Case 2: Rare Alterations and Germline vs Somatic Testing in CRC



Richard Kim, MD:In the review of this case, we have a very young gentleman with the diagnosis of a left-sided tumor that isRASandBRAFwild type. Obviously, part of the molecular profiling that is missing is MMR [mismatch repair] status. I would probably check for that because the patient is young, even though it doesn’t seem like the patient has any family history of colon cancer.

In the case of a left-sided tumor, there is some controversy. What do you do for a patient who has a left-sided tumor withRASwild-type disease? Do you use EGFR-based therapy or VEGF-based therapy? This is a question that I’ll discuss with the patient. Based on the PEAK study, the FIRE-3 study, and the CALGB 80405 study that I just presented, there seems to be a benefit in using the anti-EGFR drug over the anti-VEGF drug in left-sided tumors.

However, the main issue with using EGFR therapy in the first-line setting is toxicity and the question of maintenance therapy. Therefore, I would have a discussion with the patient about the possible overall survival benefit when using the anti-EGFR drug but would also discuss the side effects. We know that withRAS, there is a risk for paronychia if you are on the EGFR drug for a long time. So I will have a long discussion with the patient, and then we will decide whether to go with an anti-EGFR drug or an anti-VEGF drug.

Shubham Pant, MD:Richard, thank you so much. This is a case for which we have a lot to discuss. Greg, first I’ll come to you. In these patients who have wild-type disease, should we look for other mutations or not? Microsatellite instability—definitely. I think you would all agree that we should look for that. Is there anything else that we should look for in this patient?

Gregory Riedlinger, MD, PhD:It’s a little concerning that the patient is 35 years old. This is a younger patient. So certainly, as is the routine standard of care, you would want to make sure that you looked at the mismatch repair proteins. You also want to make sure there’s a good family history. You may even, potentially, refer the patient for genetic counseling, just to make sure that there’s not some type of syndrome going on. There could be additional testing there. In terms of anything you know past that point, there’s generally smaller percentages of potentially actionable mutations that larger gene panels, such as next-generation sequencing-based testing, may be able to pick up—these types of alterations. If you’re going to do these types of tests, the patient really needs to be managed at an academic medical center, where they’ll potentially be equipped to deal with some of these rare alterations.

Shubham Pant, MD:Greg, you brought up a great point. I’m going to ask you a question that we sometimes get asked. Can you tell us the difference between germline and somatic mutation testing? How are they different? Nowadays, we do a biopsy and we pick up something on next-generation sequencing. Can you explain the difference between those?

Gregory Riedlinger, MD, PhD:Germline testing essentially tests every cell in the patient’s body for a specific DNA alteration. Somatic testing generally refers to cancer-specific testing. A lot of places are doing so-called tumor-only testing. They don’t necessarily have a germline sample. With somatic testing, you may also be picking up the germline alterations. There are different algorithms that go into some of these tests, where they can sometimes try to infer that something may be germline versus somatic only in the cancer cells. That is never 100% accurate. It can be used only to give you an idea. In terms of somatic testing, you generally want 20% tumor cell nuclei to ensure that you don’t have false-negative results. So heterozygous mutation frequency of 10% in 20% tumor nuclei—most of these tests have a sensitivity to at least 5%, so you wouldn’t really worry about missing things as long as you have that amount of tumor and it’s a solid tumor specimen.

Shubham Pant, MD:Mike, I’ve seen younger patients with colorectal cancer in my clinic. What do you counsel them on? Do you send them for genetic testing? I think that’s a very important point that you brought up, Greg, because sometimes these patients may show up and probably do need to be referred to see a genetic counselor.

Michael Morse, MD:We are seeing an increase in younger patients, younger than age 50 now. That’s certainly been cause for concern because screening recommendations may need to be altered. In fact, there are now recommendations to lower the age of screening for colon cancer to age 45. So this is an important consideration when we discuss the ramifications for patients themselves, as well as their family members. I agree that in somebody with an unusual presentation, if there is a family history or if they are particularly younger in age, we should certainly offer a visit with a genetic counselor to discuss other options.

At what point would you think it’s important to test for what is probably the next most common mutation? It’s really not a mutation but an amplification ofHER2.

Gregory Riedlinger, MD, PhD:We do a lot of larger panel testing. I’m not sure, off the top of my head, what the percentages are. You can probably correct me, but I believe it’s usually somewhere around 2%.

Shubham Pant, MD:That’s right.

Gregory Riedlinger, MD, PhD:On that level they haveHER2amplification. There’s an FDA-approved drug for that. There are also other mutations in some of the other cases that are at similar, at low levels, to that. The advantage to doingHER2testing is that it’s cheaper, with immunohistochemistry, to just run that test if you’re concerned about that, as opposed to doing a large panel. However, these large panels will pick upHER2as well as other alterations.

Transcript edited for clarity.

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