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 wildtype
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
(Table 3). 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.