Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer

Andrea Sartore-Bianchi, Federica Di Nicolantonio, Michele Nichelatti, Francesca Molinari, Sara De Dosso, Piercarlo Saletti, Miriam Martini, Tiziana Cipani, Giovanna Marrapese, Luca Mazzucchelli, Simona Lamba, Silvio Veronese, Milo Frattini, Alberto Bardelli, Salvatore Siena

Research output: Contribution to journalArticlepeer-review

Abstract

Background: KRAS mutations occur in 35-45% of metastatic colorectal cancers (mCRC) and preclude responsiveness to EGFR-targeted therapy with cetuximab or panitumumab. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been found to give rise to resistance. We present a comprehensive analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression in mCRC patients treated with cetuximab or panitumumab, with the aim of clarifying the relative contribution of these molecular alterations to resistance. Methodology/Principal Findings: We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non-responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with ≥2 alterations (p

Original languageEnglish
Article numbere7287
JournalPLoS One
Volume4
Issue number10
DOIs
Publication statusPublished - Oct 2 2009

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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