Originally published as JCO Early Release 10.1200/JCO.2005.04.3224 on February 27 2006

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Use of Cigarette-Smoking History to Estimate the Likelihood of Mutations in Epidermal Growth Factor Receptor Gene Exons 19 and 21 in Lung Adenocarcinomas

DuyKhanh Pham, Mark G. Kris, Gregory J. Riely, Inderpal S. Sarkaria, Tiffani McDonough, Shaokun Chuai, Ennapadam S. Venkatraman, Vincent A. Miller, Marc Ladanyi, William Pao, Richard K. Wilson, Bhuvanesh Singh, Valerie W. Rusch

From the Departments of Surgery, Medicine, Epidemiology and Biostatistics, and Pathology, Memorial Sloan-Kettering Cancer Center; Weill Medical College of Cornell University, New York, NY; and the Genome Sequencing Center, Washington University, St Louis, MO.

Address reprint requests to Mark G. Kris, MD, Memorial Hospital, 1275 York Avenue, New York, NY 10021

PURPOSE: Lung adenocarcinomas with mutations in exons 19 and 21 of the epidermal growth factor receptor gene (EGFR) demonstrate sensitivity to gefitinib or erlotinib. Investigators have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with the highest incidence of mutations seen in never smokers.

METHODS: EGFR exon 19 and 21 mutation status was determined in 265 tumor samples using direct sequencing, polymerase chain reaction (PCR), or PCR-based restriction fragment length polymorphism analysis. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit 1 year ago), or current smokers (quit < 1 year ago).

RESULTS: We detected EGFR mutations in 34 (51%) of 67 never smokers (95% CI, 38% to 64%), 29 (19%) of 151 former smokers (95% CI, 13% to 27%), and two (4%) of 47 current smokers (95% CI, 1% to 16%). Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P < .001) or stopped smoking less than 25 years ago (P < .02) compared with individuals who never smoked. The number of smoking pack-years and smoke-free years predicted the prevalence of EGFR mutations (areas under receiver operating characteristic curve = 0.78 and 0.77, respectively).

CONCLUSION: The likelihood of EGFR mutations in exons 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 25 years ago. These data can assist clinicians in assessing the likelihood of exon 19 and 21 EGFR mutations in patients with lung adenocarcinoma when mutational analysis is not feasible.

Supported in part by Genentech Inc, the Steps for Breath Lung Cancer Research Program of the Society of Memorial Sloan-Kettering, and the Carmel Hill Fund.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

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

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