p27Kip1 in stage III colon cancer: implications for outcome following adjuvant chemotherapy in cancer and leukemia group B protocol 89803.
BACKGROUND
In retrospective studies, loss of p27(Kip1) (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-fluorouracil, and leucovorin (IFL). The primary endpoint 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 IFL (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 IFL or 5-fluorouracil/leucovorin.
Bertagnolli
Monica M
MM
Brigham and Women's Hospital, Boston, MA 02115, USA. Mbertagnolli@partners.org
Warren
Robert S
RS
Niedzwiecki
Donna
D
Mueller
Elke
E
Compton
Carolyn C
CC
Redston
Mark
M
Hall
Margaret
M
Hahn
Hejin P
HP
Jewell
Scott D
SD
Mayer
Robert J
RJ
Goldberg
Richard M
RM
Saltz
Leonard B
LB
Loda
Massimo
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053843:DNA Mismatch Repair; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis* / Q000502:physiology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D016896:Treatment Outcome
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27