Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer
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)...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558614001080 |
| _version_ | 1828475574758146048 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Giampietro Gasparini |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T06:15:59Z |
| format | Article |
| id | doaj.art-ec0682c3d48543418683dc3b06e25e8f |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-11T06:15:59Z |
| publishDate | 2014-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-ec0682c3d48543418683dc3b06e25e8f2022-12-22T01:17:59ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022014-09-0116975175610.1016/j.neo.2014.08.002Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal CancerGiampietro Gasparini0Fiamma Buttitta1Mario Rosario D'Andrea2Salvatore Tumolo3Angela Buonadonna4Ida Pavese5Stefano Cordio6Michele De Tursi7Stefania Mosconi8Luciano Stumbo9Lara Felicioni10Antonio Marchetti11Department of Oncology, San Filippo Neri Hospital, Rome, ItalyCenter of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, ItalyDepartment of Oncology, San Filippo Neri Hospital, Rome, ItalyOncology Unit Santa Maria degli Angeli, Pordenone, ItalyOncology Unit B IRCCS Centro di Riferimento Oncologico, Aviano, ItalyOncology Unit Ospedale Villa San Pietro Fatebenefratelli, Rome, ItalyOncology Unit Ospedale Garibaldi, Catania, ItalyOncology Unit Department of Clinical and Experimental Science, University of Chieti, Chieti, ItalyOncology Unit Ospedali Riuniti di Bergamo, Bergamo, ItalyDepartment of Oncology, San Filippo Neri Hospital, Rome, ItalyCenter of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, ItalyCenter of Predictive Molecular Medicine, University-Foundation, CeSI Biotech Chieti, ItalyPURPOSE: 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.http://www.sciencedirect.com/science/article/pii/S1476558614001080 |
| spellingShingle | 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 Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer Neoplasia: An International Journal for Oncology Research |
| title | Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer |
| title_full | Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer |
| title_fullStr | Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer |
| title_full_unstemmed | Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer |
| title_short | Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer |
| title_sort | optimizing single agent panitumumab therapy in pre treated advanced colorectal cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558614001080 |
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