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High Gene Expression of TS1, GSTP1, and ERCC1 Are Risk Factors for Survival in Patients Treated with Trimodality Therapy for Esophageal Cancer

¹ Thoracic Oncology Program and ² Division of Cancer Biostatistics, Duke University Medical Center, Durham, North Carolina and ³ Norris Cancer Center, University of Southern California; ⁴ Response Genetics, Inc., Los Angeles, California

Requests for reprints: David H. Harpole, Jr., Thoracic Oncology Program, Duke University Medical Center, Box 3617, Durham, NC 27710. Phone: 919-681-2249; Fax: 919-668-2417; E-mail: Harpo002{at}mc.duke.edu.

Purpose: To assess the relationship between molecular markers associated with chemotherapy resistance and survival in esophageal cancer patients treated with trimodality therapy.

Experimental Design: The original pretreatment formalin-fixed, paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 99 patients treated with concurrent cisplatin plus 5-fluorouracil plus 45 Gy radiation followed by resection at Duke University Medical Center (Durham, NC) from 1986 to 1997. cDNA was derived from the biopsy and analyzed to determine mRNA expression relative to an internal reference gene (ß-actin) using fluorescence-based, real-time reverse transcription-PCR. Possible markers of platinum chemotherapy association [glutathione S-transferase (GSTP1) and excision cross-complementing gene 1 (ERCC1)] and 5-fluorouracil association [thymidylate synthase 1 (TS1)] were measured.

Results: Cox proportional hazards model revealed a significant inverse, linear effect for TS1 with respect to survival (P = 0.007). An inverse relationship between TS1 expression and treatment response was also detected (P 0.001). Univariate analysis identified an association with decreased survival for GSTP1 3.0 (P = 0.05). In multivariate analyses, TS1 >6.0, ERCC1 >3, and GSTP1 >3 were statistically significant predictors of decreased survival (P = 0.007). Additionally, the presence of ERCC1 >3.0 or TS1 >6.0 was associated with an 2-fold increase in the risk of cancer recurrence (P = 0.086 and 0.003, respectively).

Conclusion: The measurement of relative gene expression of molecular markers associated with chemoresistance in endoscopic esophageal tumor biopsies may be a useful tool in assessing outcome in patients with trimodality-treated esophageal cancer. These data should be validated further in larger prospective studies.

Key Words: esophageal cancer • chemoresistance • trimodality therapy

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