Colon cancer

Colorectal cancer (CRC) screening has become a focal point of the practice of gastroenterology. Successful screening leads to a reduction in cancer mortality and is one of the most impactful means by which we improve population health.

Rick Boland, MD, of the Baylor Center of Gastrointestinal Cancer Research in Dallas reminded us at the annual Digestive Disease Week that carcinogenesis in colorectal cancer is a multistep process and described several pathways of which clinicians should be aware. Germline mutations (inherited) vs. somatic mutations (acquired) may be driver mutations that confer selection advantage and become targets for therapy in contrast to passenger mutations that are not mechanistic targets. Germline mutations should be considered when there is a family history of CRC, especially in a young patient, and are characteristic of familial adenomatous polyposis (APC), attenuated polyposis (MYH-MUTYH), and nonadenomatous polyposis syndromes such as Peutz-Jeghers (STK11).

Microsatellite instability is an alternative pathway to cancer. Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is representative of this pathway with common abnormalities in mismatch repair genes such as MLH1, MSH2, MSH6, or PMS2. Lynch syndrome patients are BRAF and CIMP negative. This is in contrast to a more recent pathway to cancer that arises from sessile serrated polyps that also display microsatellite instability, but are BRAF and CIMP positive.

The clinical importance of understanding the pathway through which cancer develops in an individual patient is that depending on the mechanism of tumorigenesis, different treatment strategies can prevent or treat cancer. For example, exciting novel therapies are being developed for microsatellite unstable cancers using immune checkpoint inhibitors. Aspirin can reduce CRC mortality, especially tumors that overexpress COX2 or harbor PIK3CA mutations, and have demonstrated benefit even postoperatively in patients receiving surgical resection of CRC.

I gave a talk focused on current guidelines for reducing mortality among individuals at average risk for developing CRC. The U.S. Preventive Services Task Force updated their recommendations this year and chose to focus on highlighting the importance of CRC screening between the ages of 50 and 75 years, tailored screening for those between the ages of 76 and 85 years, and stopping screening after age 85 years. However, the statement does not recommend specific tests and instead lists competing strategies of annual fecal immunochemical test (FIT) or highly sensitive fecal occult blood test (FOBT) with or without flexible sigmoidoscopy every 10 years, flexible sigmoidoscopy every 5 years, colonoscopy every 10 years, CT colonography every 5 years, and FIT-DNA every 1 or 3 years. The FIT-DNA adds a separate FIT to a stool exam for KRAS mutations, NDRG4 and BMP3 methylation, and beta-actin. There are no studies to determine whether CRC mortality is reduced, but one study demonstrated a higher sensitivity for CRC with the combined FIT-DNA, compared with FIT alone, but a lower specificity. The FDA also recently approved a blood-based CRC screening test that detects circulating methylated septin 9 gene DNA. Septin 9 is a gene that codes for GTP-binding protein and acts as a tumor suppressor that can be inactivated by methylation.

Irrespective of which strategy is pursued, colonoscopy is the final common pathway. Quality is important because there remains a disappointing rate of CRC after colonoscopy. Prior work has demonstrated significant differences in the adenoma detection rate (ADR) between endoscopists in the same practice. A recent Kaiser study found that for every 1% increase in the ADR there is a 3% decrease in the rate of cancer developing after colonoscopy.

Disruptive technology is emerging that may displace gastroenterologists from primary endoscopic screening. A self-propelled disposable colonoscope (Aer-O-Scope) has been developed that uses pneumatic pressure to advance a tethered camera through the colonic lumen guided by a joystick. Sedation is not required and the device does not need manual advancement, facilitating use by nongastroenterologists.

Uri Ladabaum, MD, of Stanford (Calif.) University presented the clinical impact of screening for hereditary and familial CRC. Lynch syndrome is characterized by a family history of cancer in at least three individuals spanning at least two generations including one with early cancer development. He reminded us that Lynch syndrome cancers are not limited to CRC but also include uterine, ovarian, gastric, small intestinal, urinary, biliary, pancreatic, and neurologic tumors. Microsatellite instability is likely present, mismatch repair gene abnormalities should be sought, and screening should include colonoscopy every 1-2 years. Aspirin chemoprophylaxis should be recommended, as should prophylactic hysterectomy and oophorectomy among affected women due to the uterine and ovarian cancer risk.

Polyposis syndromes constitute a separate group of hereditary cancers that includes familial adenomatous polyposis (FAP) arising from defects in the APC gene that may present as florid or attenuated FAP, and MYH-associated polyposis. If a patient presents with more than 10 adenomas, a polyposis syndrome should be considered. More rare syndromes include Cowden, juvenile polyposis, and Peutz-Jeghers.