Multi-Determinants Analysis of Molecular Alterations for Predicting Clinical Benefit to EGFR-Targeted Monoclonal Antibodies in Colorectal Cancer

• DOI: 10.1371/journal.pone.0007287
• Publication Date: 2009-10-01T17:17:58Z
• Authors: Andrea Sartore-Bi...; Federica Di Nicol...; 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
• Keywords: Adult; Male; Proto-Oncogene Proteins B-raf; Targeted therapy; Epidermal Growth Factor Receptor (EGFR); personalized medicine; cancer biomarkers; RAS; BRAF; Class I Phosphatidylinositol 3-Kinases; Science; Proto-Oncogene Proteins p21(ras); Phosphatidylinositol 3-Kinases; 03 medical and health sciences; 0302 clinical medicine; Proto-Oncogene Proteins; Humans; adult; aged; aged, 80 and over; antibodies, monoclonal; colorectal neoplasms; female; genes, ras; humans; male; middle aged; mutation; pten phosphohydrolase; phosphatidylinositol 3-kinases; proto-oncogene proteins; proto-oncogene proteins b-raf; receptor, epidermal growth factor; retrospective studies; ras proteins; gene expression regulation, neoplastic; agricultural and biological sciences (all); biochemistry, genetics and molecular biology (all); medicine (all); Aged; Retrospective Studies; Aged, 80 and over; Q; R; PTEN Phosphohydrolase; Antibodies, Monoclonal; Middle Aged; 3. Good health; ErbB Receptors; Gene Expression Regulation, Neoplastic; Genes, ras; Mutation; Medicine; Female; Colorectal Neoplasms; Research Article

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.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 > or =2 alterations (p<0.0001). Accordingly, PFS and OS were increasingly worse for patients with tumors harboring none, 1, or > or =2 molecular alteration(s) (p<0.001).When expression of PTEN and mutations of KRAS, BRAF and PIK3CA are concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to anti-EGFR therapies can be identified. We propose to define as 'quadruple negative', the CRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA. Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab-based therapies.