Aspirin Found to Reduce Esophageal Cancer Risk in Barrett's

March 1, 2007

SEATTLE -- Aspirin and other NSAIDs decrease the risk of progression of the most aggressive form of Barrett's esophagus to esophageal cancer, researchers here reported.

SEATTLE, March 1 -- Aspirin and other NSAIDs decrease the risk of progression of the most aggressive form of Barrett's esophagus to esophageal cancer, researchers here reported.

The researchers also identified a high-risk cluster of four known cancer biomarkers in patients with Barrett's that significantly increased their risk of developing esophageal adenocarcinoma, according to a report in PLoS Medicine.

Barrett's patients with no genetic abnormalities upon joining the study had a 12% risk of developing esophageal cancer after 10 years, whereas those with three or more abnormalities at baseline had an almost 80% risk, said Patricia Galipeau, a research technician in the laboratory of Brian Reid, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center.

Galipeau and colleagues also found that those with three or more of the biomarkers who used aspirin or other NSAIDs had a 30% risk of esophageal cancer after 10 years, while those with the same biomarkers who did not use NSAIDs had a 79% risk of developing cancer within a decade.

NSAID users took the drug at least once a week for six or more months any time during follow-up, regardless of daily frequency, duration, or type, the researchers reported.

Alterations in the genes encoding the tumor-suppressor proteins CDKN2A, TP53, and abnormalities in DNA content are common in many human cancers and their precursors, including esophageal adenocarcinoma and Barrett's esophagus, the researchers said.

Aspirin and other NSAIDs have been proposed as possible chemopreventive agents for these conditions. However, they added, until now little has been known about the ability of a biomarker panel to predict progression to cancer or how NSAID use may modulate progression.

In a 10-year prospective cohort study of 243 patients with Barrett's (189 men, 54 women, mean age 62 at baseline), biopsies were evaluated for TP53 and CDKN2A (p16) alterations, DNA content abnormalities (tetraploidy, and aneuploidy); loss of heterozygosity; methylation-specific PCR; and flow cytometry.

At 10 years, all abnormalities, except CDKN2A mutation and methylation, contributed to esophageal cancer risk significantly, ranging from loss of heterozygosity on chromosome 17 (relative risk [RR]=10.6; 95% confidence interval [CI] 5.2-21.3, P

The vast majority of patients in this cohort had gastroesophageal reflux disease and were undergoing therapy, mainly with proton-pump inhibitors. It is unclear how the frequency or severity of symptoms may have affected NSAID use by participants, the researchers said.

However, to their knowledge, they said, symptoms from reflux are not associated with intermediate endpoints or cancer in Barrett's esophagus, so it is unlikely that symptoms could explain the association of NSAID use with reduced risk of esophageal cancer.

The annual incidence of esophageal cancer among Barrett's esophagus patients is about 1%, and most patients never develop the malignancy, Dr. Reid wrote. However, he said, the outlook is grim if the cancer is not diagnosed early, with an overall survival rate of only 13.7%. For this reason, he said, Barrett's patients must undergo frequent endoscopic surveillance.

The findings of this study may ultimately help identify high-risk patients who require frequent surveillance and low-risk patients who need less frequent surveillance, or none, he said.

Also, he added, the findings may help identify patients who may benefit most from a very cost-effective, noninvasive therapy in the form of aspirin or NSAIDS.

This study is early translational research, the researchers noted, as defined by the National Cancer Institute. These results advance the understanding of the molecular mechanisms of neoplastic progression as well as the mechanisms by which aspirin and other NSAIDs may prevent cancer.

However, they said, several other types of research will be essential for these results to reach the clinic, including multicenter randomized trials and health-services research to evaluate the effect of the interventions as well as the cost effectiveness of biomarkers that could reduce the frequency of endoscopy and the number of biopsies.

Thus knowledge of the interaction of NSAIDs and somatic genetic abnormalities will help define criteria for a randomized intervention trial with a cancer endpoint, the researchers concluded.