors: Volpi
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Antonia
authors: A
authors: Martinetti
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Francesca
authors: F
authors: Battaglin
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Ilaria
authors: I
authors: Bossi
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Alessio
authors: A
authors: Pellegrinelli
authors: Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Massimo
authors: M
authors: Milione
authors: Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy.|University of Pisa, Pisa, Italy.
authors: Chiara
authors: C
authors: Cremolini
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors: Maria
authors: M
authors: Di Bartolomeo
authors: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.
authors: Alberto
authors: A
authors: Bardelli
authors: Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|Department of Oncology, University of Milan, Milan, Italy.
authors: Filippo
authors: F
authors: de Braud
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000097:blood; D000074141:Circulating Tumor DNA / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; D008565:Membrane Proteins; D048493:Proto-Oncogene Proteins B-raf; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; C117307:KRAS protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human; C482119:BRAF protein, human; C579846:NRAS protein, human