Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer

Giampietro Gasparini, Fiamma Buttitta, Mario Rosario D'Andrea, Salvatore Tumolo, Angela Buonadonna, Ida Pavese, Stefano Cordio, Michele De Tursi, Stefania Mosconi, Luciano Stumbo, Lara Felicioni, Antonio Marchetti

Research output: Contribution to journalArticle

Abstract

PURPOSE: To improve the selection of advanced colorectal cancer patients to panitumumab by optimizing the assessment of RAS (KRAS-NRAS) mutations. EXPERIMENTAL DESIGN: Using a centralized pyrosequencing RAS assay, we analyzed the tumors of 94 patients, wild-type for KRAS mutations (codons 12 to 13) by Sanger sequencing (SS), treated with panitumumab. RESULTS: By SS analysis, 94 (62%) of 152 patients were wild-type and their objective response rate to panitumumab was 17%. We first optimized the KRAS test, by performing an accurate tissue-dissection step followed by pyrosequencing, a more sensitive method, and found further mutations in 12 (12.8%) cases. Secondly, tumors were subjected to RAS extension analysis (KRAS, exons 3 to 4; NRAS exons 2 to 4) by pyrosequencing that allowed to identify several rare mutations: KRAS codon 61, 5.3%; codon 146, 5.3%; NRAS, 9.5%. Overall, RAS mutation rate was 32.9%. All patients with additional RAS mutations had progressive or stable disease, except 3 patients with mutations at codon 61 of KRAS or NRAS who experienced partial (2 cases) or complete response. By excluding from the analysis 11 cases with mutations at codons 61, no patient was responsive to treatment (P=.021). RAS wild-type versus RAS mutated cases had a significantly better time to progression (P=.044), that resulted improved (p=.004) by excluding codon 61 mutations. CONCLUSION: This study shows that by optimizing the RAS test it is possible to significantly improve the identification of patients who do not gain benefit of panitumumab. Prospective studies are warranted to determine the clinical significance of rare mutations.

Original languageEnglish
Pages (from-to)751-756
Number of pages6
JournalNeoplasia
Volume16
Issue number9
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Cancer Research

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    Gasparini, G., Buttitta, F., D'Andrea, M. R., Tumolo, S., Buonadonna, A., Pavese, I., Cordio, S., De Tursi, M., Mosconi, S., Stumbo, L., Felicioni, L., & Marchetti, A. (2014). Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer. Neoplasia, 16(9), 751-756. https://doi.org/10.1016/j.neo.2014.08.002