P27-Kip1 in stage III colon cancer: Implications for outcome following adjuvant chemotherapy in Cancer and Leukemia Group B protocol 89803 Journal Article


Authors: Bertagnolli, M. M.; S.Warren, R.; Niedzwiecki, D.; Mueller, E.; Compton, C. C.; Redston, M.; Hall, M.; Hahn, H. P.; Jewell, S. D.; Mayer, R. J.; Goldberg, R. M.; Saltz, L. B.; Loda, M.
Article Title: P27-Kip1 in stage III colon cancer: Implications for outcome following adjuvant chemotherapy in Cancer and Leukemia Group B protocol 89803
Abstract: Background: In retrospective studies, loss of p27<sup>Kip1</sup> (p27), a cyclin-dependent kinase inhibitor, has been associated with poor prognosis following colorectal cancer treatment. In a prospective study, we validated this relationship in patients enrolled on a trial of adjuvant chemotherapy for stage III colon cancer. Methods: Cancer and Leukemia Group B protocol 89803 randomized 1,264 stage III colon cancer patients to receive weekly bolus 5-fluorouracil/leucovorin or weekly bolus irinotecan, 5-fluo-rouracil, and leucovorin (lFL). The primary end point was overall survival (OS); disease-free survival was a secondary endpoint. Expression of p27 and DNA mismatch repair proteins were determined by immunohistochemistry in primary tumor and normal tissue from paraffin blocks. Data were analyzed using log-rank test. Results: Of 601 tumors analyzed, 207 (34.4%) showed p27 loss, 377 (62.8%) retained p27, and 17 (2.8%) were indeterminate. Patients with p27-negative tumors showed reduced OS [5-year OS 66%: 95% confidence interval (95% CI), 0.59-0.72 versus 75%: 95% CI, 0.70-0.79; log-rank P = 0.021]. This relationship was not influenced by treatment arm. Combination of p27 status with mismatch repair status, however, identified a small subset of patients that may benefit from lFL (n = 36; 5-year disease-free survival 81%: 95% CI, 0.64-0.98 versus 47%: 95% CI, 0.21-0.72; log-rank P = 0.042; 5-year OS 81%: 95% CI, 0.64-0.98 versus 60%: 95% CI, 0.35-0.85; log-rank P = 0.128). Conclusions: Loss of p27 is associated with reduced survival in stage III colon cancer but by itself does not indicate a significant difference in outcome between patients treated lFL or 5-fluorouracil/leucovorin. © 2009 American Association for Cancer Research.
Keywords: adult; controlled study; protein expression; treatment outcome; aged; aged, 80 and over; middle aged; major clinical study; overall survival; clinical trial; mortality; fluorouracil; cancer adjuvant therapy; disease free survival; chemotherapy, adjuvant; cancer staging; neoplasm staging; prospective study; prospective studies; controlled clinical trial; protein depletion; randomized controlled trial; colonic neoplasms; pathology; physiology; irinotecan; chemistry; cyclin dependent kinase inhibitor 1b; folinic acid; cdkn1b protein, human; signal peptide; colon cancer; mismatch repair; adjuvant chemotherapy; colon tumor; microsatellite instability; dna mismatch repair; intracellular signaling peptides and proteins
Journal Title: Clinical Cancer Research
Volume: 15
Issue: 6
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2009-03-15
Start Page: 2116
End Page: 2122
Language: English
DOI: 10.1158/1078-0432.ccr-08-2674
PUBMED: 19276255
PROVIDER: scopus
PMCID: PMC3059545
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus"
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  1. Leonard B Saltz
    791 Saltz