Rounds with the Investigators 2012 | Lung
QUESTION: I would like to know from the lung cancer investigators what is the incidence of EGFR or EML4-ALK mutations if a tumor tests positive for K-ras mutation. I have a patient who was diagnosed in 2010 and tested positive for K-ras mutation and negative for EGFR mutation. EML4-ALK testing was not performed at that time, and there is insufficient material to perform the testing from the original specimen. She has now recurred, and I wonder if there is a high enough probability of EML4-ALK mutation to perform a repeat biopsy.
DR NEIL LOVE: Steve, can you kind of present the case that was behind your question?
DR STEPHEN GRABELSKY: Sure. The question that I have in practice, not infrequently, is 2-pronged. Number 1, what, if any, incidence there is of synchronous mutations. And secondly, is there ever a change in mutation status of a tumor? And is there ever a reason to retest for mutations?
And the specific case that brought this to the forefront and why I posed this question is I have a woman in midsixties who underwent a right upper lobe lobectomy for a Stage IIA adenocarcinoma approximately 2 years ago. At that time her tumor was tested and tested positive for K-ras mutation and was negative for EGFR mutation. At that time, this was prior to us doing routine testing for EML4-ALK.
DR LOVE: She was a nonsmoker?
DR GRABELSKY: She was a former smoker, had smoked approximately a pack a day for 30 years but had quit 20 years earlier.
Two years later, she’s now presented with a recurrence in a peribronchial lymph node, which has been confirmed with endobronchial ultrasound-guided fine needle aspiration.
DR LOVE: Jyoti?
DR JYOTI PATEL: Did she get adjuvant chemotherapy?
DR GRABELSKY: Yes. I’m sorry. She received postoperative adjuvant pemetrexed and cisplatin for 4 cycles. So now it’s approximately 2 years later, and she looks like she has a local-regional recurrence. So the real issue I was facing is: There was not enough tissue on the current fine needle aspiration to perform testing for EML4-ALK. Is that something that is necessary to go back and do in someone who is K-ras-positive? Is there any evidence, any time where you would see more than 1 mutation? And again, does mutation status change over time?
DR LOVE: And I’ll throw in there, Tom: Suppose she had never had a K-ras test and she was a nonsmoker. Would that make a difference?
DR THOMAS LYNCH: So I would say, to answer a couple of questions, yes, it would make a difference. I think that, in general, there are 4 mutations now that I think we believe are what we would call actionable. So you’ve got K-ras, not because there’s anything good we can do about it but because it tells us that it’s a particularly challenging type of lung cancer to treat.
DR LOVE: Just to clarify, does that pretty much rule out EGFR mutations?
DR LYNCH: Yes. Yes. So in general, these mutations are exclusive of one another. With that said, okay, in 8 years of doing this, we’ve probably seen 4 patients who had an EGFR mutation and a K-ras mutation, I’ve heard about this at meetings. I’ve seen 1, personally. So it’s not 0, but it’s pretty close to 0, because that’s in a subset of thousands of people who’ve been tested. So you’re looking at a very, very unlikely event that they have a secondary mutation.
So the 4 key mutations are K-ras, EGFR, the EML4-ALK translocation and the ROS1 translocation. Those 4 are the ones that we think are crucial. Three of them are usually seen in never smokers or light smokers, which would be EGFR, ALK and ROS1. And the other key thing is that the driver mutation stays there the whole time. So I don’t think that K-ras will — I think if you tested her again, you’d find K-ras there again. And I don’t think it makes sense in this — I don’t think you’re obligated to go back and test for EML4-ALK. I think with K-ras being present and her being a smoker, the odds of her having EML4-ALK or ROS1, I think, are amazingly small in this setting.
I guess when I heard this — but if she was a never smoker and didn’t have K-ras, then I think you’re perfectly justified to go back and test again. And actually, that makes a lot of sense. In this case, the real question from my perspective is: Is she salvageable with chemo/radiotherapy? Can everything be located in 1 radiotherapy port? And do you think you have a chance at curative therapy? And do we believe that we can really cure patients who have a local-regional relapse 2 years later?
DR GRABELSKY: Her PET-CT scan showed no other evidence of disease outside of this one area. And we actually did elect to treat her with combined-modality therapy, similar to the SWOG regimen with the etoposide and cisplatin in combination with radiation therapy. And she’s currently completing that therapy.
DR LOVE: A related question, Jyoti, that we are getting a lot is: Which patients should be tested for mutations? Do you test them all at once, or do you do EGFR first or K-ras first? And then reflex testing, do you just do nonsmokers? Do you do nonsquamous? What’s your global approach to testing right now?
DR PATEL: So this changes every week, practically, for me. So currently our practice is to do reflex testing for all patients with nonsquamous tumors. And as of last week, everything happened at once. Two weeks ago, patients had multiplexed EGFR and RAS testing and then a week later would have ALK testing in house. And ROS1 we’re sending out currently. And that’s a very small “N.” But again, my sense is that you don’t find it unless you look. I’ve certainly been fooled by patients who are current smokers who have EGFR mutations. It is now, with the amount of tissue you need and multiplex testing, we try to test everyone. I only test patients with squamous cell tumors if they are never smokers.
DR LOVE: Which I gather doesn’t happen too often.
DR PATEL: Infrequent.
DR LYNCH: But pathologists can be wrong. I mean, not wrong. They can make a mistake.
DR LOVE: Sampling errors.
DR LYNCH: Sampling errors.