Genomic Profiling in Early CRC


Christopher Lieu, MD, discusses the standard of care for genomic profiling in early stage CRC.

Christopher Lieu, MD:Welcome to this contemporary Cancer Network K-Cast program titled “MRD and Decision-Making in Early Stage Colorectal Cancer.” I am Dr Christopher Lieu, from the University of Colorado in Denver. Our discussion is going to focus on optimizing the use of MRD [minimal residual disease] as a tool to guide decision-making in the adjuvant setting for patients at risk for recurrence. Welcome, and let’s begin.

Kristie L. Kahl:What is the role of tumor genomic profiling in colorectal cancer? Where are we, and how did we get here?

Christopher Lieu, MD:When you think about genomic profiling in colorectal cancer, this has changed dramatically in the past decade. When you think about the era of personalized therapy for metastatic colorectal cancer, that really began with the knowledge of KRAS mutations in 2008. Since that time, genomic profiling for colorectal cancer has led to critical treatment options in numerous biomarker subtypes for patients with colorectal cancer. If you think about the critical examples, we want to know about all patients with metastatic colorectal cancer. We want to know about the MSI [microsatellite instability]–high status. If a patient has MSI high, we will think about immunotherapy for this patient’s metastatic disease.

Other mutations that we focus on include NRAS because of its negative prediction in terms of use of anti-EGFR therapy. We also think about BRAF V600E mutations. We think about that in terms of the prognosis for these patients but also because there’s now an FDA-approved therapeutic option, and there are also targeted therapy options for HER2 [human epidermal growth factor receptor 2]–amplified colorectal cancer. However, I would say genomic profiling for colorectal cancer has dramatically altered the therapy for metastatic disease. Specifically, the impact on early stage colorectal cancer, stages I to III, has been extremely limited, so NCCN [National Comprehensive Cancer Network] Guidelines state that mismatch repair testing or MSI testing for colorectal answer is recommended for all patients with colorectal cancer, regardless of stage, but there is no targeted therapy options or critical genomic profiling that would alter treatment decision-making in the adjuvant setting. With ongoing trials, we hope this will change, including a large study investigating the use of immunotherapy for MSI-high stage III colon cancer. This will eventually change practice. At this time, the actionability of genomic profiling in early stage colorectal cancer is limited.

Kristie L. Kahl: With that, how do you measure specific genomic profiles of tumors in the blood? Can you comment on next-generation sequencing?

Christopher Lieu, MD:There are a lot of commercially available assays that can genomically profile cancer through circulating tumor DNA. We abbreviate this as ctDNA [circulating tumor DNA], which can yield critical information. It can aid personalized therapy for patients with metastatic colorectal cancer. The panels tested via ctDNA are typically smaller than the panels that are applied to tissue specimens. Additionally, because the half-life of ctDNA is so short, it represents a way to test sequencing in real time without the need for tissue, and that genomic profiling is really giving you a good snapshot of what’s happening in the body at that time. The genomic profiling of tumors through ctDNA can provide 2 critical pieces of information. The first is that ctDNA can be detected. This means that there’s a presence of a tumor in the body that’s releasing that ctDNA into the bloodstream. Of course, the second piece of information that is important is the real-time mutational profiling of the tumor, which may guide therapy.

Kristie L. Kahl: What is the difference between driver mutations and passenger mutations in colorectal cancer? What is the relevance of passenger mutations from a clinical perspective?

Christopher Lieu, MD: This is a great point in terms of knowing that even if a typical colorectal cancer may have somewhere between 30 and 70 currently detectable mutations, a driver mutation is any alteration that gives that cancer cell a fundamental growth advantage for its cancer transformation. This differs from passengers’ mutations in that the passenger mutations don’t necessarily determine the development of the cancer or the metastatic potential of a cancer. There is 1 study that suggested that only 1 of 10 mutations detected in a cancer may help drive the cancer growth in metastases. Therefore, the driver mutations are what we consider to be critical in terms of effectively targeting metastatic colorectal cancer. I’d also say that the detection of passenger mutations can be helpful as well.

If you think about early stage colorectal cancer and the detection of MRD, if passenger mutations are present in the tumor, and they can also be detected in the blood, that would be representative of MRD because you’re detecting tumor DNA, even if those mutations aren’t driving the cancer. Regarding the passenger mutations, especially when thinking about circulating tumor DNA and MRD, that would count as positive, even if those mutations were not driving the cancer itself.

Transcript edited for clarity.

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