Advancements in Colorectal Cancer: Treating Specific Patient Populations

Pashtoon Kasi, MD, MS, oncologist, director of colon cancer and liquid biopsy research, Weill Cornell Medicine, describes several recent advancements in specific subsets of colorectal cancer and emphasizes the role of biomarker testing for optimizing treatment strategies.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In this episode, Dr Pashtoon Kasi describes advancements in several subsets of patients with colorectal cancer and stresses the importance of biomarker testing.

Hi, my name is Pashtoon Kasi. I'm an oncologist at Weill Cornell Medicine. I'm the director for colon cancer research here, as well as the director for liquid biopsy research at our Precision Medicine Institute.

One recurring theme, that I think is very relevant to other tumor types but colorectal cancer more than others, is that advances are coming, as one of my colleagues put it, in subsets of subsets. That's where biomarker testing can then identify patients who may benefit from a different approach as opposed to the generic chemotherapy-based approach, if not in first line, then later line.

Over the years, we saw the mismatch repair deficient/microsatellite instability-high group of colorectal cancer get separate attention. This is now moving from later line to first line, and now even in the neoadjuvant setting, there was very provocative data to show how immunotherapy for this subset can have a tremendous and even curative impact, a word we never use in the stage 4/advanced setting.

Going along the same story is the subset of KRAS BRAF wild-type. Regarding biomarker testing, at the 2022 ASCO Annual Meeting, for the first time, it cemented the thought process that in the first line, for the left-sided KRAS BRAF wild-type patient population, and I would even add HER2- to that story, will benefit more from an anti-EGFR based approach. That's another subset.

At the ESMO World Congress on Gastrointestinal Cancer 2022, we saw data from the so-called MOUNTAINEER study for the HER2+ subset. If you look at the left-sided KRAS BRAF wild- types subset, that was a 90% of what constituted the MOUNTAINEER trial. There are three dual HER2 blockade regimens in the NCCN guidelines. With the MOUNTAINEER data, I think that's something that we also see being incorporated soon.

No precision medicine biomarker talk would be complete without talking about the druggable KRAS G12C subset. After lung cancer, colorectal cancer is the predominant tumor type that has KRAS G12C mutations. There is flurry of drugs, from sotorasib to adagrasib to other G12C inhibitors that are being used or enrolled in combination.

Gone is the era where 2%, or 4%, or anything in that single-digit percentage was not considered meaningful. Given all these subsets, the role of biomarker testing cannot be overemphasized.

The other subset that also brings biomarker testing into question is those who have the NTRK or the TRK fusions. There's a lot of talk about how expensive these drugs are, but for the select patients who have the NTRK or TRK fusions, they have some tremendous durable responses, which sometimes have led to curative, intense surgeries, things that we never saw before. That's why you have tissue-agnostic approval for NTRK fusion inhibitors.

On biomarker testing, it's also important to realize that one site doesn't fit all, and not all testing is alike. Tissue testing has advantages over liquid. Liquid can fill the void where tissue is not available. When it comes to the tissue, it's DNA vs RNA, and often for fusions, the gold standard is considered tissue RNA.

When people say “biomarker testing,” that could mean a lot of things. As a peer, patient, caregiver, or provider, it's important to know what testing was pursued on what platform. Platforms that were done even a few years ago have improved over time. I would argue the same biomarker testing that was done three years ago from the same platform is probably now different. It may yield results that may be more relevant to the patient now.

Finally, I think for colorectal cancer, it is important to recognize that there is a rise in young onset. For reasons that are still under research investigation, individuals in their twenties, thirties, and forties are getting diagnosed with advanced or metastatic colorectal cancer. They tend to be more left-sided or rectal, again, for reasons that we are still exploring.

What that also means is these are patients who are otherwise healthy, so they probably go through a lot of therapies during their journey with cancer. In terms of knowing what the best drugs are, biomarker testing is as relevant for these patients as it is for the older patient population. You can identify people who may benefit from precision medicine.

This young onset colorectal cancer, in which we were seeing a global rise in the numbers, is important to mention. That's why the age of screening has been moved from 50 to 45. Biomarker testing is key, and I think it should be relevant for all cancers, particularly for colorectal cancer this year and getting this information as soon and upfront as possible. Conducting testing that is panel-based or commercial or considering liquid as well would be the way forward.

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