Simple Test May Help Predict the Need for Repeat Colonoscopy

Liam Davenport

July 06, 2015

BARCELONA, Spain ― A simple panel of genetic biomarkers may be able to predict which individuals are at high and low risk of developing colorectal cancer following screening colonoscopy, and therefore could identify those who should have repeat screening, say a team of researchers from Luxembourg.

Presenting their data here at the 17th World Congress on Gastrointestinal Cancer (WCGC), the researchers say that a panel of eight genetic markers, derived from a simple comparison of case patients and control individuals, can identify patients at risk for colorectal cancer with a high sensitivity and specificity.

Interestingly, a panel using just three of the studied markers was almost as good as the full set and may offer a low-cost solution for determining which patients should be recalled for repeat colonoscopy.

Principal investigator Mario Dicato, MD, head of the Research Laboratory of the Luxembourg Foundation for Research on Cancer and Blood Diseases, explained the value of their of approach of looking for a simple biomarker test based on comparing case patients and control persons.

Speaking to Medscape Medical News, he said: "Patients with cancer have a clear pattern of these markers, but you cannot, without doing a long-lasting clinical study, predict who will get cancer, and so you would have false negatives and false positives. You get wrong predictions with all markers."

"It would be very risky to say, 'You should have colonoscopy.' But it would be even more risky to say that you should not have one."

Dr Mario Dicato

He continued: "So it makes sense just to turn the thing around and to study the normal population that undergoes colonoscopy. In this normal population, there will be people who will have a cancer. That's why you do the colonoscopy, [and] the advice is to repeat at a certain time ― 5, 8, 10 years, depending on where you are and how you function."

"Let's say 10 years. You tell them, 'Come back in 10 years.' There is a certain number of people who will have a cancer in this 10 years. The number is relatively small, otherwise you would tell everyone to come next year."

For Dr Dicato, because the test identifies people who are at higher risk for cancer, "it would make sense to tell them, 'You have yours 3 years earlier than planned, or maybe 5 years, but have it early.' "

Developing the Index

To identify candidates for the test, the researchers initially compared 185 colorectal cancer patients and 93 control participants, from which they found an association between colorectal cancer and single-nucleotide polymorphisms or deletions in the genes TGFBR1, GSTT1, INSR, telRNA, LRRC1, GSTM1, CHR8, and FOXO1.

Using a discriminant function, the data from all the tests were combined and condensed into a single index that gave the best discrimination between case patients and control persons.

From this, they defined low-risk and high-risk profiles for patients who would require further repeat colonoscopy for early cancer detection, as well as thresholds to determine the optimum economic performance of the test in terms of the cost of false positives or negatives.

The researchers found that increasing the number of genetic variations included in the index increased the sensitivity and specificity of its ability to determine which patients would require repeat colonoscopy.

For example, the sensitivity and specificity of the index when using all eight markers was 74.6% and 77.4%, respectively. However, the respective percentages were 70.3% and 67.7% when only three variants were used, namely, TGFBR1, GSTT1, and INSR.

The receiver operating characteristic curve of the trade-off between sensitivity and specificity indicated that including all eight variants in the index enabled better discrimination between case patients and control persons than including just three variants, although the difference was small.

The investigators note that although the cost of the test depends on the number of biomarkers included in the panel and the specific biomarkers chosen, they estimate that it would likely be in the range of $50 and $100 per patient, far less than the cost of repeat colonoscopy.

They also note that the test could be performed on a patient at any age, including those considered too young to undergo colonoscopy.

Blood Test Could Be Done at Anytime

Coinvestigator Garry Mahon, PhD, Research on Cancer and Blood Diseases, Luxembourg, told Medscape Medical News that one of the advantages of the test is that it uses standard blood samples, with the presumption being that the genetic variants they have identified are in the germline.

Dr Garry Mahon

Therefore, "The test could be done at any time, and if a blood sample is being drawn for some other purpose, a fraction could be used for this," Dr Mahon said.

He added that they are now planning a follow-up study. "We will look at the people having the second colonoscopy and see if, among those who were negative in the first one, there is a higher frequency coming up positive in the second one," he said.

Discussing whether they will end up using the full panel of eight markers or just three, Dr Dicato noted: "At some point in time, the increment you get by adding becomes really small, and since we want first to establish in patients who are having repeat colonoscopies where we are, it doesn't really make sense to add just a hairline to your [results], because that would be more complicated."

Approached for comment, Dirk Arnold, MD, director of the Department of Medical Oncology at Klinik für Tumorbiologie, Freiburg, Germany, told Medscape Medical News that "this is a nice piece of work."

Dr Dirk Arnold

"I think the goal is clear: They would like to identify some kind of biomarker which could prevent patients without any risk for necessary screening colonoscopy," he said, adding: "On the other hand, they would like to intensify screening colonoscopy in patients which are at risk to develop colon cancer."

Dr Arnold continued: "We know that many tumors are based on germline mutations, meaning in the genome, you find information that there is a certain risk that colon cancers do develop, and this is an obvious test with relatively high positive predictive value to say which patients are at risk to develop this."

However, the negative predictive value of the test is less clear, he pointed out, and so it is not possible to draw definitive conclusions as to which patients should not undergo screening colonoscopy.

Summarizing, Dr Arnold said: "For the moment, I wouldn't draw any conclusions out of this. I wouldn't say this clearly says yes or no. But I think it deserves further analysis."

"The fascinating thing is that they have two different panels, with a larger panel and a panel with only three markers, and, interestingly, the low-cost panel with only three markers is as good in its predictive value as the extended panel. So therefore there may be a chance that this really contributes to decision making."

The study was supported by the Belgian Télévie Organization and by the Fondation de Recherche Cancer et Sang, Luxembourg. The authors have disclosed no relevant financial relationships.

17th World Congress on Gastrointestinal Cancer (WCGC): Poster PD-011. Presented July 3, 2015.

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