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Thymidine Phosphorylase Expression ‘Useful’ as Predictive Marker of Response to Capecitabine

Thymidine Phosphorylase Expression ‘Useful’ as Predictive Marker of Response to Capecitabine

SEATTLE-Expression of thymidine phosphorylase (TP), an enzyme involved in capecitabine (Xeloda) metabolism, may be a "useful" predictive marker for response to capecitabine in patients with colorectal cancer. The results of a study using capecitabine plus irinotecan (CPT-11, Camptosar) for first-line treatment of metastatic colorectal cancer were reported by Philip J. Gold, MD, director of clinical research at the Swedish Cancer Institute in Seattle (abstract 3520). "Patients who were TP-positive had a better outcome than patients who were TP-negative, with respect to response and time to tumor progression," Dr. Gold said. A total of 67 previously untreated patients enrolled in the phase II study of oral capecitabine plus irinotecan, which was found to be a "very active regimen," Dr. Gold said. As reported at ASCO 2003 (abstract 1158), the objective response rate for first-line capecitabine/irinotecan was 45% (30 patients). Three Key Enzymes Evaluated
As a part of that study, investigators planned a biomarker analysis to see if expression of certain enzymes correlated with response. The principal investigator for that analysis was Neal J. Meropol, MD, director of the Gastrointestinal Cancer Program and the Gastrointestinal Tumor Risk Assessment Program, Fox Chase Cancer Center, Philadelphia. Specifically, investigators evaluated three key enzymes:

  • thymidylate synthase, the main target of fluoropyrimidine activity; dihydropyrimidine dehydrogenase, responsible for inactivation of fluorouracil (5-FU); and
  • TP, which catalyzes the last step in converting capecitabine to 5-FU, and is expressed to a greater degree in tumor vs normal tissue.
Expression of those three enzymes was evaluated using two different modalities: immunohistochemistry (IHC) and gene expression analysis using reverse transcriptase polymerase chain reaction (RT-PCR). The results of the IHC analysis suggested that TP was a predictive marker. The response rate in TP-positive primary tumors was 65% (22 of 34 patients), vs 27% (4 of 15 patients) in TP-negative primary tumors. Response rate also correlated with TP status in evaluation of metastatic site tumors (61% for TP-positive tumors vs 14% for TP-negative tumors). The RT-PCR analysis confirmed these findings, both for primary and metastatic tumors. For example, investigators found response was more likely in tumors with levels of TP mRNA greater than the mean (86% vs 38%). Neither of the other enzymes evaluated (thymidylate synthase and dihydropyrimidine dehydrogenase) were shown to be predictive of response or time to progression on IHC and RT-PCR analysis. "TP is important in the conversion of capecitabine to 5-FU, so one could postulate that the more TP that's around, the more capecitabine that could get converted into 5-FU and enter the tumor cell," Dr. Gold said. Models Needed
Further investigations will be needed to confirm these results and develop models to integrate TP into the management of colorectal cancer, investigators said. "In the not too distant future, probably within the next 5 to 7 years ... we will be able to run a profile on what [biomarkers] are most relevant, and tailor the therapy," he said. "So if we know a patient has a high TP level in the tumor, [that patient] may be a good candidate to get capecitabinebased therapy."
 
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