Integrated molecular dissection of the epidermal growth factor receptor (EFGR) oncogenic pathway to predict response to EGFR-targeted monoclonal antibodies in metastatic colorectal cancer

Andrea Sartore-Bianchi, Katia Bencardino, Federica Di Nicolantonio, Federico Pozzi, Chiara Funaioli, Valentina Gambi, Sabrina Arena, Miriam Martini, Simona Lamba, Andrea Cassingena, Roberta Schiavo, Alberto Bardelli, Salvatore Siena

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)19-28
Number of pages10
JournalTargeted Oncology
Volume5
Issue number1
DOIs
Publication statusPublished - Mar 2010

Keywords

  • Biomarkers
  • Colorectal cancer
  • EGFR
  • Monoclonal antibodies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Pharmacology (medical)
  • Medicine(all)

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