Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 26, No 16 (June 1), 2008: pp. 2690-2698
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.15.5580

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Publisher's Note
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Braun, M. S.
Right arrow Articles by Seymour, M. T.
PubMed
Right arrow Articles by Braun, M. S.
Right arrow Articles by Seymour, M. T.

Predictive Biomarkers of Chemotherapy Efficacy in Colorectal Cancer: Results From the UK MRC FOCUS Trial

Michael S. Braun, Susan D. Richman, Philip Quirke, Catherine Daly, Julian W. Adlard, Faye Elliott, Jennifer H. Barrett, Peter Selby, Angela M. Meade, Richard J. Stephens, Mahesh K.B. Parmar, Matthew T. Seymour

From the Leeds Institute of Molecular Medicine and St James's Institute of Oncology, University of Leeds; the National Cancer Research Institute Colorectal Clinical Studies Group; and the Medical Research Council Clinical Trials Unit, London, United Kingdom

Corresponding author: Matt Seymour, MA, MD, FRCP, St James's Institute of Oncology, St James's University Hospital, Leeds LS9 7TF, United Kingdom; e-mail: matt.seymour{at}leedsth.nhs.uk

Purpose: Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer.

Methods: The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival.

Results: One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, < 10%; moderate, 10% to 50%; or high, > 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio [HR], 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker.

Conclusion: Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.

Supported by the United Kingdom Medical Research Council (FOCUS Trial, ISRCTN 79877428); Cancer Research UK; the Kaberry Fellowship, administered by the Leeds Teaching Hospitals Charitable Foundation; the Bobby Moore Research Fund, administered by Cancer Research UK; Yorkshire Cancer Research, and the Cookridge Hospital Gastrointestinal Cancer Research Unit Fund. The Medical Research Council Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (CR08) trial was funded by the United Kingdom MRC and conducted under the auspices of the United Kingdom National Cancer Research Institute Colorectal Cancer Studies Group, with additional support from Sanofi-Synthelabo, Rhone Poulenc Rorer/Aventis Pharma, Baxter, and Wyeth.

M.S.B. and S.D.R. contributed equally to this work.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: ISRCTN79877428 [controlled-trials.com] .




This article has been cited by other articles:


Home page
JCOHome page
C. J. Allegra and J. K. Benedetti
Don Quixote and the Quest for Personalized Medicine
J. Clin. Oncol., June 1, 2008; 26(16): 2619 - 2620.
[Full Text] [PDF]



About
JCO
 Editorial
Roster
 Advertising
Information
 Librarians &
Institutions
 Rights &
Permissions
 PDA Services

Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online