We found that tumor PIK3CA mutation and regular use of aspirin after diagnosis had a significant interactive effect on survival among patients with colorectal cancer. Specifically, among patients with mutated-PIK3CA tumors, regular use of aspirin after diagnosis was associated with significantly increased survival. In contrast, patients with wild-type PIK3CA tumors did not appear to derive a benefit from aspirin use after diagnosis. In addition, the effect of aspirin appeared to be most pronounced in patients who had tumors with both PIK3CA mutation and PTGS2 expression. Our data support the hypothesis that aspirin use after diagnosis may have a differential effect on survival, depending on the presence or absence of tumor PIK3CA mutation.
Our data suggest that regular use of aspirin is suitable for testing as an adjuvant treatment in patients with mutated-PIK3CA
cancers and that PIK3CA
mutation status may serve as a tumor biomarker that predicts the response to adjuvant aspirin treatment. Our data also suggest that even relatively low doses of aspirin may prolong survival among patients with mutated-PIK3CA
cancer. Nevertheless, because of the small numbers of deaths in some subgroups, we must be cautious in interpreting our data. Furthermore, since our current analysis was not prespecified when the cohorts were initially enrolled, and testing of multiple hypotheses through subgroup analyses increases the possibility of a false positive result,34
our findings need to be confirmed by analyses of independent data sets.
A possible alternative explanation for our findings is that aspirin use before diagnosis, which is related to aspirin use after diagnosis, may be associated with the occurrence of indolent tumor subtypes, particularly among mutated-PIK3CA
tumors. We previously reported that aspirin use before diagnosis by itself was not associated with prognosis among patients with colorectal cancer.8
In our current analysis, we analyzed the effect of aspirin use after diagnosis according to both PIK3CA
mutation and aspirin use before diagnosis (). Although statistical power was limited, the results suggest that the association between aspirin use after diagnosis and increased survival is probably not explained by aspirin use before diagnosis. Colorectal cancers are a heterogenous group of complex diseases, as indicated by molecular pathological epidemiology35-37
and the unique tumor principle.11
Thus, it is not possible to explain tumor behavior on the basis of one or a few biomarkers alone. The interplay among inflammation, aspirin, and tumor molecular features is suggested by the current study and our previous studies.8,22
The proportion of mutated-PIK3CA
tumors was the same (17%) among users and nonusers of aspirin before diagnosis, despite our main finding that aspirin use after diagnosis appeared to prevent progression of disease in patients with mutated-PIK3CA
tumors. One reason for this apparent discrepancy may be related to tumor evolution. During tumor evolution, tumor cells are subject to changes in their own genome, epigenome, proteome, and metabolome and to changes in the local microenvironment.11
Thus, their dependence on an inflammatory microenvironment probably varies according to the specific phase of tumor evolution, which may result in the differential interaction of aspirin use and PIK3CA
mutation in the early phase of evolution (before diagnosis) versus the late phase (after diagnosis).
Our previous data8
suggested that patients who use aspirin before diagnosis may not benefit from aspirin use after diagnosis. However, our current study provides evidence of a beneficial effect of aspirin use after diagnosis if the colorectal cancer has PIK3CA
mutation, irrespective of aspirin use or nonuse before diagnosis. This finding may prove to have substantial implications for decisions about treatment.
In our current study, the strongest effect of aspirin use was in patients who had tumors with both PIK3CA
mutation and PTGS2 expression. We must interpret these results with caution, however, because of the multiple subgroup analyses and limited statistical power. Nonetheless, our current findings are not inconsistent with those of our previous study,8
which showed a strong antitumor effect of aspirin on PTGS2-positive colorectal cancer. Experimental evidence supports cross-talk between the PI3K and PTGS2 pathways.20,21
In combination with the experimental observation that aspirin can induce cell apoptosis through PTGS2-independent pathways,38,39
our data may provide support for an antitumor effect of aspirin in addition to that of PTGS2 inhibition, although the exact mechanisms need to be clarified.
A “colorectal continuum” hypothesis that is distinctive from the long-standing “proximal versus distal colorectum” model has recently been proposed.33,40
The frequencies of molecular features such as a high level of microsatellite instability and extensive CpG island methylation, as well as BRAF
mutations, appear to increase continuously from the rectum to ascending colon.33
Considering a gradual transition of gut biogeography, the inhibitory effect of aspirin on cancer may differ according to both the specific site of the tumor and its molecular features. Our current study lacked statistical power to examine effect modification according to both PIK3CA
mutation status and the specific tumor site, and larger studies should address this question.
Our study has several strengths. We collected data on aspirin use both before diagnosis and after diagnosis; this allowed us to examine the potential influence of the timing of aspirin use in relation to the cancer diagnosis. Since all study participants were health professionals with knowledge of medications, the accuracy of self-reported information on aspirin use was probably high. Furthermore, our comprehensive molecular pathological epidemiology database,35-37
with accumulated data on various lifestyle factors, tumor molecular features, and clinical outcomes, provided a unique opportunity to test our specific hypothesis of the interactive prognostic effect between aspirin use and PIK3CA
Our current study also has some limitations. Data on cancer treatment were limited. Given that all patients received a diagnosis before July 1, 2006, we assume that chemotherapy use did not differ substantially according to PIK3CA mutation status, information that was unavailable to the treating physicians. Moreover, our multivariable survival analysis was adjusted for cancer stage (I, II, III, or IV), and decision making for treatment was largely based on the stage of the cancer. In addition, we had limited information about cancer recurrence; nevertheless, with adequate follow-up time in the current study, colorectal cancer–specific survival served as a reasonable measure of the colorectal cancer–specific outcome.
In conclusion, this study suggests that regular use of aspirin after the diagnosis of colorectal cancer is significantly associated with increased survival among patients with mutated-PIK3CA tumors but not among patients with wild-type PIK3CA tumors. This relationship appeared to be independent of aspirin use before diagnosis. PIK3CA mutation may serve as a tumor biomarker that predicts the response to the initiation of aspirin therapy in patients with newly diagnosed colorectal cancer.