Comprehensive Molecular Panel Testing in GI Cancers

At the 2020 Great Debates & Updates in Gastrointestinal Cancer, Scott Kopetz, MD, PhD, MD Anderson Cancer Center, Houston, Texas, engaged in a stimulating debate regarding comprehensive molecular panel testing in GI Cancers.

While his opponent, Al B. Benson III, MD, FACP, FASCO, Professor of Medicine in the Division of Hematology and Oncology at Northwestern University Feinberg School of Medicine, Chicago, Illinois, argued that comprehensive molecular panel testing in GI cancers is a waste of medicine, Dr Kopetz advocated in its favor.

“There's a proportion of practicing oncologists who still aren’t using NGS panel testing, and I really want to make the case that as the field has changed, now that we’re three, four years down the line from this data, that there really should be a wider proportion of utilizations,” said Dr Kopetz.

Although finding a significant mutation burden in certain GI cancers, such as colon cancer, is quite uncommon, testing early and broadly can lead to a greater survival outcome in the patient.

This is particularly useful in testing the tumor mutational burden (TMB), which can not be detected with a single gene panel test and must undergo next-generation sequencing (NGS) testing.

Proper assessment of TMB can then lead to the deployment of PD1 inhibitors, which have shown high efficacy in treating MSI-High cancers. Specifically, in a study on the efficacy of PD-1 Inhibition with pembrolizumab in patients with MSI-High non-CRC cancers, a total of 86 patients across 12 different cancer types had an objective response rate (ORR) of 53% (21% CR). In patients with pancreatic cancer the ORR was 62% and the disease control rate (DCR) was 75%.

The median progression free survival (mPFS) and median overall survival (mOS) were not reached.

Furthermore, PD1/LD1 inhibitor-based therapy also yielded high efficacy in patients with POLE mutations. As with TMB, POLE mutations can not be detected through a single gene and need more comprehensive testing.

In a study of 121 patients, 15 with pathogenic POLE mutations and 104 with benign/VUS, those whose mutations were pathogenic had a median PFS of 15.3 months, while the median PFS of benign/VUS patients was 4.9 months (P = .151). The 33 patients with pathogenic (15) and benign (18) only had a median PFS of 15.3 and 2.8 months, respectively.

Other points brought to the table by Dr Kopetz during the debate included that comprehensive molecular panel testing allows us to use FDA-approved therapies that are available instead of using new experimental methods.

However, he made it clear that MSI-H is rare outside of colorectal and gastric cancer, but it can lead to potentially curative therapy.

“What’s relevant today may change and we're too focused in ordering just the three our four genes that we think are relevant in 2020, by the time the patient may be needing something in 2022 the landscape certainly, and hopefully, will have changed and I think we need to make sure we’re doing a test,” Dr Kopetz concluded. —Alexandra Graziano

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