Our results demonstrate an association between baseline plasma sTNFR-2, but not CRP or IL-6, and subsequent risk of colorectal cancer. Moreover, the inverse association between regular aspirin and NSAID use on risk of colorectal cancer appeared to be restricted to women with high baseline levels of sTNFR-2. To our knowledge, this study is the first to directly examine the role of sTNFR-2 in relation to risk of colorectal cancer.
Our data support a role for chronic inflammation in the pathogenesis of sporadic colorectal cancer, but suggest that circulating biomarkers of inflammation have varying ability to predict risk of incident cancer. Specifically, we did not find an association between colorectal cancer and CRP or IL-6, consistent with several other studies.18, 21–26
In contrast, prior studies have observed an increased risk of colorectal cancer associated with CRP.15–19
Each of these positive studies examined populations that included a significant proportion of men, with the strongest associations observed in a cohort comprised entirely of male smokers.15
In contrast, our null results for CRP and colorectal cancer were most consistent with those observed in the only other cohort comprised entirely of women.26
Thus, it is possible that some of the divergent results across studies of CRP may be related to sex. In support of this hypothesis, several studies have demonstrated significant differences in the inflammatory marker profile among women compared with men.12, 40
Animal data also demonstrate sex-based differences in cytokines associated with inflammation-related cancers.41
Nonetheless, the precise reasons for the different results for CRP and colorectal cancer across studies remain largely speculative.
Although our results for CRP and IL-6 were null, we did find an association between sTNFR-2 and risk of colorectal cancer. In support of our findings, previous studies in this cohort have shown that sTNFR-2 is associated with risk of coronary heart disease and diabetes mellitus,10, 12, 42
conditions related to systemic inflammation and also associated with risk of colorectal cancer.13, 14
sTNFR-2 is considered a reliable surrogate marker for tumor necrosis factor-α (TNF-α) since it is more stable in stored frozen samples and less influenced by diurnal variation.11, 43–47
Compared with CRP and IL-6, sTNFR-2 may be more strongly associated with colorectal cancer since TNF-α not only independently promotes cellular proliferation and inhibits apoptosis, but is also a key upstream regulator of CRP and IL-6.48
Thus, sTNFR-2 may be a superior marker of the specific pro-inflammatory milieu that predisposes to long-term development of cancer. Moreover, sTNFR-2 may also be a biomarker of deranged insulin resistance pathways through TNF-α-mediated inhibition of insulin signaling. Insulin resistance may represent an independent mechanistic pathway which promotes colorectal carcinogenesis.49
Our results for sTNFR-2 are also consistent with findings from the North Carolina Diet and Health Study (DHS). In this cross-sectional study, TNF-α levels were positively associated with prevalent colorectal adenomas.50
However, our findings contrast with a secondary analysis of a clinical trial of aspirin and/or folic acid in the prevention of recurrent colorectal adenomas. 51
In that study, changes over three years in plasma levels of sTNFR-2 were not associated with adenoma recurrence among high-risk patients with prior adenoma. The discordant findings in the aspirin trial compared with our study or the DHS may reflect the inability of inflammatory markers to determine risk of recurrent adenoma rather than initial adenoma or cancer.
We also observed that initiation of aspirin or NSAIDs was more strongly associated with lower risk of colorectal cancer among women with high levels of baseline sTNFR-2 than among women with low levels of sTNFR-2. This supports the hypothesis that aspirin and NSAIDs, at least in part, reduce risk of colorectal neoplasia through anti-inflammatory pathways. This is consistent with prior findings in this cohort in which we observed that aspirin use specifically reduced risk of colorectal cancers that over-expressed the pro-inflammatory COX-2 (PTGS2) isoenzyme.3
Other data examining the role of inflammatory markers in determining responsiveness to anti-inflammatory drugs are limited. Most prior studies relating anti-inflammatory drug use to inflammatory markers only examined drug exposure at the time of blood collection.15, 16, 18, 19, 21, 50
However, it is difficult to interpret these studies since the concurrent use of aspirin and NSAIDs directly influences the baseline level of inflammatory markers,50, 51
precluding an evaluation of the effect of these drugs according to pre-treatment levels. In the clinical trial of aspirin/folic acid neither baseline levels nor changes in post-treatment levels of sTNFR-2 modified the association of aspirin treatment with risk of recurrent adenoma.51
However, these results may reflect the potential limitation of using sTNFR-2 levels among high-risk patients with established neoplasia. Moreover, the doses of aspirin used by the women in our study (mean=7 standard aspirin tablets/week) were considerably higher than the aspirin dose (81 mg/day) that was effective in preventing recurrence in this randomized trial.1, 52
Finally, sTNFR-2 may influence the effect of aspirin/NSAID use on initial risk of invasive cancer but not recurrent adenoma.
The strengths of our study include its prospective design and high follow-up rate. Our measures of plasma inflammatory markers before diagnosis of cancer minimize potential bias related to elevation of these markers by the cancer itself. Moreover, because our risk estimates were essentially unchanged after excluding cases within 2 years of blood draw, our results are unlikely to be related to occult malignancy. We also had prospectively collected data on aspirin/NSAID use as well as potential lifestyle factors that could confound the relationship between colorectal cancer and inflammation. Notably, our associations between aspirin/NSAID use and risk of colorectal cancer have been validated by the results of randomized control trials.53
Finally, because we obtained data on aspirin/NSAID use both before and after blood collection, we were able to disentangle the effect of concurrent anti-inflammatory drug use on inflammatory marker levels with the specific influence of these drugs on colorectal cancer risk among treatment-naïve individuals.
We acknowledge several limitations to our study. First, we obtained only one baseline measure of inflammatory markers. However, others have shown that these markers are generally consistent over several years among the same individual.25, 54
Moreover, intraindividual variation in levels over time would tend to attenuate our observed associations.54, 55
Second, plasma inflammatory markers are likely to be a relatively non-specific assessment of the tissue-specific inflammatory pathways most relevant for colorectal carcinogenesis. Third, our cohort was comprised entirely of women. Thus, additional studies are needed to generalize our findings to men. Fourth, because our cohort was a case-control study of incident colorectal cancer nested within a prospective cohort, our study design did not permit an examination of adenoma, colorectal cancer-specific mortality, overall mortality, or the adverse consequences of aspirin use. However, we have previously shown significant relationships between aspirin use and risk of adenoma, colorectal-cancer specific mortality, overall mortality, and cardiovascular and gastrointestinal side effects in detailed, separate analyses of the larger cohort.32, 56–59
Finally, we cannot exclude the possibility that our associations with sTNFR-2 may reflect residual confounding resulting from imperfectly measured lifestyle risk factors. However, even if sTNFR-2 is not causally related to colorectal carcinogenesis, this would not diminish its potential as a surrogate biomarker for relevant pro-inflammatory, pro-carcinogenic lifestyle factors or exclude inflammation as a mechanistic basis for colorectal cancer.
In conclusion, plasma sTNFR-2, but not CRP or IL-6 is associated with the development of colorectal cancer. Anti-inflammatory drugs appear to reduce risk of colorectal cancer among women with high baseline levels of sTNFR-2 but not among women with low levels of sTNFR-2. Although these results should be viewed as exploratory and require confirmation, they support a role for chronic inflammation in colorectal cancer pathogenesis and the potential of using inflammatory markers to define subsets of the population that may obtain differential benefit from anti-inflammatory drugs.