Johanna C. Bendell, MD: So, it sounds like for stage II, this is where we might question whether or not we use adjuvant therapy. Things like, if you’re going to use an assay like Oncotype DX or [are] thinking MSI [microsatellite instability], that may or may not change your thought for treatment.

Heinz-Josef Lenz, MD, FACP: Yes.

Johanna C. Bendell, MD: Dirk, if you saw a stage II patient, tell us about what you would definitively test and why.

Dirk Arnold, MD, PhD: Well, this is an interesting question, because I’m now speaking from the European perspective, because when we look at the 2 sides of the Atlantic, we say we have to see how we fail in really characterizing what the prognosis is and what contributes to the improvement. I will say we do know that most of the patients with stage II are cured by surgery alone. And we do know that we can reduce the risk of death from this disease by about 3% to 3.5% with 5-FU [fluorouracil], if at all.

And the question is really, should the risk stratification be on a molecular basis as hindsight, and then MSI status? And microsatellite instability, it’s clearly the main driver. Or is it more [based] on clinical factors which should make or drive the decision—and clinical factors are insufficient now to evaluate lymph nodes, as well as less clear—but also grading and tumor budding, and whatever infiltration may play a role from the clinical [perspective], as well as abstraction or operation in a perforation situation, etc.

And it is not entirely clear what is the dominant driver for [a] patient’s prognosis and what should be the trigger for a treatment decision. Isn’t the clinical situation which is over, let’s say trumping the MSI status. Or is it the makeshift in between and this in the complexity of decision making stage II for me.

Heinz-Josef Lenz, MD, FACP: Can I add something, because I think it’s an incredible mystery. In MSI-high [disease], stage II is very good because we know we harm patients with chemotherapy. In stage III, equal; not good, not bad. And in stage IV, very bad. How is that possible? So, there is a lot of research now going on. How is that explainable? It can only be explained that it’s not nonrandom, and it’s a very, very specific mutational spectrum you’ll find in stage II, stage III, and stage IV—and it’s the opposite. So, I think we will hear in the future much more about why we see this opposite prognostic value in different stages of colon cancer.

But I want to come back to the NGS [next-generation sequencing] because it seems like overkill. I mean, we’re thinking, “Is this guy crazy doing NGS?” But I think it will become, potentially, standard because only when you have the NGS data, [can you] look at liquid biopsy. Because if you don’t have the NGS data, you don’t know what you see in the blood—if this is a false-negative, a false-positive, and so on. So, I think we need to know what are the tumor-specific mutations, when we want to really discuss the outcome of a liquid biopsy; which I’m sure we will discuss a little bit later. That may change the way we look at active and treatment.

Johanna C. Bendell, MD: So right now, what I’m hearing from you, part of the stage II population maybe doesn’t necessarily have a benefit from chemotherapy.

Dirk Arnold, MD, PhD: Or they have such a good prognosis, if say you have these MSI patients which have such an excellent prognosis, from the molecular basis, that it is not justified to treat them when they recur.

Zev A. Wainberg, MD: And I think that’s pretty clear, and that’s been clear for some time, that even before the data [have] emerged with MSI, that patients who have T3N0 MSI should not be getting chemotherapy.

Heinz-Josef Lenz, MD, FACP: They’re harmed.

Dirk Arnold, MD, PhD: But Zev, I may add, what should we do when one of these patients was operated on [on] the conditions of an obstructional perforation and has a more or less insufficient lymph node count or a borderline lymph node count? You have the information from 12/12 tumor-free lymph nodes—no more, no less. And the patient is MSI-high. How do we judge this patient? Is it really that excellent [a] prognosis if he’s operated on the perforation?

Heinz-Josef Lenz, MD, FACP: I agree with Dirk. Well, one of my biggest dilemmas are the stage II, the T4s.

Johanna C. Bendell, MD: The high-risk stage IIs, yes.

Heinz-Josef Lenz, MD, FACP: The T4s, and MSI-high. Okay?

Heinz-Josef Lenz, MD, FACP: Now, we know from subgroup analysis these patients do extremely well, the T4s and MSI. We all see that in our practices, these big tumors and no lymph nodes. How can this be? There must be biology with it when a tumor grows 8, 9 centimeters and cannot go to the lymph nodes. It’s a different beast. But I don’t know if we have… We don’t have the definite data. But I’m struggling within the clinic, too. Should we do or not? And often the patient is saying, “I don’t want to get treatment because I don’t want to take a chance,” rather than me saying, “You should get it.”

Transcript Edited for Clarity