SEATTLE – “Biomarkers have a promising role in the early detection and risk stratification of colonic neoplasia,” Dr. Hemant K. Roy said at a joint meeting by Global Biomarkers Consortium and World Cutaneous Malignancies Congress.
A better, personalized strategy for screening the population is needed given the current limitations of colonoscopy, he said. “Unfortunately, we know that the endoscopic capacity and funding are really inadequate to perform colonoscopy on the entire average at-risk population, which is greater than 100 million Americans over the age of 50. Juxtaposed with this is the fact that most screenings by colonoscopy are negative for a significant lesion.
Dr. Hemant K. Roy
“In retrospect, most colonoscopies are squandered if you just look at colonoscopy as a cancer prevention tool. The solution may be a better risk stratification tool, to develop a prescreen that can detect patients most likely to benefit from colonoscopy,” he said.
Biomarker tests
Numerous colorectal cancer biomarkers are being evaluated in various physiologic compartments, according to Dr. Roy, professor of medicine and chief of the section of gastroenterology, Boston University Medical Center. The development of these biomarkers is complicated by several factors, such as the heterogeneity of the neoplasia and the large number of mutations found in this cancer.
Most of those being investigated for screening are still in the earlier phases of development. One now on the market is a blood test for methylated SEPT9 (ColoVantage). Its sensitivity is 48% for colorectal cancer but only 11% for advanced adenomas (Gut. 2014 Feb;63(2):317-25). “This represents a small step forward, but it is available,” Dr. Roy said.
Among other promising blood tests is the microRNA MiR-21 assay. This assay was found to have an area under the curve of 0.92 for the detection of colorectal cancer and 0.81 for the detection of adenomas (J Natl Cancer Inst. 2013 Jun 19;105(12):849-59).
A stool DNA test on the market (Cologuard) outperformed the fecal immunochemical test (FIT) for detecting colon cancer, with a sensitivity of 92% and a specificity of 87% (N Engl J Med. 2014 Apr 3;370(14):1287-97). But the sensitivity was only 42% for advanced adenomas. “This is our real target, and this is a problem, especially as the Cologuard test, while good, is expensive at about $500 a test,” he said.
Fecal microRNA biomarkers have also shown some promise, with a pair found to perform well for differentiating individuals with advanced adenomas and cancers from unaffected peers (Cancer Epidemiol Biomarkers Prev. 2010 Jul;19(7):1766-74). “While this needs to be repeated, it has some potential,” Dr. Roy commented.
Tissue tests exploit the fact that, in general, the entire large intestine is exposed to the same genetic and environmental influences. “The corollary is that we can potentially look in the rectum or at other lesions in the colon and predict risk throughout the colon,” he explained.
Promising tissue biomarkers include nanoarchitectural changes in endoscopically normal-appearing rectal mucosa that appear to reflect the risk of carcinogenesis throughout the colon (Cancer Res. Jun 1;72(11):2720-7) and microsatellite instability, which can be used as part of an algorithm to identify Lynch syndrome (Gastroenterology. Aug;147(2):502-26).
Clinical applications
“Our long-term goal is to take the general population and find these biomarkers, to narrow down our conventional cancer-screening group,” Dr. Roy explained. An additional goal is developing noninvasive tests that are more acceptable to patients than colonoscopy.
Although a randomized trial showed colonoscopy performs better than FIT at detecting advanced adenomas among patients who actually undergo screening, the difference is attenuated among all patients offered screening, likely due in part to poorer compliance with colonoscopy (N Engl J Med. 2012 Feb 23;366(8):697-706).
“You could say, we should do colonoscopy on everyone [eligible], and I’m a gastroenterologist, so that would make me very happy,” Dr. Roy commented. “But if we can’t get people to undergo the test, and with the costs associated with it and the really very small number of people in whom we actually find a significant polyp, we need a better strategy. And that is where I think a biomarker approach is going to be very helpful.”
He predicted risk-stratified use of screening tests in the future. “I think [we will see] a combination approach, with the highest-risk patients going directly to colonoscopy and the lowest-risk patients getting less sensitive biomarker-based tests,” he said.
Biomarkers may also be applied clinically to help inform colorectal cancer chemoprevention, for example, by identifying patients most likely to benefit from aspirin therapy and by helping to assess whether the dose should be altered, according to Dr. Roy. To this end, research on tissue biomarkers suggests that aspirin’s risk-reducing benefit is limited to individuals with higher 15-PDGH expression in normal colonic mucosa (Sci Transl Med. 2014 Apr 23;6(233):233re2).