DR GOLDBERG: So this is a young woman who, as is commonly the case when you see young patients, had symptoms that took a long time to recognize. She had 9 months of abdominal discomfort before she presented with sort of a crisis of pain and was found to have a near-obstructing sigmoid tumor.

She had a CT scan in the emergency room. It showed multiple large liver metastases. Before she was referred to me, she had a left hemicolectomy, had a T3 tumor with 3 positive nodes, so a Stage IIIA except for the fact that she had metastatic disease.

We did do molecular testing, obviously concerned about possible Lynch syndrome because of her age. MSI was normal. KRAS testing was normal, but she had the dreaded BRAF V600E mutation, suggesting to me that she had aggressive disease.

DR LOVE: Let me just kind of go around here. Obviously, this is a difficult situation. She has this BRAF mutation on top of her clinical course. Charlie, what would you be thinking?

DR FUCHS: The FOLFOXIRI data really look interesting vis-à-vis BRAF. And maybe that’s a good idea in somebody with bulky disease with a BRAF mutation.

One other point that I think is important to make is that — and we sort of alluded to this — is that all BRAF mutations or all patients with BRAF mutations may not be alike. And it’s, I think, very important that Rich mentioned that the patient did not have microsatellite instability, because there’s an association — MSI-high tumors are more likely to be BRAF mutated than BRAF wild type. And if you have a BRAF mutation and you’re MSI high, that may not be a bad prognosis. In fact, it suggests it isn’t. But if you have a BRAF mutation and you’re microsatellite stable, those are the people that do poorly. So when you look at BRAF mutation, it’s important to also know their MSI status.

DR LOVE: Would you be thinking about FOLFOXIRI and bev in this lady if she did not have a BRAF mutation?

DR FUCHS: I probably would not. I haven’t routinely used it in a setting where — unless I really think that this person is so far along with the burden of disease that I just have no options and I may miss out on second-line therapy.

DR LOVE: Johanna?

DR BENDELL: I probably, if I didn’t have access to BRAF mutation clinical trials, would say FOLFOXIRI/bev. But I actually encourage my docs to try to test for BRAF not only to know a little bit about prognosis, but to try to key those patients into getting to a clinical trial as quickly as possible, because as Rich alluded to, these guys will progress very quickly. And they might lose out on windows. I have a lot of physicians who have emailed me from the community about patients who have been rapidly progressive. They finally check a BRAF, but by the time they get the result back, the patient’s too sick for further therapy.

DR LOVE: Again, this same lady, 30 years old, multiple large liver mets, without BRAF mutation?

DR BENDELL: Potentially FOLFOXIRI/bev, if she’s got such incredible liver disease. The other thing that I have done for some of these patients is, I’ve done FOLFOX plus bevacizumab and then done liver-directed therapy, so between radioembolization and chemoembolization. I realize the data is not as strong there. But for people who have bulky, bulky liver disease where I need to get it under control quickly, it would come into consideration.

DR LOVE: Okay. So again, just off the top of your head, you get an email, Philip, this lady with a BRAF and without BRAF.

DR PHILIP: Actually, I saw a 30-year-old 2 days ago. And I didn’t have the BRAF on the patient. And a younger patient who can tolerate the FOLFOXIRI, my plan was to start her on FOLFOX plus bevacizumab.

The point to make about the BRAF testing and those things for the community, at this point in time KRAS has strong support, but a complex genetic disease like colorectal cancer, I think the future probably is going to be more like multiple gene mutation panels, where you can identify more the course of the disease rather than single genes that are here or there. So the BRAF is prognostic. We do it, but I don’t think it’s something which I would recommend everyone does it, because at this point in time a prognostic marker is a prognostic marker. It may not help you much, especially in a disease where the treatment options aren’t that many and you really have to go through all of them, unless there is a treatment that is contraindicated in a given genetic mutation. And that would be KRAS, for sure, in this situation.

DR LOVE: So just to be clear, though, in terms of this patient you just saw, you were thinking about it because he’s younger?

DR PHILIP: He was a young patient, who was a 30-year-old. He had good performance status, you would expect. And my experience in the past in those patients, for some reason, has been that they don’t do well. It could be the BRAF. It could be the MSI or whatever, or some other genetic marker which we don’t know of yet.

DR LOVE: Interesting. Again, Randy, 30-year-old patient with metastatic disease, what would you be thinking?

DR HECHT: We tend to use 2 cytotoxics, rather than 3 cytotoxics in people. I think this woman was — her symptoms were corrected by the surgery. That being said — as the point has been made with the TRIBE trial, I think with BRAF that’s actually very interesting, though we do not routinely check it.

We seem to be having a rash of 30-year-olds. I also am treating a 30-year-old patient. In fact, she was 29 when we started with 2 drugs, with actually capecitabine and oxaliplatin, 2 cytotoxics plus bevacizumab. Actually had her scan on her 30^th birthday and had a nice response. This was actually about 2 weeks ago. And so patients can still have — the differences are not huge. There was more the survival differences at the end with 3 drugs versus 2 drugs.

When you look at first-line trials — I’m always struck with how few patients actually go on to other…we think of almost all our patients in practice really going on to second line. But it really is, and I wonder in the community, whether it’s even worse, is that the thing I think Charlie had pointed out, is that the patients that you worry who fall off, who never really go on, I actually was going through some trial data. And I’m always impressed at how few patients end up getting second- and third-line — even on study, get third-line therapy. But I would probably, in this woman who’s relatively asymptomatic, treat with 2 drugs.

DR LOVE: Eileen, again, in general, how did you think through this case?

DR O'REILLY: Yes. So I would echo the thoughts that have been presented, but coming from an institution that has a strong interest in liver-directed therapy, that would be high up on our list, presuming she has only liver-confined disease. And that perhaps even with taking out her primary, we might even consider putting a pump in at that time and offer both systemic and regional-based treatments. Response rates that are high in the front-line setting and high even in a second-line setting.

DR LOVE: How many patients in the last year have gotten pump therapy, of yours?

DR O'REILLY: Of mine? Maybe 10.

DR LOVE: Rich? What happened with this lady?

DR GOLDBERG: So what happened with this woman is she elected to go on a FOLFOX plus aflibercept first-line trial. This lady was treated before the trial data had been presented. She didn’t have such bulky liver disease that I was worried she was going to have liver failure. She had normal liver function studies.

I’m happy to say her CEA fell promptly from 200 to about 50. She got about 4 months of treatment before the liver surgeon, who had initially said not resectable, said, “Now I can take her to the operating room.” She had a segmentectomy, so a big liver operation, and then a wedge resection of a left lobe lesion, recovered well from surgery and now has got a CEA of 4.2, so in the normal range. And I’m treating her with FOLFOX without aflibercept. She came off the clinical trial when she went to liver surgery.

I don’t routinely use a biologic in patients who’ve been fully resected. I don’t continue bevacizumab. And I’m hopeful that her future course will be a positive one.

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