Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer
Articolo
Data di Pubblicazione:
2011
Abstract:
Purpose: KRAS mutations represent the main cause of resistance to anti-epidermal growth factor
receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). We evaluated
whether highly sensitive methods for KRAS investigation improve the accuracy of predictions of anti-EGFR
MoAbs efficacy.
Experimental Design: We retrospectively evaluated objective tumor responses in mCRC patients treated
with cetuximab or panitumumab. KRAS codons 12 and 13 were examined by direct sequencing, MALDITOF
MS, mutant-enriched PCR, and engineered mutant-enriched PCR, which have a sensitivity of 20%,
10%, 0.1%, and 0.1%, respectively. In addition, we analyzed KRAS codon 61, BRAF, and PIK3CA by direct
sequencing and PTEN expression by immunohistochemistry.
Results: In total, 111 patients were considered. Direct sequencing revealed mutations in codons 12 and
13 of KRAS in 43/111 patients (39%) and BRAF mutations in 9/111 (8%), with almost all of these
occurring in nonresponder patients. Using highly sensitive methods, we identified up to 13 additional
KRAS mutations compared with direct sequencing, all occurring in nonresponders. By analyzing PIK3CA
and PTEN, we found that of these 13 patients, 7 did not show any additional alteration in the PI3K
pathway.
Conclusions: The application of highly sensitive methods for the detection of KRAS mutations
significantly improves the identification of mCRC patients resistant to anti-EGFR MoAbs. Clin Cancer
Res; 17(14); 4901–14.
Tipologia CRIS:
03A-Articolo su Rivista
Elenco autori:
Molinari F*; Felicioni L*; Buscarino M*; De Dosso S; Buttitta F; Malatesta S; Movilia A; Luoni M; Boldorini R; Alabisio O; Girlando S; Soini B; Spitale A; Di Nicolantonio F; Saletti P; Crippa S; Mazzucchelli L; Marchetti A; Bardelli A;† Frattini M† (*Shared first authorship - †Co-Senior authors)
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