title: Integrated molecular dissection of the epidermal growth factor receptor (EGFR) [corrected] oncogenic pathway to predict response to EGFR-targeted monoclonal antibodies in metastatic colorectal cancer.
abstract: The introduction of KRAS testing as a diagnostic tool to select patients for epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies for metastatic colorectal cancer is widely regarded as a key advance in the field of personalized cancer medicine. Oncologists are now facing emerging issues in the treatment of metastatic colorectal cancer, including: (i) the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients; (ii) the explanation of rare cases of patients carrying KRAS-mutated tumors who have been reported to respond to either cetuximab or panitumumab and (iii) the discovery of mechanisms of secondary resistance to anti-EGFR antibody therapies. Here we discuss the potential role of comprehensive dissection of the key oncogenic nodes in the EGFR signaling cascade to predict resistance and sensitivity to EGFR monoclonal antibodies in metastatic colorectal cancer. Current data suggest that, together with KRAS mutations, the evaluation of BRAF and PIK3CA/PTEN alterations could also be useful for selecting patients with reduced chance to benefit from EGFR-targeted therapy. Furthermore, measuring EGFR gene copy number also appears relevant to positively identify responders. Up until now, each of these markers has been mainly assessed as a single event, often in retrospective analyses and patients' series. As these molecular alterations display overlapping patterns of occurrence, this adds considerable complexity to the drawing of an algorithm suitable for clinical decision-making. We suggest that in the near future comprehensive molecular analysis of the entire oncogenic pathway triggered by the EGFR should be performed, thus enhancing the prediction ability of individual markers.
authors.affiliation: The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy. andrea.sartorebianchi@ospedaleniguarda.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Katia
authors.initials: K
authors.lastname: Bencardino
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Federico
authors.initials: F
authors.lastname: Pozzi
authors.forename: Chiara
authors.initials: C
authors.lastname: Funaioli
authors.forename: Valentina
authors.initials: V
authors.lastname: Gambi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.forename: Andrea
authors.initials: A
authors.lastname: Cassingena
authors.forename: Roberta
authors.initials: R
authors.lastname: Schiavo
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003657:Decision Making; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000276:immunology; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D054316:Biomarkers, Pharmacological; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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