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Assessing the Causes of Lung Cancer in Never-Smokers
Dr Wakelee

The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.

The real question, of course, is why do people get lung cancer who have never smoked? We don't really know. We think it could be related to second hand smoke, and perhaps it's happening in childhood even more so. It might be from vehicle exhaust, and a lot of work is being done there. Cooking fumes have been the culprit in several studies, especially in poorly ventilated kitchens. Occupational exposures including paint in a recent analysis. Radon exposure is a big risk and something especially in the mountain states, people look at radon levels in their house and important, and that can be a thing to test for.

There are a lot of environmental toxins, such as asbestos and arsenic, and then there's a family risk. It's much, much lower when we talk about cancer risks like colon cancer families and breast cancer families. It's not of that magnitude, but there certainly are families where lung cancer tends to run in the family. We see this especially when the lung cancer is diagnosed very early, there's been a hint that certain genes might be related to family lung cancer -- but we have a lot of work still to do on that.

Overall, though, we don't quite know the reasons why people get lung cancer, but we are starting to understand more about what has happened on a molecular basis, especially in people who never smoked but develop lung cancer.lung-adenocarcinoma-genetics (Click on image to enlarge)

The slide/figure above is focusing on adenocarcinoma, which is the most common type of non-small cell lung cancer in people who have never smoked. If we look just at the never smokers, that red part of this pie chart is even smaller, because we can often figure out a culprit molecular defect. We're getting closer to being able to figure out what has led to lung cancer, even if we don't know why it has happened.

Those different abbreviations along the side of the pie chart are different genes where we've found mutations, or changes in people who have lung cancer, especially those that have not smoked. There's one called K-RAS, EGFR, --probably many in the audience have heard about that -- the epidermal growth factor receptor -- and those are the two biggest. The smaller ones most people probably have not heard about: B-RAF, MEK, HER2; but one that has been making the news recently is ELM4-ALK, and I'll talk more about that as we go through. The rest of the slide just talks about frequency in which these are found, and then also some drugs that are being developed that hopefully will work in patients that have those very specific mutations.

Here we have data with the epidermal growth factor receptor inhibitors. Erlotinib targets the epidermal growth factor receptor, or EGFR, and when the drug was being developed, people noticed that those who were having a really good response were a little bit different than everybody else. They tended to be more women, have adenocarcinoma and especially tended to never smoke.


This got people wondering what's different and led people to look at that EGFR gene, where they found particular mutations, genetic changes, that were very distinctive in certain people who had lung cancer; and in those patients, particularly who had really good responses to erlotinib (Tarceva) and to another drug called gefitinib (Iressa), which is like erlotinib. They both target that EGFR protein.

Next I'll talk about the IPASS (Iressa Pan-Asia Study) trial, which done when people realized that patients who had adenocarcinoma and really hadn't smoked much seemed to be responding better to gefitinib and erlotinib. A trial was designed in Asia just looking at patients who fit that model, and they either received gefitinib or they got chemo first line, trying to see if maybe these EGFR inhibitor drugs were even better than chemo in people who fit that sort of grouping, especially the never smokers. They were looking largely at what we call progression-free survival, which is time from when you start a drug until you need to change to a new treatment.

The results of the trial were a little bit confusing in its general context, if you just looked atq all of the patients who never smoked who were in Asia and you gave them the gefitinib versus the chemo. It wasn't clear that one was better than the other. You had this crossing curve for the progression and for survival, no difference whatsoever.


I just mentioned that people had been figuring out that these EGFR mutations were very relevant. We now know that non-small cell lung cancer patients who have mutations in the EGFR can be very, very responsive to the EGFR drugs, gefitinib and erlotinib. The reason is because those mutations, when they're present, they turn the EGFR protein on all the time. Normally you have to get a signal to turn that protein on, but when you have these mutations it's like turning the light switch on and leaving it on all the time.

The most common mutations are in parts of the gene called exon 19or exon 21, and about 10% of people in the US have these mutations, 10% of the people who have lung cancer. It's about 30% of the people who have never smoked, and in parts of Asia, up to 70% people who have never smoked and have adenocarcinoma have these EGFR mutations. It's not a huge percentage of all lung cancer, but it's a very high percentage of those who've never smoked to get lung cancer -- and again, we don know why the mutations happen. We just know that they're there, and in patients that have them, they respond very differently to treatment than people who don't.


The figure above is looking at that same IPASS trial, only instead of looking at everybody, it's looking at those who either had an EGFR mutation (on the left) or who didn't have an EGFR mutation (on the right). And on the left you can see in green the people getting gefitinib who had an EGFR mutation did better than the people getting chemo. But on the other hand, if you didn't have the mutation, even though you were a never smoker and had adenocarcinoma and you were in Asia, you were much better off getting the chemo. That's that orange line. This is looking at survival and how many people are still living with their disease.

This is a very striking indication that we should be looking for these mutations, especially in people who have never smoked, to help us figure out which treatments are better. In this particular trial, 60% of people in the study did have the EGFR mutation, which is not surprising, because it was a never smokers in Asia.

The next thing that we've looked is this ELM4-ALK and this is a very new discovery. This particular molecular defect was identified just three years ago, representing the first time anyone had heard about this ELM4-ALK. It's two genes that are fused together: ELM4 and ALK.

ALK has been known for a while, because it's involved in some lymphomas and is an aggressive thing, but no one expected to find it in lung cancer until this discovery by a group of Japanese investigators. They figure out that about 4% of people with lung cancer have this translocation and that for those people, that 4%, this is really what's causing them to have cancer.

Again we don't know why it happens. We don't know why this fusion protein develops, but we know that for those who do have it, it's really the driving force behind their cancer, and it's almost only seen in adenocarcinoma -- not in small cell, not in squamous -- just adeno, and again more in non smokers. Where we say 4% of all comers, it's probably about 10% of people who have never smoked who get lung cancer and in parts of Asia. In one study out of china China where they looked at patients who had adenocarcinoma and who had never smoked, who did not have EGFR mutation, did not have the KRAS mutation, about 40% had this group had ELM4-ALK. So it's actually pretty common for the non smokers.

What this next figure is showing is very exciting results with a drug called crizotinib, which at this time is just for patients who have that ELK4-ALK translocation.


Here, what this figure is showing is that the black line in the middle what you'd see if you had started the treatment and nothing happened at all: you'd be right at that line. If you started the treatment and your tumor kept growing, then those are the upward lines to the far left. That's growth unfortunately. But the vast majority of people who are on the study, who have that ELM4-ALK translocation and got crizotinib, their tumor shrunk. The length of the line indicates how much the tumor shrunk. The person who's in red (far right) had a great response: the tumor was pretty much gone, and there were a lot of other patients where it looks like the tumor is almost gone.

This is really exciting, to see a drug where we know the target, which is that ALK translocation, and when you give the drug to patients who have that ALK translocation, they have really good responses. Unfortunately, this is less than 4% of all patients, but it's about 15% or so of the young never smokers with lung cancer, and in certain parts of Asia and even maybe higher, especially if we know that they don't have the EGFR mutation.

So in summary for lung cancer in non smokers, about 10% of men and about 20% of women in the US with lung cancer who have never smoked, rates are higher in certain ethnic groups, and in Asia. It's unclear if the rates are increasing, but that's the suspicion of many of us. We really don't know all the causes, but we now do know some of the molecular causes. What's happening on the molecular basis and being able to target it and we're learning about new treatments all the time.

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