Genetic advances push personalization of cancer prevention

BOSTON – The avenues for identifying those individuals most likely to benefit from surveillance and chemoprevention of colorectal cancer (CRC) are multiplying, experts agreed at the 2017 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.

In a series of three consecutive presentations, the first updated efforts to improve germline genetic testing. The second identified biomarkers that appear likely to improve the risk-to-benefit ratio from aspirin in cancer prevention. The third cautioned about the potential pitfalls of genetic testing for cancer risk even though the overall effect was to highlight the value of this tool when performed appropriately.

Novel tools for germline testing

“Probably the most significant impact of germline genetic testing in GI oncology is the result of technological advances in genetic analysis such as multigene panel testing coupled with novel thinking as to who should be tested,” Sapna Syngal, MD, director of gastroenterology at Dana-Farber/Brigham and Women’s Cancer Center, Boston, said in an interview.

Dr. Syngal noted that the management of hereditary cancers differs from that of sporadic cancers in several ways – the surgical management of cancer, screening, and surveillance after the treatment of the primary cancer, surveillance for associated cancers, screening and surveillance of family members, and reproductive counseling.

In her talk, “Novel Tools to Accelerate Implementation of Germline Genetic Testing,” Dr. Syngal discussed the PREMM (Prediction Model for MLH1 and MSH2 gene mutations) risk assessment tool first developed in 2006. The web-based PREMM calculates a risk score based on personal and family histories, Dr. Syngal said. “If an individual scores above a certain threshold, they are referred to genetic counseling and possibly testing,” she noted.

A second-generation tool for identifying patients at increased genetic risk for CRC, called PREMM1,2,6, was based on a larger patient sample, and published in 2011. That model “is recommended by the National Comprehensive Cancer Network for testing for Lynch syndrome, so its use is already part of clinical practice in gastroenterology,” Dr. Syngal reported.

A third model, called PREMM5, was developed on the basis of an even larger patient sample, and it is now being tested in primary care practices with plans in the works to implement the model in general gastroenterology, oncology, and ob.gyn. settings, she added.

“There are probably about 1 million people in the United States who have Lynch syndrome and don’t know it,” according to Dr. Syngal, who noted that PREMM can be completed in only a minute or two by clinicians or patients once they collected information about CRC history among their blood relatives.

Ultimately, the same approaches can be applied to risk assessment for other GI cancers in which the goal is to first identify patients at an increased likelihood of having a genetic mutation that predicts cancer risk and then employing multigene panels to narrow down those who could benefit from specific surveillance strategies.

However, by itself, the work to develop better strategies to identify Lynch syndrome is important, according to Dr. Syngal. When a group of experts was recently convened under the Cancer Moonshot Program championed by former Vice President Joe Biden, “Lynch syndrome was identified as the top priority in terms of cancer prevention” over the coming 5-10 years.
 

Biomarkers for GI cancer chemoprevention

In the case of acetylsalicylic acid (ASA), which is known to prevent CRC and other cancers of the GI tract, “we need to do some real thinking about molecular and genetic markers that could be used for precision medicine,” according to Andrew T. Chan, MD, MPH, AGAF, chief of the clinical and translational epidemiology unit at Massachusetts General Hospital, Boston.

Citing a long list of studies and trials that have associated aspirin with protection against CRC, including a randomized controlled trial in Lynch syndrome, Dr. Chan characterized the evidence of a chemoprotective effect from ASA against GI cancer as “overwhelming.” However, not all individuals may derive a favorable risk-to-benefit ratio due to the antiplatelet effects of ASA that increase risk of bleeding events in the GI tract and elsewhere.

The best approach to providing a favorable risk-to-benefit ratio may involve identifying biomarkers that predict benefit. The progress in understanding how ASA inhibits pathways of tumor development has provided candidates, according to Dr. Chan, citing a series of studies, including those conducted at his center.

One proof of concept was derived from work in evaluating tumor expression of cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. Dr. Chan explained that prostaglandin are linked to many downstream cancer-promoting pathways. In a study that involved molecular analysis on tumor specimens from patients who participated in a cohort study, the presence of the COX-2 isoenzyme was a differentiator.

“When the evaluation was performed according to COX-2 status, we saw about a 30% reduction in risk for COX-2-positive tumors. In contrast, we did not see any appreciable reduction in risk in tumors that were COX-2-negative,” Dr. Chan reported.

Although Dr. Chan acknowledged that about 80% of CRC tumors are COX-2-positive, which may explain why CRC protection from ASA is observed in an unselected population, he reported that this study has supported pursuit of additional biomarkers, particularly those that might predict protection from ASA before or at the very earliest stages of the neoplastic process.

One such candidate is 15-prostaglandin dehydrogenase (15-PGDH) enzyme, which is known to catabolize or breakdown prostaglandin. When 15-PDGH levels were evaluated in normal tissue samples adjacent to CRC tumors, there was about a 50% reduction in risk of CRC in those with high 15-PGDH “but there was actually no reduction in risk among those with low 15-PGDH,” Dr. Chan reported.

Currently, ASA prophylaxis for preventing CRC is recommended by the U.S. Preventive Services Task Force in individuals who also have an increased risk of cardiovascular disease, but there is no accepted formula for weighing CRC risk against risk of bleeding. Biomarkers like 15-PGDH could be instrumental in guiding decisions for gastroenterologists.

“So you can imagine a strategy in which the endoscopist removes the polyp and also takes a biopsy of adjacent normal tissue to determine whether there are sufficient levels of 15-PGDH to potentially predict whether ASA will have a preventive effect,” Dr. Chan said.

There are other biomarkers also being pursued for their same potential to identify patients with a high likelihood to benefit from ASA, which Dr. Chan suggested could help clinicians determine when ASA is appropriate.

In clinical medicine, “we think a lot about biomarkers in respect to predicting who will benefit from cancer therapy, but we have thought less about whether we have the ability to use biomarkers to determine who would potentially be benefiting from a preventive intervention,” Dr. Chan said.