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

SEATTLE-Expression ofthymidine phosphorylase (TP), an enzymeinvolved in capecitabine (Xeloda)metabolism, may be a "useful"predictive marker for response tocapecitabine in patients with colorectalcancer. The results of a study usingcapecitabine plus irinotecan (CPT-11,Camptosar) for first-line treatment ofmetastatic colorectal cancer were reportedby Philip J. Gold, MD, directorof clinical research at the Swedish CancerInstitute in Seattle (abstract 3520)."Patients who were TP-positive had abetter outcome than patients who wereTP-negative, with respect to responseand time to tumor progression," Dr.Gold said.A total of 67 previously untreatedpatients enrolled in the phase II studyof oral capecitabine plus irinotecan,which was found to be a "very activeregimen," Dr. Gold said. As reportedat ASCO 2003 (abstract 1158), theobjective response rate for first-linecapecitabine/irinotecan was 45% (30patients).Three Key Enzymes Evaluated
As a part of that study, investigatorsplanned a biomarker analysis tosee if expression of certain enzymescorrelated with response. The principalinvestigator for that analysis wasNeal J. Meropol, MD, director of theGastrointestinal Cancer Program andthe Gastrointestinal Tumor Risk AssessmentProgram, Fox Chase CancerCenter, Philadelphia.Specifically, investigators evaluatedthree key enzymes:

• thymidylate synthase, the maintarget of fluoropyrimidine activity; dihydropyrimidine dehydrogenase,responsible for inactivation offluorouracil (5-FU); and
• TP, which catalyzes the last stepin converting capecitabine to 5-FU,and is expressed to a greater degree intumor vs normal tissue.

Expression of those three enzymeswas evaluated using two different modalities:immunohistochemistry(IHC) and gene expression analysisusing reverse transcriptase polymerasechain reaction (RT-PCR).The results of the IHC analysis suggestedthat TP was a predictive marker.The response rate in TP-positiveprimary tumors was 65% (22 of 34patients), vs 27% (4 of 15 patients) inTP-negative primary tumors. Responserate also correlated with TPstatus in evaluation of metastatic sitetumors (61% for TP-positive tumorsvs 14% for TP-negative tumors).The RT-PCR analysis confirmedthese findings, both for primary andmetastatic tumors. For example, investigatorsfound response was morelikely in tumors with levels of TPmRNA greater than the mean (86% vs38%).Neither of the other enzymes evaluated(thymidylate synthase and dihydropyrimidinedehydrogenase)were shown to be predictive of responseor time to progression on IHCand RT-PCR analysis."TP is important in the conversionof capecitabine to 5-FU, so one couldpostulate that the more TP that'saround, the more capecitabine thatcould get converted into 5-FU andenter the tumor cell," Dr. Gold said.

Models Needed

Further investigations will be neededto confirm these results and developmodels to integrate TP into themanagement of colorectal cancer, investigatorssaid."In the not too distant future, probablywithin the next 5 to 7 years ... wewill be able to run a profile on what[biomarkers] are most relevant, andtailor the therapy," he said. "So if weknow a patient has a high TP level inthe tumor, [that patient] may be agood candidate to get capecitabinebasedtherapy."