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Annals of Oncology Advance Access originally published online on February 22, 2007
Annals of Oncology 2007 18(4):752-760; doi:10.1093/annonc/mdm003
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© 2007 European Society for Medical Oncology

lung cancer

Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib

FR Hirsch1,2, M Varella-Garcia1, F Cappuzzo1,3, J McCoy4, L Bemis1, AC Xavier1, R Dziadziuszko1, P Gumerlock4, K Chansky4, H West4, AF Gazdar5, L Crino3, DR Gandara4, WA Franklin2 and PA Bunn, Jr1,*

1 Division of Medical Oncology
2 Division of Pathology, Department of Medicine, University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, CO, USA
3 Bellaria Hospital, Div. of Medical Oncology, Via Altura 3, 40139 Bologna, Italy
4 Southwest Oncology Group, 1730 Minor Ave, Ste 1900, Seattle, WA 98101-1468, USA
5 Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593, USA

* Correspondence to: Dr P. A. Bunn Jr, University of Colorado Cancer Center, PO Box 6511, Mail Stop 8117, Aurora, CO 80010, USA. Tel: +1-303-724-3155; Fax: +1-303-724-3162; E-mail: paul.bunn{at}uchsc.edu

Background: Biological markers for optimal selection of patient to epidermal growth factor receptor (EGFR)-targeted therapies are not established in advanced non-small-cell lung cancer (NSCLC).

Patients and methods: EGFR/HER2 gene copy number by FISH, EGFR protein and pAKT expression by immunohistochemistry (IHC) and EGFR and KRAS mutations were tested in 204 gefitinib-treated NSCLC patients.

Results: Increased EGFR and HER2 gene copy number (FISH+), EGFR protein overexpression (IHC+), EGFR mutations and pAKT overexpression were all associated with significantly higher response rates (33%, 29%, 22%, 39% and 20% respectively). EGFR FISH+ (32%) and IHC+ (61%) correlated with improved survival, while EGFR mutations (27%), KRAS mutations (26%) and pAKT expression (69%) did not. In multivariate survival analysis EGFR FISH and IHC were independent predictive markers. EGFR FISH+/IHC+ patients (23%) had a median survival of 21 months versus 6 months for double-negative patients (30%).

Conclusion: Combination of EGFR FISH and IHC is effective predictor for benefit from gefitinib. Patients with double-negative results are unlikely to benefit in western NSCLC populations.

Key words: epidermal growth factor receptor, gefitinib, gene copy number, non-small-cell lung cancer, protein expression

Received for publication August 28, 2006. Revision received November 9, 2006. Accepted for publication January 5, 2007.


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