Molecular Testing and First-Line Therapy in mCRC

Wells Messersmith, MD:In this case, you wouldn’t have to order more molecular testing, because you know there’s aKRASmutation. Generally speaking, we also test forNRAS, butKRASandNRASmutations are rarely coexistent. Once you have a mutation in the pathway, there really isn’t an additional selection pressure to have a second mutation. So, it would be sufficient once you detect thatKRASmutation to proceed. And we knew that this patient was microsatellite stable—that’s really the other key test. It’s important also to knowBRAFstatus, but, again,KRASandBRAFare similar pathways, and so it’s very rare that you have mutations in both of those.

Getting a more complete molecular testing can also be important in some cases; it’s just that it’s a minority of cases. But most specialized centers nowadays are getting full mutational profiling to see if there are other things that might be targetable down the line—usually in later lines of therapy—but it’s something that might be targetable often on a clinical trial with one of the tyrosine kinase inhibitors or one of the other pathway inhibitors, and also for clinical trial eligibility. So, at this point in time, you have enough information to start treatment; you don’t need to wait. But while the patient is on first-line treatment, which generally lasts 10 months as the average for progression-free survival, we’ll often go ahead and get additional testing.

FOLFOX/bevacizumab is a very common regimen to use in this situation. Many people would also substitute capecitabine for the infusional 5-FU. So, instead of FOLFOX, it would be CAPOX. And it’s often used because there’s no hair loss, less diarrhea. Of course, you do have to watch out for neuropathy. And so, from a cytotoxic backbone, that is FOLFOX or FOLFIRI; many people will choose FOLFOX on that basis. The people who are strong advocates of FOLFIRI would argue that you don’t have a cumulative side effect like neuropathy that gets worse each time you get it. And so, they like to start with an irinotecan-based regimen, and that’s fine.

Now, let’s talk about the biologics. In this case, bevacizumab was chosen. That’s a very reasonable first-line regimen. It’s on the label, it’s on all the guidelines, and it’s typically very well tolerated. You have to watch out for things like hypertension. There’s bleeding and clotting events, but these are quite rare. You have to look out for proteinuria, but, again, it’s rare that you actually have to adjust the dosages. And you don’t have things like rash that you have with EGFR inhibitors, which many patients aren’t eager to get because you have an acne-like rash over the face, the upper chest, and the back that can really impact quality of life.

So, for that reason, this is a very common regimen. I’d say it’s one of the most common regimens that’s chosen in the United States. In Europe, on the other hand, they often tend to favor more the FOLFIRI regimens, in part because of cost. Historically, irinotecan came off the patent first, and so it was cheaper. And so, many of the countries in Europe would start with an irinotecan-based regimen. And as I said, that’s quite reasonable to do.

In this case, because it’s aKRAS-mutated tumor, even though it’s on the left side, we still would not use anEGFR-targeting monoclonal antibody, such as panitumumab or cetuximab, in the first-line setting, because those have been shown to either have no benefit or potentially cause harm.

It’s important to talk with the patient about what their goals of therapy are and what tolerance they have for side effects. And you can have very reasonable, intelligent patients who have very different opinions on that. You’ll have patients who say, “Doctor, I want the most aggressive chemotherapy regimen you have, even if I’m not that symptomatic, because I just feel more comfortable hitting this cancer hard. I want to make it shrink on scan, and I’m fine with managing side effects—it’s really not a big deal.” Other patients who are equally smart but maybe have a slightly different value system might say, “You know, I really don’t want a bunch of different aggressive type of chemotherapy drugs. I don’t want a lot of side effects if you’re not going to cure me. If you’re not going to cure me, then this is really palliative therapy, and so why would I tolerate a lot of side effects?” And so, trying to elicit that from the patient to get a sense of it…unfortunately, because cancer is so common, it strikes hundreds of thousands of people; most people know somebody who’s had cancer. It could be a family member; it could be a friend. People will often come in with fairly strong preconceived notions about it. And, of course, chemotherapy is different for different diseases. So, I’ve had patients who had a friend with a leukemia who had to be inpatient for a bone marrow transplant. That’s very intense chemotherapy. And so, you really can’t extrapolate from that and say that that’s the experience that’s someone’s going to have with colorectal cancer.

And then, finally, I think a big driver from my standpoint to talk with a patient about is, what are their symptoms now? If you have a patient who has no symptoms from their cancer, if you think about it, from a quality of life standpoint, you can only go downhill because all chemotherapy has side effects. And if they’re feeling fine, then it doesn’t make a lot of sense to try to make a CAT scan look pretty. You know you want your patient to look good and to have a good quality of life and to feel good, but it doesn’t make a lot of sense to try to shrink the tumor with 6 different chemotherapy drugs. And so, that’s also important, as well.

If patients are having pain, if there’s an organ that’s about to be cut off by a tumor—such as one in the liver that’s going to hit the bile ducts, one that’s against the urethra that might hit the kidneys, or it’s invading a muscle or a bone that might break, or something where you’re worried—if this thing grows 10% or 20%, my patient’s going to have a big problem. So, in those cases, I tend to be more aggressive, because I feel like I’m doing a benefit by making it shrink. But there’s a lot of patients who for whom it won’t help all that much to make the tumor shrink. They want to work full time. Financial concerns are often major with cancer patients—all the co-pays and other issues that come up. They want to keep their job. If they lose their job, they’re going to lose their insurance. And these are very real concerns that people have. And so, for patients who aren’t symptomatic, I tend to try to get away with as little as I can to try to preserve that quality of life, so that we both know I’m not going to cure them, and at least the time they have—which, hopefully, will be a long time—is of the best quality that I could make it.

Transcript edited for clarity.

Progression of Left-Sided mCRC

February 2016

• A 66-year-old man reported with constipation, bloating, abdominal pain and weight loss of 12 pounds in 2 months
• PMH: mild hypertension, well-controlled on CCB
• Lab evaluation: Grade 2 anemia (Hb 9.2 g/dL)
• Colonoscopy revealed a7-cm mass in sigmoid colon
• CEA, 80 ng/mL
• The patient underwent sigmoid colectomy
• Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue;
  • Biopsy: 7of 12 resected nodes positive
  • Molecular testing:KRASmutation in codon 12 of exon 2; microsatellite stable
• CT scan showed several lesions in both lobes of the liver, measuring up to 17 mm in diameter, and 3 small lesions (<6 mm) in the left lower pulmonary lobe
• Diagnosis: Stage 4 colorectal cancer
• The patient received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• The patient was continued on bevacizumab maintenance

February 2017

• One year after starting therapy, the patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed progression in three of the liver lesions and one lesion in the right pulmonary lobe
• The patient was started on FOLFIRI and continued bevacizumab

January 2018

• Eleven months later, CEA level rose significantly
• Follow-up CT showed progressive disease in the lung and liver
• The patient is interested in knowing his options at this stage