Originally published as JCO Early Release 10.1200/JCO.2008.18.2675 on October 27 2008

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Cohort Study of Fatty Acid Synthase Expression and Patient Survival in Colon Cancer

Shuji Ogino, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Gregory J. Kirkner, Andrew T. Chan, Takako Kawasaki, Edward L. Giovannucci, Massimo Loda, Charles S. Fuchs

From the Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School; Department of Pathology, Channing Laboratory, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; Department of Epidemiology, Harvard School of Public Health; and Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA

Corresponding author: Shuji Ogino, MD, PhD, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115; e-mail: shuji_ogino{at}dfci.harvard.edu

Purpose Energy balance seems to be important in the pathogenesis of colon cancer. Fatty acid synthase (FASN) is physiologically regulated by energy balance and is often upregulated in colorectal cancer. Nonetheless, the influence of FASN expression on patient outcome is uncertain.

Patients and Methods Using the database of 647 patients with colon cancer in two independent cohort studies, FASN overexpression was detected in 84 tumors (13%) by immunohistochemistry. Cox proportional hazards models calculated hazard ratios (HRs) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and related tumoral features, including KRAS, BRAF, p53, microsatellite instability and the CpG island methylation phenotype.

Results There were 279 deaths, including 160 colon cancer–specific deaths. FASN overexpression was associated with a significant reduction in colon cancer–specific mortality by both univariate and multivariate analyses (adjusted HR, 0.41; 95% CI, 0.19 to 0.89) and an insignificant trend toward improved overall mortality (adjusted HR, 0.75; 95% CI, 0.50 to 1.13). Notably, the effect of FASN expression on mortality might be different according to body mass index (BMI; P_interaction = .019); the adjusted HR of overall mortality for FASN overexpression was 0.63 (95% CI, 0.39 to 1.02) among patients with BMI less than 27.5 kg/m² and 2.91 (95% CI, 1.19 to 7.12) among those with BMI 27.5 kg/m². Moreover, the adverse effect of moderate overweight/obesity on overall survival was limited to FASN-positive tumors (adjusted HR, 4.10; 95% CI, 1.14 to 14.8; BMI 27.5 kg/m² v < 27.5 kg/m²).

Conclusion Among nonobese patients with colon cancer, tumoral FASN overexpression is associated with improved survival, whereas among moderately overweight or obese patients (BMI 27.5 kg/m²), FASN overexpression may predict a worse outcome.

published online ahead of print at www.jco.org on October 27, 2008

Supported by National Institutes of Health Grants No. P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 (S.O.), and in part by the Bennett Family Fund for Targeted Therapies Research, and by the Entertainment Industry Foundation (EIF) through the EIF National Colorectal Cancer Research Alliance. K.N. was supported by a fellowship grant from the Japanese Society for Promotion of Science.

None of the funding agencies had any role in design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

S.O. had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

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

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