Overview of Metastatic Colorectal Cancer: Presentation and Molecular Testing

Transcript:

Tanios S. Bekaii-Saab, MD: Colorectal cancer is one of the most common cancers. Unfortunately, with colorectal cancer, most of the patients will present at some point of their diagnosis with metastatic disease. Early on, 20% will, but ultimately about half of the patients will present with metastatic disease. One of the trends that’s most disturbing that we’re seeing across cancers, but specifically with colorectal cancer, is the emergence of young adult-onset colorectal cancer. We’re seeing an epidemic of patients presenting at a younger age from their 20s, 30s, 40s, lower than the typical age of 50 and above. In fact, the guidelines for colonoscopies have changed, moving the first colonoscopy or the first screening test from 50 to 45. We’re even thinking [about bringing] this closer to 40 to meet the changing epidemiology of this disease. [There are] many reasons why this may be happening. Some relate to lifestyle, others to changes in the microbiome with things we grew up with eating, drinking. Also, there is certainly an epidemic of obesity in the western part of the world. All these may have contributed somewhat, although we don’t have tons of clarity about what’s driving this.

As we’re seeing a lot of these patients presenting to us with metastatic colorectal cancer, the main question is, how do we diagnose these patients? How do we establish the level of spread of the disease? Also, an understanding of what’s driving their cancer. Given the availability of a lot of agents that specifically target certain subsets of patients, it is important to have this in hand as we’re planning for our treatment. With the usual scanning, occasionally PET [positron emission tomography] scanning and other modalities, we are able to stage the patients. It’s important to understand which patients have oligometastatic disease because they follow a different pathway, where there’s involvement of more of a multidisciplinary approach: the surgeon, the interventional radiologist, and radiation oncologists and others. Most of the patients will fall into the bucket of widely metastatic disease: patients that wouldn’t otherwise be eligible for local regional approaches.

For those patients after staging, as part of the planning for treating those patients, it is key for us to understand the genomic landscape of what is driving their cancer. That’s important, as it can give us prognostic information, but very importantly, also predictive information in terms of the target. So, we typically and widely send liquid biopsies [circulating tumor DNA] on all patients [for testing]. Every patient who presents to the clinic, sometimes even before we see them—our nurse navigators have been doing this more automatically, where applicable. [We send] a tissue assessment as well. The reason why we do the liquid, in addition to the tissue, is the liquid’s turnaround. So, the ctDNA [circulating tumor DNA] turnaround is about a week or so. The tissue is a little bit longer, and some of it gets complicated by the fact that we may not be able to find the tissue. It may be a different institution. However, the blood, the patient is there, we take a blood sample from him, and we send it for testing. There are limitations for the liquid biopsies. Although it’s quite sensitive and has a high concordance rate with the tissue in about 15% to 20% of the patients, we may still miss on a target depending on the level of shedding of the tumor, etc. If you find it in liquid, it’s certainly in tissue. If you don’t, you still have to wait for the tissue. That’s important for the planning.

Some of the things that we look for or important aspects—if you had to pick 4 elements to start with, it would be the presence of RAS mutations, BRAF V600E mutations, MSI-high [microsatellite instability-high] tumors, and then HER2 [human epidermal growth factor 2] amplifications now added to the mix. Why? Because RAS mutations tell you that you can’t use EGFR [epidermal growth factor receptor] inhibitors, but also with G12C and other emerging targets, we even have some first-line studies and second-line studies looking at targeting G12C, KRAS G12C. BRAF V600E indicates a very aggressive biology of the disease. We have opportunities to target this later, but now studies also look at earlier lines of therapy, but because it predicts for very aggressive biology, like RAS mutations, if we don’t have a targeted strategy, then we want to move with triplet therapy where applicable.

HER2 amplifications are important because, one, we have studies in the first line that are targeting HER2-amplified tumors. They also indicate that those patients with HER2-amplified tumors are resistant to EGFR inhibitors. Now, these tumors that overexpress HER2 tend to be left sided and RAS wild type. Those are the patients for whom we typically think about an EGFR inhibitor. About 8% of those patients who have left-sided RAS wild-type also have HER2 amplified. Those patients should not get EGFR inhibitors. It’s important to have that in hand. In our institution, we’ve been doing more consistently IHC [immunohistochemistry] and FISH [fluorescence in situ hybridization] testing, which has a turnaround of about 2 to 5 days, automatically on tissue tested by our pathologist. That’s helping at least put this in front of us waiting for next-generation sequencing testing. Also, waiting on the liquid and then the tissue.

Then finally, MSI-high [testing], which is automatically done now on all solid tumors, including colorectal cancer. We have data with first-line pembrolizumab that for about 40% to 50% of the patients, it may be the only agent they’ll ever see in their life because they do fantastic and many of them are cured of their disease. So it’s important to have that. These are the 4 that I say at the minimum you need to have before planning for the next step. But of course, it would be nice to have the whole landscape. We’re learning more and more what that means as we move forward with more agents coming to the first line.

Transcript edited for clarity.