KU Cancer Center to test whether omega-3 can prevent colon cancer in Lynch patients
March 29, 2019
By Kristi Birch
Colorectal cancer is the second-leading cause of cancer death in the United States, but for most Americans with access to health care, it's also largely preventable. Regular colonoscopy screening, beginning at age 50, enables doctors to snip out polyps-growths in the colon that sometimes become malignant-before they turn into cancer, or at least find the cancer early enough to be curable.
But for people with Lynch syndrome, an inherited genetic condition that predisposes people to various cancers, colorectal cancer poses a much greater threat. While people at average risk for colon cancer have a lifetime chance of developing the disease of just under 5 percent, people with Lynch syndrome have as much as an 80 percent chance. As was the case with Kansas City Royals pitcher Tim Hill, who found out he has Lynch syndrome when he was diagnosed with colon cancer at age 25, the syndrome also typically causes the disease to develop earlier in life. For these patients, colonoscopy screening is recommended to start as early as age 20 to 25. Because Lynch syndrome accounts for just 3 percent of colon cancer cases, this high-risk group doesn't always receive as much research attention as the larger average-risk population.
Lynch syndrome, which has no symptoms other than a strong family history of colon, uterine, and other gastrointestinal cancers, can be detected by a genetic blood test. So far, a more aggressive screening schedule is the only known safe and effective strategy to fend off colon cancer from developing in these patients. Chemoprevention, the use of a medication or supplements to stop cancer from occurring, may offer a complementary approach with screening.
"Even though people with Lynch syndrome have the greatest chance of getting the disease, most chemoprevention trials are not focused on patients with a genetic predisposition, but on patients who get the disease spontaneously," said Anwaar Saeed, M.D., assistant professor of medicine and a gastrointestinal oncologist at the University of Kansas Cancer Center. "There's a huge unmet need to develop more feasible chemoprevention options for Lynch patients."
Saeed is looking to change that. She is launching the first clinical trial to examine the effectiveness of fish oil supplements, which contain omega-3 fatty acids, in protecting against colon cancer for people with Lynch syndrome. Omega-3 fatty acids have anti-inflammatory properties that have been shown to reduce the size and number of tumors in patients with familial adenomatous polyposis, another rare, inherited condition that causes so many polyps to form that patients often need to have their colon removed. Saeed's study is funded by the Cancer Prevention and Survivorship program and the Investigator-Initiated Trial (ITT) Steering Committee, both at the KU Cancer Center.
"This trial is an opportunity to find a feasible and effective chemopreventive method for this vulnerable population, which we also regard as an orphan population because it accounts for less than 5 percent of colorectal cancer patients," said Saeed.
For the colon to stay healthy, the cells that line the colon must regenerate themselves every few days. To do that, the cells must replicate their DNA. But sometimes when the DNA is cloning itself, mistakes-known as mutations-happen. Luckily, the body has genes that fix the erroneous DNA.
People with Lynch syndrome have damaged versions of one type of those fix-it genes called DNA mismatch repair genes. When these genes are broken and can't do their job, mutated genes accumulate, and the result is runaway cell growth. That's cancer.
Unfortunately, scientists have not yet found a way to repair those resulting mutated genes. "We can't fix mutations in people," said Dan Dixon, Ph.D., co-leader of the Cancer Prevention and Survivorship program, who is collaborating with Saeed on the trial. "So the idea with this study is, what can we control? Well, we can control inflammation."
Inflammation - the immune system's response to an irritant or injury - helps accelerate cancer cells growing out of control. Inflammation also has been shown to increase the number of mutations. Colon cancer is associated with high levels of a lipid (fatty acid) called Prostaglandin E2, which helps activate the body's inflammatory response. More PGE2 generally means more inflammation. And more inflammation for Lynch patients means a greater chance they won't escape colon cancer.
Aspirin, an anti-inflammatory agent, was found to be effective in preventing colorectal cancer in Lynch patients, but aspirin is effective only at high doses, which can cause gastrointestinal bleeding and stomach ulcers. "We have clinical evidence that aspirin works in this population, but given its associated side effects, aspirin lacks the universal feasibility," said Saeed. "So we're trying to find an alternative agent that has anti-inflammatory effects but without these side effects."
A safe study
The beauty of omega-3 fatty acids in fish oil is that they are expected to curb the production of PGE2 and reduce inflammation without the possibility of harming the patient's gastrointestinal system. That safety is key. "For a patient with Lynch syndrome, we educate them on more frequent colonoscopies, oftentimes every one to three years, and the importance of removing polyps, but high-risk patients often want to be more proactive than just cancer screening," said Jennifer Klemp, Ph.D., a cancer risk counselor and co-leader of the Cancer Prevention and Survivorship program. "But at the same time, we could try a preventive agent that's a natural product, and many high-risk patients find that an attractive option."
Part of Klemp's role in the study is helping identify potential participants with Lynch syndrome to participate in the trial. For 12 months, these study participants will take a daily moderate dose of a prescription fish oil supplement. It can take many years, much longer than the time period of the study, for actual colon cancer to develop, but the researchers will know if the fish oil was effective by monitoring changes in the patients' biomarkers at the beginning and end of the study.
Blood, urine and stool samples will be taken, and colonoscopies will be performed, before and after the 12-month period. The researchers will examine and compare the results to look for reductions in the patients' biological markers of inflammation, cell growth and death, and possible tumor development.
If the researchers are right, and the omega-3 fatty acids appear to have a chemopreventive effect, then the next step would be a more comprehensive study over a longer period of time.
"The future longer and larger study could possibly test the same omega 3 fatty acids product in different doses and in combination with other anti-inflammatory drugs like aspirin in lower doses," said Saeed.
"Maybe we find that we can reduce someone's chance of getting colorectal cancer from 80 to 20 percent," said Dixon. "Or maybe we could lower the dose of aspirin, so that the person takes both fish oil and baby aspirin."
If they are successful, then people with Lynch would finally have some safe way, other than screening, to protect themselves from cancer. "Personally, I believe the essence of practicing oncology is to prevent cancer before it becomes clinically visible," said Saeed. "This clinical trial is a low-risk sincere effort to capitalize on prior research developments and to support our mission toward preventing colon cancer in the Lynch population."