Molecular determinants of efficacy for 5-FU-based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy-related genes.

• 5-Fluorouracil (5-FU)-based regimens remain a cornerstone in the treatment of colorectal cancer (CRC). However, the attendant toxicity prevents these regimens from reaching maximum therapeutic potential. In this retrospective analysis, we examined the pretreatment expression of 18 genes in archival tumor bank samples from patients with advanced CRC to determine if one or more of the selected genes showed promise as either a prognostic or predictive marker of 5-FU-based treatment outcomes. One hundred and forty-four CRC patient samples (collected from 1983 to 2004) were analyzed via real-time PCR for gene expression. Univariate analyses were used to correlate gene expression with efficacy and time-to-event variables. Low thymidine phosphorylase (TP), dihydrofolate reductase, dihydropyrimidine dehydrogenase (DPD), excision repair cross-complementing 1 (ERCC1) and thymidylate synthase gene expression were associated with better time-to-progression in the entire population. Low TP, DPD and ERCC1 expression were independently associated with improved overall survival. Low TP gene expression was also predictive of response. This study suggests that TP gene expression in particular is a predictive as well as a prognostic biomarker for advanced CRC patients. Gene panels assessing pretreatment TP, DPD, ERCC1, dihydrofolate reductase and thymidylate synthase gene expression may help improve the therapeutic potential of 5-FU- or other novel antifolate-based regimens. Further analysis of the prognostic or predictive value of these genes in prospective trials in CRC patients seems warranted.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

Nyckelord

Adult

Aged

Aged

80 and over

Antimetabolites

Antineoplastic

therapeutic use

Colorectal Neoplasms

drug therapy

genetics

mortality

DNA-Binding Proteins

genetics

Dihydrouracil Dehydrogenase (NADP)

genetics

Endonucleases

genetics

Female

Fluorouracil

therapeutic use

Humans

Male

Middle Aged

RNA

Messenger

analysis

Retrospective Studies

Thymidine Phosphorylase

genetics

5-FU

ERCC1

Irinotecan

Oxaliplatin

TP

TS

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)