Overview of Molecular Testing in Colorectal Cancer

Jaclyn Hechtman, MD, provides an overview of the history of molecular testing in colorectal cancer and how testing has evolved.

Andrea Cercek, MD: Hello and welcome to this OncLive Insights® “My Treatment Approach: Targeting HER2 in Metastatic Colorectal Cancer.”I’m Andrea Cercek, section head of colorectal cancer and codirector of the center for young-onset colorectal and gastrointestinal cancers at Memorial Sloan Kettering [Cancer Center in New York]. Joining me today is my colleague, Dr Jaclyn Hechtman.

Jaclyn Hechtman, MD: Hi, it’s a pleasure being here. Thank you, Dr Cercek, for introducing me. I am a former Memorial Sloan Kettering Cancer Center pathologist. Now, I am the director of precision oncology diagnostics at Miami Cancer Institute. I am also an associate pathologist at Baptist Hospital here in Miami, Florida. It’s a pleasure seeing you again, Dr Cercek.

Andrea Cercek, MD: It’s great to see you, we miss you. Let’s get started.

We’ll be discussing molecular testing in metastatic colorectal cancer. Jaclyn, can you provide us with a brief historical overview of molecular testing within colorectal cancer, and how this field has evolved and continues to evolve?

Jaclyn Hechtman, MD: Until the last maybe 8 years, molecular testing had been done by piecemeal methodology, namely Sanger sequencing. The first target in colon cancer to be a part of the precision oncology diagnostics portion of oncology was EGFR. We weren’t testing colon cancer for EGFR; we were testing for things that would confer primer resistance to EGFR inhibitors. That would be KRAS mutations, NRAS, and we would also test for BRAF V600E mutations. In the very beginning, this was done by Sanger sequencing.

More recently it’s been done with next-generation sequencing. In the last few years, we’ve seen quite an explosion of different targets, and with these broader panels, where we were doing it piecemeal before, we can now test for multiple alterations at once. These other alterations include amplifications in HER2, fusions, and also now extended testing for mutations in KRAS and NRAS; rather than just doing 1 Sanger reaction, we’re looking at various enzymes within KRAS and NRAS. We’re also looking at BRAF V600E, as well as signatures, so our next-generation sequencing panel can also assess the microsatellite instability [MSI] status. That is how things have evolved from piecemeal, simple molecular tests to larger comprehensive, broader next-generation sequencing assays.

Andrea Cercek, MD: That’s a great overview of where we were, and how far we’ve come in under a decade, in the last 8 years, as you mentioned. We’ve really made progress in identifying targets of potential resistance to drugs that we have available, but then excitingly and importantly, also potential targets that we have drugs available for that could improve outcomes. MSI is certainly one of those. You mentioned the other key targets in colorectal cancer, namely KRAS and NRAS mutations for drugs we shouldn’t use like anti-EGFR inhibitors, and BRAF mutations because we do have BRAF-targeting combinations now. MSI-high obviously with immunotherapy or mismatch repair-deficient tumors, NTRK gene fusions also we have a target for. Then importantly, HER2 amplification, which is a newer target in colorectal cancer but has certainly been around for a long time in other diseases like breast and gastric cancer.

I should clarify too that KRAS now is an active target as well, so it’s not just a negative marker in terms of telling us that we shouldn’t use anti-EGFRtherapy. We now have drugs that target KRAS, specifically KRAS G12C. That’s exciting too and sort of a recent development.

Transcript edited for clarity.

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