Cited by 159Colorectal Cancer Treatments and StudiesLung Cancer Treatments and MutationsGenetic factors in colorectal cancer

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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·2011·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-10-3137

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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, MALDI-TOF 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. ©2011 AACR.

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Authors: 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.
Affiliations: Istituto Oncologico della Svizzera Italiana (CH)
Authors' Affiliations: 1Institute of Pathology; 2Ticino Cancer Registry, Locarno, Switzerland; 3Department of Pathology, Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy; 4Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy; 5Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Departments of 6Pathology and 7Oncology, Civil Hospital, Legnano, Italy; Departments of 8Medical Sciences and 9Oncology, University School of Medicine, Novara, Italy; Departments of 10Pathology and 11Medical Oncology, Santa Chiara Hospital, Trento, Italy; and 12FIRC Institute of Molecular Oncology, Milan, Italy
Istituto Cantonale di Patologia (CH)
ORCID: Malatesta, Sara
Boldorini, Renzo
Alabiso, Oscar
Crippa, Stefano
Marchetti, Antonio
Bardelli, Alberto
Frattini, Milo
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2011-07-15
Volume: 17
Issue: 14
Pages: 4901-4914
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-10-3137
OpenAlex: W2135672185
Cited by: 159
References: 51
Citations by year: 2025: 2 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 7 · 2018: 8 · 2017: 11 · 2016: 14 · 2015: 20 · 2014: 27 · 2013: 26 · 2012: 26
FWCI: 13.21
Type: journal article
Language: en
Open access: closed
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords: KRAS mutation, metastatic colorectal cancer, anti-EGFR monoclonal antibody, cetuximab, panitumumab, treatment resistance, BRAF mutation, PIK3CA, PTEN, PI3K signaling, MALDI-TOF mass spectrometry, direct sequencing, predictive biomarkers
MeSH terms: Aged, Antibodies, Monoclonal, Antineoplastic Agents, Base Sequence, Female, Humans, Male, Middle Aged, Mutation, Neoplasm Metastasis, Prognosis, Proto-Oncogene Proteins, Sensitivity and Specificity, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Treatment Outcome, ras Proteins, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins B-raf, PTEN Phosphohydrolase, Kaplan-Meier Estimate, Class I Phosphatidylinositol 3-Kinases, ErbB Receptors

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Increased Detection Sensitivity for KRAS Mutations Enhances the Prediction of Anti-EGFR Monoclonal Antibody Resistance in Metastatic Colorectal Cancer

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