For the last several years, we've known that never-smokers are more likely to have a significant and long-lasting response to EGFR inhibitors. Since then, we've learned that EGFR mutation status is quite correlated with smoking status and is the more important, likely driving factor, but all of this work has led to a new focus on never-smokers and smoking history in general. In fact, prior to about 5-10 years ago, we didn't consistently record much of a smoking history for patients because it wasn't appreciated as being relevant. Now, not only do we realize it's an important factor, but we're moving beyond the over-simplified view that smoking history is just a "yes/no" answer. We couldn't expect that it would be that simple.

We do know that the lung cancers in never-smokers tend to be more genetically simple than those of long-term smokers, and this makes sense: without the mutagenic ("mutation-inducing") effect of cigarettes, which tend to lead to cancers caused by a critical mass of multiple genetic insults over time, lung cancer in never-smokers tends to occur more directly by getting a direct hit through a random mutation on a critical signal in cell growth and division, such as EGFR, EML4-ALK, or others yet to be identified. That's also why the lung cancers in never-smokers in lung cancer may have an "Achilles heel" if you can find and turn off the switch with an EGFR or ALK inhibitor, while our gains against smokers in lung cancer tend to be more "chipping away" than dramatic shrinkage. They have multiple drivers and aren't amenable to being turned off with a single mechanism. But of course, mutations don't just pile up at the time you light your 100th cigarette (since "never-smoker" status is defined as having smoked fewer than 100 cigarettes in a lifetime); instead, there are plenty of people who smoked very little a long time ago and just happened to get a lung cancer like that seen in a never-smoker. So there's likely a spectrum of people with one or a few very important mutations on one end and many, many less significant mutations all added together as the other extreme. So smoking status is more of a continuous variable (can be anywhere in a range, like height) than a discrete variable (like being pregnant or not).

In fact, that's what the relatively scant evidence shows us. Several years ago, the folks at Memorial Sloan-Kettering Cancer Center (MSKCC) published work from their own more detailed analysis of smoking history, which recorded both "pack-years" (the product of average number of packs per day x number of years smoking) and time since a patient quit, if applicable. Patients were tested for the EGFR mutation, and the investigators found that never-smokers had the highest rate of having an EGFR mutation (51%) (yes, we knew that), but also that ex-smokers had a higher rate of the EGFR mutation than current smokers (19% vs 4%). All of these numbers are higher than seen in some other North American studies, probably because of some self-selection of patients who head out to MSKCC (patients with EGFR mutations are more likely to seek an opinion there). But also quite importantly, patients who quit smoking many years ago had a higher probability of having an EGFR mutation than people who quit smoking just a few years ago, as shown in the table on the right, in the slide below:

(Click on image to enlarge)

Since then, the few studies that have looked at ex-smokers with any granularity have supported the same conclusion. The group from Massachusetts General Hospital in Boston found that the probability of a person having an EGFR mutation dropped by 5% for every pack-year of smoking history (not an absolute 5% change, but relatively less than the probability for a little less smoking history). And a group from Japan noted similar trends but higher proportions of patients with an EGFR mutation overall: 54% of never-smokers, 27% of former smokers, and 15% of current smokers. They also found that the EGFR mutation rate was similar, over 50%, for the ex-smokers with less than a 20 pack-year smoking history but dropped steadily as pack-years increased. And the early work with EML4-ALK mutations is looking very similar, with some centers using a cut-off of a 10 to 15 pack-year smoking history for including patients for testing because they are appearing to have a reasonably high yield for the mutation.

At this point, though, there's still not much evidence because most of our research doesn't record smoking history in any formal, uniform way beyond never-smoker, ex-smoker, or current smoker status, so we don't capture time since someone quit or a good estimation of their smoking history in pack-years. In this respect, the Memorial and Harvard groups in the US, as well as some Japanese centers, are really leading the way. I think this work all converges to convince us that smoking history isn't as simple as a yes/no answer and that our lung cancer research moving forward should demand a higher level of information about smoking history because it's likely to be very relevant as we move toward re-classifying lung cancers by their genetic patterns.