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An Impactful Year for Molecular Testing in GI Cancers

Angelica Welch
Published: Tuesday, Aug 22, 2017

Antonia Sepulveda, MD, PhD
Antonia Sepulveda, MD, PhD
The guidelines released in 2017 are going to serve as the foundation for molecular testing for all gastrointestinal (GI) cancers, says Antonia R. Sepulveda, MD, PhD.

In an interview at the PER® 1st Annual International Congress on Oncology Pathology™, Sepulveda, a professor of pathology and cell biology and vice chair for translational research at Columbia University, discussed the importance and utility of genetic testing in GI cancers, as well as noteworthy developments in microsatellite instability (MSI), BRAF, and KRAS testing in colorectal cancer (CRC).

OncLive: Can you please disease the guidelines for biomarker testing in GI cancers?

Sepulveda: There were 2 main guidelines released recently for gastroesophageal cancer testing as well as for CRC biomarker testing. Guidelines currently exist for gastric and esophageal adenocarcinoma, and patients who have advanced or metastatic CRC that may benefit from trastuzumab (Herceptin). In those patients, we should test for HER2 expression, which is done by immunohistochemistry and in some cases—particularly in patients who have a score of 2+ by immunohistochemistry—we should also perform a test to determine whether there is amplification of HER2 using FISH or other hybridization methods. 

In addition, a more broad and comprehensive guideline was published for CRC molecular testing recently. The guideline included 21 recommendations and addresses which biomarkers should be tested for patients who are being considered for anti-EGFR monoclonal antibody therapy. Among those tests, one must test for RAS mutations, which include the extended RAS testing, including mutations in the genes KRAS and NRAS. In addition, other assays, such as MSI, DNA mismatch repair, are also recommended for testing in these guidelines. 

The guidelines also provide a lot of guidance in terms of which tissues should be tested and which assays should be used…There are a number of other aspects of laboratory testing management, as well.

Which patients should receive MSI testing?

It is a little different for CRC than other GI cancers. CRC is the main cancer that patients who have Lynch syndrome—hereditary nonpolyposis CRC—present in the GI tract. There is a recommendation for testing all patients who present with CRC for DNA mismatch repair deficiency and/or its surrogate marker, MSI. This is called universal testing and it is being recommended in order to identify and help make the diagnosis for those patients who may have Lynch syndrome.

Now, for other tumors of the GI tract—gastric cancer, and esophageal cancer—guidelines have not really been established as to which patients should be tested. However, it is known that up to one-fourth of gastric cancer worldwide may actually be considered MSI-positive, while esophageal cancer tends to be less frequently MSI-positive. 

At this point, those tests in gastric and esophageal cancer should be considered and performed when the patients are being considered for PD-1 blockade immunotherapy, which is considering very recent data that has been published.

When should patients with CRC receive testing?

When testing, one cannot utilize diagnostic biopsy material or the resection specimen or metastatic or recurrent tissue, which usually tends to be obtained through biopsy or fine needle aspiration. Therefore, we will have less material available for testing. 

For CRC in particular, the guidelines state that testing recurrent or metastatic CRC tissue is preferable, however, if that is not available, we can use the data from primary tumor tissue, either as the diagnostic biopsy, or the resection material, because there is very good correlation in terms of mutational state. That being said, heterogeneity in CRC and other cancers is well known, so, whenever possible, having the results from the metastatic lesion would be preferable. I would also add that, while that is true, considering that we are doing DNA mismatch repair and MSI testing in CRC upfront in a universal fashion, the mutational panels provide all of the information in the genes of interest—particularly RAS gene mutations and BRAF mutations.

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