Case 2

Van Morris:

We’ll move on to our second case now, this is what do we do in patients with newly diagnosed microsatellite instability–high metastatic colorectal cancers. This is a 74-year-old male who presents to your clinic with newly diagnosed stage IV adenocarcinoma of the ascending colon. His imaging studies reveal lung metastases and diffuse lymphadenopathy suspicious for metastatic disease. A lymph node is biopsied and confirms the diagnosis of metastatic colorectal cancer.

He has a medical history significant for type II diabetes, coronary artery disease, and stage II chronic kidney disease. He has no family history of any cancer. There’s no colorectal cancer in his family, nobody he can remember with a history of uterine cancer. He otherwise appears well. His ECOG performance status is 0, his exam is unremarkable.

And on further testing, his pathology is notable for the loss of MLH-1 expression and his NGS testing reveals BRAF V600E mutation as well. I’m going to start by asking Dr. Pedersen, can you talk about just what is the overall prevalence of microsatellite instability–high status in the general population of patients with metastatic colorectal cancer, and is there a difference between that and patients with BRAF V600E metastatic colon cancer?

Katrina Pedersen:

In stage IV colorectal cancer, you see microsatellite instability not all that commonly, actually. It’s only about 4%, 5% if you're being generous of the overall population who’s diagnosed at stage IV. It's actually much more common to have MSI-high related cancers found in the stage I/II setting. And even III and they’re more likely to be cured at that point. As far as BRAF V600E mutations go, it’s also quite rare. I do see a range reported that goes anywhere from 6% up to as high as 15%. I’d say in my clinical practice, it really is what I see most commonly published, about 8%. Certainly fewer than 1 in 10 patients who has a BRAF V600E mutation. And they can overlap, they certainly do co-occur. And you can see that sometimes as a sign that this patient has not inherited their microsatellite instability.

Van Morris:

Yeah. Definitely a higher co-occurrence of BRAF V600E mutations and a microsatellite instability–high status. Dr. Parikh, this patient comes to your clinic and has done his reading and you tell him there’s a microsatellite instability–high status with the pathology report and he asks you, “Do I need to have my children tested for an inherited genetic syndrome? What’s the likelihood that I’ll pass this colorectal cancer onto my children?” What is the likelihood that in a situation like this with a either BRAF V600E mutation, a loss of MLH-1 expression on immunohistochemistry with a promoter hypermethylation, can you talk about what’s the likelihood of a genetic syndrome here?

Aparna Parikh:

Yeah, I think as Dr. Pedersen alluded to, it’s almost pathognomonic for acquired alteration, sort of somatic alteration, so very unlikely. I think that being said, there’s a movement to potentially advocating that maybe all colorectal cancer patients should get germline testing independent of mismatch-repair status. Which routinely and by most institutions is almost reflexively done. I think for this particular patient, I would feel comfortable and confident in saying that it’s unlikely to be Lynch, but again, it’s not yet endorsed in the guidelines for everyone, but there is a movement toward more universal germline testing.

Van Morris:

I couldn’t have said that any better at all. I really agree with everything you all are saying. I think this also highlights another unique aspect of the BRAF V600E population, with the biology. Which is that these tumors tend to be more globally hypermethylated, and the driver here is why this patient may have a microsatellite instability–high tumor is the addition of the methyl groups onto the promoter of the MLH-1 gene. This translates down to loss of expression of the MLH-1 protein and why this patient has a microsatellite instability–high status.

My next question would be what treatment recommendation would you have for this patient? And I’ll point this to Dr. Pedersen. Again, we could ask the questions like there’s pembrolizumab if he has an MSI-high tumor, this is an untreated patient, but there’s BRAF/EGFR with encorafenib/cetuximab in the second-line setting. Chemotherapy with FOLFOX/bevacizumab, standard front-line chemotherapy for unprofiled patients with metastatic colorectal cancer or irinotecan/cetuximab.

Katrina Pedersen:

So most prospective data for MSI-high BRAF V600E–mutated metastatic colorectal cancer has really shown that there is still significant benefit in approaching it as you would approach non-BRAF–mutated MSI-high tumors, which is to approach it with immunotherapy, a PD-1 checkpoint inhibitor, for instance. KEYNOTE-177, which was the front-line trial that randomized patients to receive either pembrolizumab versus investigator’s choice front-line chemotherapy doublets did show significant benefit from using upfront immunotherapy with pembrolizumab compared to the conventional chemotherapy approach. And that trial did enroll patients who did have BRAF V600E mutations and again, they seem to have similar outcomes. With this particular patient, I would approach it like that, although depending on how fit they were, I might also consider an approach combining it with CTLA-4 checkpoint inhibition.

Van Morris:

Yeah, exactly. So the CheckMate 142 trial that was, I think it published earlier this year, that was at the trial that looked at as Dr. Pedersen is referencing the combination of nivolumab and ipilimumab in the front-line setting for patients with MSI-high deficient mismatched-repair metastatic colorectal cancer. And close to 40% of the patients on that study had BRAF mutations. The patients with the co-occurrence of the MSI-high tumors and the BRAF V600E, they tended to do just as well in the subgroup analyses as when you looked at the other molecular annotated subgroups of patients, the KRAS-mutated and then the BRAF/KRAS/NRAS wild-type populations as well.

One of the questions our fellows often ask when they rotate through our clinics is when you look at the KEYNOTE-177 data, that was the trial that compared chemotherapy versus pembrolizumab in the front-line setting for patients with MSI-high metastatic advanced colorectal cancer. Even though pembrolizumab did meet its primary endpoint, when you still look at the Kaplan-Meier curves, 40% of the patients out of the gate did not respond to immunotherapy. It’s one of the natural assumptions one could make is, “Well, we know that BRAF V600E is a poor prognostic biomarker, is that the BRAF V600E patients who did especially poorly with the pembrolizumab and that it accounted for that 40%?” But when the authors looked in a subset analysis, that was not the case at all. And the BRAF V600E population of patients on the KEYNOTE-177 trial, they fared better with pembrolizumab than they did in the chemotherapy arm.

I think it’s just really important for oncologists to remember that if, as Dr. Pedersen mentioned, it’s really the MSI-high status, which is driving the biology and should be driving the treatment plan here. And we should still probably at this time be offering these patients pembrolizumab outside of a clinical trial versus chemotherapy BRAF V600E–mutated or not.

There is a trial that’s looking at adding a BRAF/EGFR combination. This is the SEAMARK trial that’s looking at patients with untreated metastatic colorectal cancer who have MSI-high tumors and also have BRAF V600E mutation. Everybody on the trial gets treated with standard-of-care pembrolizumab. Patients are just randomized to either pembrolizumab alone as standard treatment for MSI-high metastatic colorectal cancer or pembrolizumab with encorafenib and cetuximab. Hopefully building upon this immune activation that Dr. Parikh referenced earlier with the synergy between MAP kinase and immunotherapy. Those, of course, were in the MSS setting, but this trial is looking to hopefully replicate some of that in the MSI-high setting as well.