title: Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Michele
authors.initials: M
authors.lastname: Nichelatti
authors.forename: Francesca
authors.initials: F
authors.lastname: Molinari
authors.forename: Sara
authors.initials: S
authors.lastname: De Dosso
authors.forename: Piercarlo
authors.initials: P
authors.lastname: Saletti
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cipani
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marrapese
authors.forename: Luca
authors.initials: L
authors.lastname: Mazzucchelli
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.forename: Milo
authors.initials: M
authors.lastname: Frattini
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins