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Increased EGFR Gene Copy Number Detected by Fluorescent In Situ Hybridization Predicts Outcome in Non–Small-Cell Lung Cancer Patients Treated With Cetuximab and Chemotherapy

Fred R. Hirsch, Roy S. Herbst, Christine Olsen, Kari Chansky, John Crowley, Karen Kelly, Wilbur A. Franklin, Paul A. Bunn, Jr, Marileila Varella-Garcia, David R. Gandara

From the Southwest Oncology Group, San Antonio; M.D. Anderson Cancer Center, Houston, TX; University of Colorado Cancer Center, Aurora, CO; University of Kansas Cancer Center, Kansas City, KS; and the University of California Davis Cancer Center, Davis, CA

Corresponding author: Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center, E 17th Ave, Aurora, CO 80010; e-mail: Fred.Hirsch{at}UCHSC.edu

Purpose: Epidermal growth factor receptor (EGFR) gene copy number detected by fluorescent in situ hybridization (FISH) has proven to be useful for selection of non–small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors. Here, we evaluate EGFR FISH as a predictive marker in NSCLC patients receiving the EGFR monoclonal antibody inhibitor cetuximab plus chemotherapy.

Patients and Methods: Two hundred twenty-nine chemotherapy-naive patients with advanced-stage NSCLC were enrolled onto a phase II selection trial evaluating sequential or concurrent chemotherapy (paclitaxel plus carboplatin) with cetuximab.

Results: EGFR FISH was assessable in 76 patients with available tumor tissue and classified as positive (four or more gene copies per cell in 40% of the cells or gene amplification) in 59.2%. Response (complete response/partial response) was numerically higher in FISH-positive (45%) versus FISH-negative (26%) patients (P = .14), whereas disease control rate (complete response/partial response plus stable disease) was statistically superior (81% v 55%, respectively; P = .02). Patients with FISH-positive tumors had a median progression-free survival time of 6 months compared with 3 months for FISH-negative patients (P = .0008). Median survival time was 15 months for the FISH-positive group compared with 7 months for patients who were FISH negative. (P = .04). Furthermore, survival favored FISH-positive patients receiving concurrent therapy.

Conclusion: These results are the first to suggest that EGFR FISH is a predictive factor for selection of NSCLC patients for cetuximab plus chemotherapy. Prospective validation of these findings is warranted.

Supported by the National Cancer Institute Specialized Program for Research Excellence (SPORE) in Lung Cancer Grant No. P50 CA 058187 and the Cancer Center Core Grant No. P30 CA 046934 to the University of Colorado Health Science Center and by Grants No. CA38926 and CA32102 to the Southwest Oncology Group.

Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.