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Longitudinal Data Hint That Gene Expression Can Predict Aspirin Benefit in Colon Cancer Prevention

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NEW YORK (GenomeWeb) — Researchers led by a team from Case Western University have found strong evidence in data from two large longitudinal studies that expression of 15-PGDH, a gene product linked to prostaglandin pathways, may predict whether or not a patient will benefit from aspirin for colorectal cancer prevention.

The study, published last week in Science Translational Medicine compared outcomes among subjects from the Nurses' Health Study and the Health Professionals Follow-Up Study, identifying 270 cases of colorectal cancer for which the researchers could also measure expression levels of 15-PGDH in normal colon tissue using PCR. The group found that aspirin seemed to inhibit cancer only in those with high-PGDH levels.

Evidence that aspirin reduces the risk of colorectal cancer has been apparent in observational studies, including the two longitudinal cohorts the group analyzed, as well as in randomized controlled trials, according to the authors. But it has also been clear in this data that sensitivity to the drug varies between individuals.

According to the researchers, widespread use of aspirin as a colon cancer preventive is not recommended because of uncertainty about the risk-benefit profile. By identifying a molecular subset that is actually responding to the drug this profile could potentially be improved.

"You certainly don’t want to be giving aspirin every day to those who will have no benefit. Some of them will develop ulcers, so it's not a fair thing to do," Sanford Markowitz, a senior author of the study and a professor of cancer genetics at Case Western told PGx Reporter.

According to Markowitz, he and his colleagues thought, based on biological and clinical evidence in earlier studies, that 15-PGDH might be a promising candidate to explain variation in patients' sensitivity to aspirin's tumor-inhibitory effects.

In their recent study, the researchers divided subjects from the two longitudinal cohorts who had high versus low 15-PGDH levels in samples from their normal colon and cross checked these two subsets against patients' reported aspirin use. The group found that the benefit of regular aspirin use in decreasing colon cancer risk was limited to the group with high 15-PGDH.

This finding, the authors wrote, supports the hypothesis that aspirin's anticancer activity in the colon might be partly dependent on high 15-PGDH expression, and conversely, that low expression of the marker may contribute to patients' resistance to the drug's tumor-preventive effect.

In the study, subjects with high 15-PGDH expression in their normal colon who used aspirin regularly had a hazard ratio of 0.51 compared to those who were non-users, and this remained significant after adjusting for lifestyle and other risk factors, the team reported. Meanwhile, those with low 15-PGDH expression had little difference in their cancer risk whether they were aspirin users or not.

"We basically saw risk cut in half in the one group and no benefit at all in the other," Markowitz said.

According to the researchers, these associations were true both across the two cohorts, and looking at each longitudinal study separately.

Although the evidence is preliminary and retrospective, Markowitz said that based on accumulating knowledge from animal and other human studies it makes sense to expect that the association seen in his team's recent study may hold up if followed up with a prospective study.

Ideally, he said, that would be the next step, although it's not clear that it will be easy to fund such a study.

"What we'd like is a prospective randomized study where we take folks who we know are forming colon polyps and are at risk for more and randomize them — half to aspirin and half to placebo. You'd get a colon biopsy beforehand and measure PGDH so you know who is PGDH-high and PGDH-low and then follow them over 36 months or so" to see who develops more polyps and who doesn't, Markowitz said.

Another possible study could look at subjects with Lynch syndrome or other familial colon cancer syndromes. "Those would both be the gold standard, but both would be somewhat expensive so we have to see what we can persuade people to fund," he added.

Downsides to the group's completed study include the fact that they were limited to a small subset of the larger longitudinal cohorts for whom they could assess 15-PGDH levels, as well as the fact that these levels were assessed after patients were diagnosed with cancer.

However, Markowitz said, earlier research has indicated that 15-PGDH levels remain fairly stable over time, so the researchers believe its unlikely that measuring after cancer was present would have influenced the study results.

"We did publish other results last year where we looked at PGDH levels in the colons of people separated by four months and … it doesn’t obviously vary over time," he said. "Also, the tissue that was used for this was on average about a foot away from the [patients'] tumors, so we think the likelihood is that PGDH is not changed because we looked after people had cancer," he said.

According to its authors, despite the fact that the study will need to be confirmed and replicated, the results suggest strongly that 15-PGDH levels in normal colon tissue might be exploited to identify individuals with the greatest likelihood of benefit from regular aspirin use as a preventive treatment.

According to Markowitz, the way this could play out in clinical practice, would be through sampling of the normal colon during routine colonoscopies for patients with family history of cancer or other risk factors.

"There is so much more PGDH in the colon than blood, that you cant really tell if someone is high or low from a blood test," he said. "So it has to be a tissue test, but it's not hard to do."

"The people who you are going to consider giving aspirin to are those with family history or who have had polyps and they are already getting a colonoscopy [so you] just have to get a small biopsy of the normal colon tissue," he added. "It takes about 30 seconds, and you would just take that and send it to a hospital pathology lab who could recreate the test we did in our study, which is not a very complicated test."

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