Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas

J A McKay, C Lloret, G I Murray, P G Johnston, R Bicknell, F Y Ahmed, J Cassidy, H L McLeod

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

A wide range of tumor response is seen amongst patients with the same stage of colorectal cancer, even with the use of uniform chemotherapy. The significant economic and personal impact of chemotherapy provides the impetus for the identification of markers of response for use in guiding patient treatment. However, practical constraints prevent evaluation of all putative markers in a definitive manner. In this study, the enrichment approach was evaluated by examining the expression of a panel of putative response markers in selected patient populations with advanced colorectal cancer (i.e., those demonstrating the best and the poorest clinical response to a standardized 5-fluorouracil/folinic acid chemotherapy regimen). Patients showing a good response had a significantly increased survival when compared with poor responders (P=0.0013), Markers were then ranked for clinical importance based on differences in expression between the two groups. This allows for the relatively rapid and inexpensive investigation of multiple markers, using defined patient groups. Bcl-2 overexpression in primary colorectal tumor specimens was found to correlate with clinical response of metastatic deposits to chemotherapy (P=0.044), as did the site of the primary tumor (P=0.011). However, no clear association was observed between response status and the other examined factors (p53, PCNA, TP, MMPs 1, 2 or 9, TIMPs 1 or 2, TS, Dukes' stage at initial diagnosis, histological grade, sex or age). This approach has allowed prioritization of markers of clinical response on which larger, statistically definitive studies will be performed.

Original languageEnglish
Pages (from-to)153-158
Number of pages6
JournalInternational Journal of Oncology
Volume17
Publication statusPublished - 2000

Keywords

  • colorectal cancer
  • enrichment approach
  • markers
  • 5-fluorouracil
  • immunohistochemistry
  • MATRIX METALLOPROTEINASES
  • THYMIDYLATE SYNTHASE
  • BCL-2 EXPRESSION
  • BREAST-CANCER
  • PROTEIN OVEREXPRESSION
  • TISSUE INHIBITORS
  • TUMOR
  • P53
  • SURVIVAL
  • ADENOCARCINOMAS

Cite this

Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas. / McKay, J A ; Lloret, C ; Murray, G I ; Johnston, P G ; Bicknell, R ; Ahmed, F Y ; Cassidy, J ; McLeod, H L .

In: International Journal of Oncology, Vol. 17, 2000, p. 153-158.

Research output: Contribution to journalArticle

McKay, J A ; Lloret, C ; Murray, G I ; Johnston, P G ; Bicknell, R ; Ahmed, F Y ; Cassidy, J ; McLeod, H L . / Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas. In: International Journal of Oncology. 2000 ; Vol. 17. pp. 153-158.
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AB - A wide range of tumor response is seen amongst patients with the same stage of colorectal cancer, even with the use of uniform chemotherapy. The significant economic and personal impact of chemotherapy provides the impetus for the identification of markers of response for use in guiding patient treatment. However, practical constraints prevent evaluation of all putative markers in a definitive manner. In this study, the enrichment approach was evaluated by examining the expression of a panel of putative response markers in selected patient populations with advanced colorectal cancer (i.e., those demonstrating the best and the poorest clinical response to a standardized 5-fluorouracil/folinic acid chemotherapy regimen). Patients showing a good response had a significantly increased survival when compared with poor responders (P=0.0013), Markers were then ranked for clinical importance based on differences in expression between the two groups. This allows for the relatively rapid and inexpensive investigation of multiple markers, using defined patient groups. Bcl-2 overexpression in primary colorectal tumor specimens was found to correlate with clinical response of metastatic deposits to chemotherapy (P=0.044), as did the site of the primary tumor (P=0.011). However, no clear association was observed between response status and the other examined factors (p53, PCNA, TP, MMPs 1, 2 or 9, TIMPs 1 or 2, TS, Dukes' stage at initial diagnosis, histological grade, sex or age). This approach has allowed prioritization of markers of clinical response on which larger, statistically definitive studies will be performed.

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