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Expert Outlines Clinical Implications of Precision Medicine in GI Cancers

Angelica Welch
Published: Thursday, Aug 30, 2018

 Shirley Michelle Shiller, DO
Shirley Michelle Shiller, DO
Regarding precision medicine in gastrointestinal (GI) cancers, pathologists are working to determine which patient populations should undergo which molecular tests.

State of the Science Summit™ on Gastrointestinal Cancers, Shirley Michelle Shiller, DO, a pathologist at Baylor University Medical Center, discussed the clinical application of precision medicine in GI cancer.

Colorectal Cancer

For patients with colorectal cancer (CRC), Shiller said that testing is recommended for KRAS, NRAS, and BRAF mutations. These 3 mutations constitute over 50% of the genetic changes in CRC, she added. Identifying these markers can guide therapy, provide prognostic data, and can be relevant in Lynch syndrome work-up. BRAF V600E is the relevant target in the colon that does not necessarily apply in other sites of origin, and does allow a patient to get targeted therapy, Shiller explained.

Other recommended testing from collaborative groups includes screening for Lynch syndrome on all colorectal adenocarcinomas. This is not only in an effort to guide treatment, but also as a method to guide the patient for surveillance of extraintestinal manifestations and overall global management.

Gastric Cancer

In gastric and gastroesophageal junction (GEJ) cancers, the guideline-recommended testing for inoperable locally advanced, recurrent, or metastatic disease is HER2, mismatch repair deficiency (dMMR), microsatellite instability (MSI) status, and PD-L1 expression.

The same interpretive guidelines for breast cancer are recommended for HER2 testing in gastric/GEJ cancers; however, Shiller said she is unsure this is the best approach. The National Comprehensive Cancer Network (NCCN) guidelines recommend using immunohistochemistry (IHC) first for HER2. Moreover, screening for dMMR and MSI can potentially guide therapy in the pan-cancer setting. Shiller said that it is important to keep in mind that gastric cancer is one of the extraintestinal manifestations for Lynch syndrome.

Esophageal Cancer

In esophageal cancer, NCCN guidelines recommend hereditary predisposition testing with tylosis, nonepidermolytic palmoplantar keratosis (PPK), Howel-Evans syndrome, Familial Barrett’s Esophagus, Bloom’s syndrome, and Fanconi anemia. Additionally, the guidelines recommend hereditary predisposition testing to be overseen by a genetics specialist.

"De novo mutations are known to occur in each of these syndromes, meaning that they may have a relatively innocuous and uninformative pedigree or family history. However, it could be originating with that individual, and the rate of that varies upon entities," Shiller explained.

Approximately 5% to 10% of gastric cancer is familial, while 3% to 5% is hereditary. Shiller said that these percentages are likely underestimated because testing is underutilized for patients in this setting. Hereditary cancer predisposition syndromes that include gastric cancer are hereditary diffuse gastric cancer, Lynch syndrome, juvenile polyposis syndrome, and Peutz-Jeghers syndrome.

Pancreatic Cancer

For patients with pancreatic cancer, the NCCN guidelines recommend dMMR/MSI testing. Shiller said that the overwhelming majority of pancreatic cancer is KRAS mutation–positive, which potentially suggests that these patients may respond to MEK inhibition.

With respect to hereditary predisposition to pancreatic cancer, at least 10% of cases are familial. The entities that have pancreatic cancer as part of their syndromic presentation are BRCA1/BRCA2-associated hereditary breast and ovarian cancer; Lynch syndrome with mutations of MLH1, PMS2, EPCAM, MSH2, and MSH6; Fanconi Anemia and BRCA pathway genes ATM, PALB2, FANCC, and FANCG; familial malignant melanoma tracking with CDKN2A mutations; familial pancreatitis which includes PRSS1, SPINK1, and CFTR; Peutz-Jeghers syndrome; familial adenomatous polyposis-adenomatous polyposis coli; and Li-Fraumeni syndrome with a mutation in the TP53 gene.

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