Aspirin May Be Targeted Therapy for Colon Cancer

Nick Mulcahy

October 23, 2012

Aspirin, the mainstay of the medicine cabinet, appears to resemble a high-tech targeted therapy in the treatment of patients with a subtype of colorectal cancer, according to a study published in the October 24 issue of the New England Journal of Medicine.

Patients with PIK3CA-mutated tumors who regularly used aspirin after their diagnosis had a significant survival benefit — a 46% reduction in overall mortality and an 82% reduction in colorectal-specific mortality. However, patients with wild-type PIK3CA who regularly used aspirin after diagnosis did not have a mortality benefit of any kind.

These findings come from a retrospective analysis of 2 large cohort studies in the United States: the Nurses' Health Study and the Health Professionals Follow-up Study.

If the findings are validated prospectively, clinicians could have a new biomarker — and adjuvant therapy — for colorectal cancer, say the authors, led by Xiaoyun Liao, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts.

Given how common the PIK3CA mutation is, this might be big news, according to an expert not involved with the study.

"Since more than 1 of 6 primary colorectal tumors harbors PIK3CA mutations, targeted use of adjuvant aspirin could have a major effect on the treatment of colorectal cancer," writes Boris Pasche, MD, from the University of Alabama at Birmingham, in an accompanying editorial.

Aspirin may well become...a 21st-century targeted therapy Dr. Boris Pasche

"Aspirin may well become one of the oldest drugs to be used as a 21st-century targeted therapy," he says.

This study adds to the literature from multiple cohort studies on the antitumor effect of aspirin in colorectal cancer. Earlier this year, British investigators reported that aspirin use is associated with reduced tumor progression and recurrence in patients with a diagnosis of colorectal cancer.

However, the study by Dr. Liao and colleagues is novel because it shows that aspirin can work in a subset of patients who are identifiable by a relatively easily detected biomarker, PIK3CA.

Nevertheless, the value of mutated PIK3CA as a predictive biomarker needs to be confirmed, said Alok Khorana, MD, from the James P. Wilmot Cancer Center at University of Rochester Medical Center in New York, who was not involved with the study.

It is perfectly reasonable to consider daily aspirin after a diagnosis of colorectal cancer Dr. Alok Khorana

In the meantime, "it is perfectly reasonable to consider daily aspirin after a diagnosis of colorectal cancer after an informed discussion with patient regarding risks, benefits, and evidence," Dr. Khorana told Medscape Medical News. He recommended low-dose aspirin (81 mg/day).

Both Dr. Pasche and the investigators warn that the study sample was small.

There were 964 patients with rectal or colon cancer in the 2 cohorts, but only 152 of those carried a PIK3CA mutation. Still, the effect of aspirin on survival among patients was considerable.

Of the 90 patients with PIK3CA-mutated tumors who did not use aspirin after diagnosis, 23 (26%) died within 5 years. However, of the 62 who used aspirin regularly after diagnosis, only 2 (3%) died within 5 years (P < .001).

In contrast, aspirin appeared to have no effect on patients with wild-type tumors. The 5-year cumulative colorectal-cancer-specific mortality was the same (15%) for users and nonusers of aspirin after diagnosis (P = .92).

Contradictory Finding Explained

In both cohorts, documentation of the use of standard-dose (325 mg) aspirin began in the 1980s. After 1992, to reflect the increasing use of low-dose aspirin, participants were asked to convert 4 low-dose tablets to 1 standard-dose tablet in their response, the investigators explain. Ultimately, "aspirin use" was defined as the regular use of aspirin during most weeks, and "nonuse" was defined as no regular use of aspirin during most weeks.

These data allowed the investigators to determine whether patients diagnosed with colorectal cancer used aspirin before and after diagnosis.

They found that the same proportion of patients with wild-type and mutant PIK3CA used aspirin before their diagnosis; thus, before-diagnosis use was not skewed between the 2 subgroups.

However, in what appears to be a contradictory result, the proportion of PIK3CA-mutated tumors was the same (17%) among users and nonusers of aspirin before diagnosis.

If aspirin provides an antitumor effect in PIK3CA-mutated tumors, logic would dictate that there would be fewer cases of the mutated colorectal cancers in aspirin users than in nonusers. In other words, aspirin should also have a preventive effect.

The investigators note that this "apparent discrepancy" might be related to "tumor evolution." The tumor microenvironment might evolve in such a way that there is a "differential interaction of aspirin use and PIK3CA mutation in the early phase of evolution (before diagnosis) versus the late phase (after diagnosis)."

Study Findings Not Entirely Novel

Previously, in a prospective study involving 1239 patients with a diagnosis of stage I, II, or III disease, researchers found that regular aspirin use after a diagnosis of colorectal cancer was associated with a 21% reduction in overall mortality and a 29% reduction in colorectal-cancer-specific mortality (JAMA. 2009;302:649-658).

A subgroup analysis from that study showed that the reduction in overall mortality and colorectal-cancer-specific mortality was observed exclusively in patients with primary tumors that overexpressed the enzyme known as prostaglandin-endoperoxide synthase 2 (PTGS2, formerly known as cyclooxygenase-2).

These findings on the postdiagnosis use of aspirin and PTGS2 were recently replicated in a large Dutch study (Br J Cancer. 2012;106:1564-1570).

However, as Dr. Liao and his colleagues point out, PTGS2 is not an ideal biomarker because it cannot be easily assessed with commonplace immunohistochemistry. "Considering the challenges in standardizing PTGS2 immunohistochemical assays across pathology laboratories, other molecular biomarkers...are needed to better identify patients with colorectal cancer who will derive a benefit from aspirin," they write.

PIK3CA, which is detectable with standard immunohistochemical methods, might be their sought-after biomarker.

This study was supported by the National Institutes of Health, the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. Some of the study authors and Dr. Pasche report financial relationships with nonprofit companies or industry, as detailed in the papers. Dr. Khorana reports being a consultant to Bayer.

N Engl J Med. 2012;367:1596-1606, 1650-1651. Abstract, Editorial


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