Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer

Francesca Molinari, Lara Felicioni, Michela Buscarino, Sara De Dosso, Fiamma Buttitta, Sara Malatesta, Alessandra Movilia, Marco Luoni, Renzo Boldorini, Oscar Alabiso, Salvatore Girlando, Barbara Soini, Alessandra Spitale, Federica Di Nicolantonio, Piercarlo Saletti, Stefano Crippa, Luca Mazzucchelli, Antonio Marchetti, Alberto Bardelli, Milo Frattini

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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.

Original languageEnglish
Pages (from-to)4901-4914
Number of pages14
JournalClinical Cancer Research
Volume17
Issue number14
DOIs
Publication statusPublished - Jul 15 2011

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Epidermal Growth Factor Receptor
Colorectal Neoplasms
Monoclonal Antibodies
Mutation
Codon
Polymerase Chain Reaction
Phosphatidylinositol 3-Kinases
Research Design
Immunohistochemistry
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer. / Molinari, Francesca; Felicioni, Lara; Buscarino, Michela; De Dosso, Sara; Buttitta, Fiamma; Malatesta, Sara; Movilia, Alessandra; Luoni, Marco; Boldorini, Renzo; Alabiso, Oscar; Girlando, Salvatore; Soini, Barbara; Spitale, Alessandra; Di Nicolantonio, Federica; Saletti, Piercarlo; Crippa, Stefano; Mazzucchelli, Luca; Marchetti, Antonio; Bardelli, Alberto; Frattini, Milo.

In: Clinical Cancer Research, Vol. 17, No. 14, 15.07.2011, p. 4901-4914.

Research output: Contribution to journalArticle

Molinari, F, Felicioni, L, Buscarino, M, De Dosso, S, Buttitta, F, Malatesta, S, Movilia, A, Luoni, M, Boldorini, R, Alabiso, O, Girlando, S, Soini, B, Spitale, A, Di Nicolantonio, F, Saletti, P, Crippa, S, Mazzucchelli, L, Marchetti, A, Bardelli, A & Frattini, M 2011, 'Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer', Clinical Cancer Research, vol. 17, no. 14, pp. 4901-4914. https://doi.org/10.1158/1078-0432.CCR-10-3137
Molinari, Francesca ; Felicioni, Lara ; Buscarino, Michela ; De Dosso, Sara ; Buttitta, Fiamma ; Malatesta, Sara ; Movilia, Alessandra ; Luoni, Marco ; Boldorini, Renzo ; Alabiso, Oscar ; Girlando, Salvatore ; Soini, Barbara ; Spitale, Alessandra ; Di Nicolantonio, Federica ; Saletti, Piercarlo ; Crippa, Stefano ; Mazzucchelli, Luca ; Marchetti, Antonio ; Bardelli, Alberto ; Frattini, Milo. / Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 14. pp. 4901-4914.
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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.",
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T1 - Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer

AU - Molinari, Francesca

AU - Felicioni, Lara

AU - Buscarino, Michela

AU - De Dosso, Sara

AU - Buttitta, Fiamma

AU - Malatesta, Sara

AU - Movilia, Alessandra

AU - Luoni, Marco

AU - Boldorini, Renzo

AU - Alabiso, Oscar

AU - Girlando, Salvatore

AU - Soini, Barbara

AU - Spitale, Alessandra

AU - Di Nicolantonio, Federica

AU - Saletti, Piercarlo

AU - Crippa, Stefano

AU - Mazzucchelli, Luca

AU - Marchetti, Antonio

AU - Bardelli, Alberto

AU - Frattini, Milo

PY - 2011/7/15

Y1 - 2011/7/15

N2 - 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.

AB - 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.

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