We conducted this study to examine the influence of cyclooxygenase-2 (COX-2, PTGS2) expression on outcome of colon cancer patients. We have found that COX-2 overexpression appears to predict an inferior cancer-specific survival, independent of various clinical and molecular variables. The adverse effect of COX-2 overexpression was consistent across most strata of patient and tumoral characteristics, in particular across the two independent cohort studies. Our data support an adverse effect of COX-2 overexpression on survival of colon cancer patients.
Considerable experimental evidence supports a role of COX-2 in colorectal carcinogenesis (2
). Randomized, placebo-controlled trials have uniformly shown that selective COX-2 inhibitors prevent adenoma recurrence among patients with a prior history of adenoma (5
). COX-2, possibly through production of inflammatory prostaglandins, may regulate angiogenesis, apoptosis, or tumor cell invasiveness (2
). We have previously shown that aspirin use decreases a risk for colon cancers that are positive for COX-2, but not a risk for COX-2-negative cancers, providing additional evidence for a role of COX-2 in colon carcinogenesis (25
Studying molecular alterations and clinical outcome is important in cancer research (41
). Our data support a role of COX-2 in determining biological behavior of colon cancer. COX-2 has been examined as a predictive biomarker in cancer (3
). Previous studies are conflicting regarding prognostic significance of COX-2 in colorectal cancer with some (3
) supporting and others (4
) refuting independent adverse effect of COX-2. These discrepant results are likely due to differences in patient cohorts, COX-2 detection methods, criteria for COX-2 overexpression, and multivariate survival analysis models. Our current study has comprehensively examined the effect of COX-2 on patient survival independent of clinical characteristics and other molecular events, including statuses of p53 alterations, mutations in KRAS
, microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP). All of these molecular events are potential confounders for the association between COX-2 and patient survival.
The relationship between COX-2 overexpression and p53 alteration has been examined previously. In one in vivo
study, inhibition of COX-2 by celecoxib led to p53 activation in colon cancer cells (22
). In other studies, COX-2 expression was inhibited by wild-type p53 in murine embryo cell lines (17
), whereas COX-2 overexpression was induced by p53 and nuclear factor-kappa B (NFKB1) in esophageal and colon cancer cells (23
). It may be possible that COX-2 and p53 regulate each other to form a feedback loop. Thus, it may not be surprising to find a significant interactive effect of COX-2 and p53 alterations on patient survival. This possible interaction of COX-2 and p53 alterations needs to be further examined and confirmed by future studies.
Our study has several advantages including a large number of colon cancers in the two prospective cohort studies with adequate follow-up, as well as extensive data on disease characteristics and other important tumoral molecular events. Thus, we have been able to demonstrate an effect of COX-2 on patient survival, independent of clinical and other tumoral predictors of clinical outcome.
As a limitation of this study, data on cancer treatment are limited in our cohorts. Nonetheless, it is unlikely that chemotherapy use differed according to tumoral COX-2 status, especially since such data were not available to patients or treating physicians. In addition, beyond cause of mortality, data on cancer recurrences were not available in these cohorts. Nonetheless, given the median survival for metastatic colon cancer was approximately 10 to 12 months during much of the time period of this study, colon cancer-specific survival should be a reasonable surrogate for cancer-specific outcomes. Despite the apparent effects of COX-2 expression on colon cancer-specific mortality, the influence of COX-2 on all-cause mortality was considerably attenuated. This is likely due to deaths unrelated to colon cancer in our cohort studies.
There is variability in grading COX-2 expression and presently there is no widely accepted standardized classification scheme. False positive and false negative results are well-known problems in immunohistochemistry. Nonetheless, previous studies have demonstrated that Western and Northern blot analysis highly correlate with immunohistochemical expression of COX-2 (49
), and our classification of COX-2 overexpression resulted in a similar proportion of COX-2 overexpressing tumors as other investigators (3
). Moreover, we assessed COX-2 overexpression through central, blinded review of tumor specimens with rigorous comparison to internal controls with the substantial inter-observer agreement (92%, κ=0.62). Our COX-2 expression data in relation to MSI and CIMP are in agreement with studies by other investigators (18
). Finally, any random misclassification of COX-2 status would have conservatively biased our results toward finding no significant difference in patient survival according to tumoral COX-2 expression.
In conclusion, this large prospective study of colon cancer patients suggests that COX-2 upregulation is independently associated with a worse colon cancer-specific mortality. In addition, when compared to patients with tumors negative for both COX-2 and p53, patients with tumors positive for COX-2 exhibit longer survival regardless of p53 status. Our finding that COX-2 overexpression is associated with poor patient outcome may have significant clinical implications, considering an emerging role of COX-2 and its pathway as chemotherapeutic and chemopreventive targets.