Abstract | BACKGROUND: METHODS: Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups ( chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not ( chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p<0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant ( chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16). INTERPRETATION: FUNDING: Merck KGaA.
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Authors | Kenneth J O'Byrne, Ulrich Gatzemeier, Igor Bondarenko, Carlos Barrios, Corinna Eschbach, Uwe M Martens, Yevhen Hotko, Cornelius Kortsik, Luis Paz-Ares, Jose R Pereira, Joachim von Pawel, Rodryg Ramlau, Jae-Kyung Roh, Chih-Teng Yu, Christopher Stroh, Ilhan Celik, Armin Schueler, Robert Pirker |
Journal | The Lancet. Oncology
(Lancet Oncol)
Vol. 12
Issue 8
Pg. 795-805
(Aug 2011)
ISSN: 1474-5488 [Electronic] England |
PMID | 21782507
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 Elsevier Ltd. All rights reserved. |
Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Biomarkers, Tumor
- KRAS protein, human
- Proto-Oncogene Proteins
- Vinblastine
- EGFR protein, human
- ErbB Receptors
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
- Cetuximab
- Cisplatin
- Vinorelbine
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Topics |
- Aged
- Antibodies, Monoclonal
(therapeutic use)
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
(therapeutic use)
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Biomarkers, Tumor
- Carcinoma, Non-Small-Cell Lung
(drug therapy, genetics)
- Cetuximab
- Cisplatin
(therapeutic use)
- Clinical Trials, Phase III as Topic
- ErbB Receptors
(genetics)
- Female
- Genetic Predisposition to Disease
- Humans
- Immunohistochemistry
- Lung Neoplasms
(drug therapy, genetics)
- Male
- Neoplasm Staging
- Prognosis
- Proto-Oncogene Proteins
(genetics)
- Proto-Oncogene Proteins p21(ras)
- Retrospective Studies
- Treatment Outcome
- Vinblastine
(analogs & derivatives, therapeutic use)
- Vinorelbine
- ras Proteins
(genetics)
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