Lung Cancer / Mesothelioma
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Loading ...As I’ve mentioned in some prior posts, there is increasing recognition that lung cancer in never-smokers may be a different disease. Some of this has been defined by working backward from treatment results, where we’ve seen that never-smokers are consistently among the greatest beneficiaries of EGFR inhibitor therapies like Iressa or Tarceva. But there are some general principles and recurring themes with regard to the genetics of lung cancer in never-smokers.
In most cases, lung cancer develops from an accumulation of mutations in a cell over many years, even decades. A multitude of problems in the cell control mechanisms need to go awry before a cancer can grow rapidly and independently of inhibitory signals, while still having a blood supply and getting waste removed. The checks and balances within the cell are so complex that it often takes more than 10 or even 20 mutations in the same cell before it reaches the “critical mass” to become a cancer cell. For lung cancer, most of these mutations are induced by tobacco smoke. Because of these trends, lung cancer is a disease more common with advancing age, with a median age now for initial presentation of about 70 years.
In contrast, never-smokers appear to develop cancer not from an accumulation of multiple mutations that aggregate over the course of many years to eventually become a full-fledged cancer, but rather from a random few mutations that very efficiently derail the cellular control mechanisms. Therefore, tumors from never-smokers tend to have a much smaller array of problems and be “genetically simpler” (abstracts here and here).
Although it was a small study, one trial provides a good illustration by comparing “gene signatures”, the genetic profiles looking at a collection of potentially relevant genes, from tumor and non-tumor lung in six smokers with lung adenocarcinoma compared with the tumor and non-tumor lung tissue from six never-smokers (abstract here). The authors found that four times as many genes were different between the lung cancer tumor and normal tissue of never-smokers compared with smokers.
(Click on image to enlarge)
This suggests that lung cancer develops out of collection of shared defects throughout the lungs in smokers (a field defect), but in never-smokers, the tumor arose due to a random event pretty much out of the blue. Another corollary of this concept is that the genetic profiles of the tumor tissue in smokers is very similar to the non-tumor lung tissue in the same person, and very different from tumor tissue in never-smokers, which is very different from non-tumor tissue in the same never-smoker. While we’re talking about tissue results from just a dozen patients, these results are very intriguing and have led to larger subsequent studes that are trying to characterize genetic differences between smokers and never-smokers who develop lung cancer.
Of course, one key question is whether there are therapeutic implications here. I believe that there are, as I’ve described in the subject archives on never-smoker lung cancer, and/or the core concepts section just to distill down to the basics. As I mentioned above, EGFR appears to be a central part of this story, but to me the general principle is that if never-smoker lung cancer is often much more genetically simple, if we happen to hit it right we can make a very striking and prolonged input. We haven’t even really begun to give a good luck at whether never-smokers may respond unusually well to standard chemo or avastin or some other novel therapy. All we know is that they are the most common MAJOR beneficiaries of EGFR inhibitors like tarceva. But the next big question is whether there are other drugs out there that can have anything close to the impact of tarceva in never-smokers. The trials dedicated to never-smokers are just starting to get off the ground.
Posted in: Core Concepts, Lung Cancer, Never-Smokers with Lung Cancer, Pathology/Lung Cancer Subtypes
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Dr. West: Is it really true that NO analyses of never-smoker subgroups have been done outside of EGFR inhibitors? I’m a little surprised, since in a large phase III study, you might easily have a 150 person never-smoker subgroup (even for post-hoc analysis). Also, smoking status could potentially explain other differences. For instance, if Alimta is more effective than Gemzar with respect to adenocarcinoma, it’s entirely possible (given the correlation between smoking status and histology) that this result is entirely an artifact of non-smokers being more likely to have adenocarcinoma (and, hypothetically, more likely to respond to Alimta).
I guess the other question is what never-smoker studies are going on right now. I know that you’ve got the two on Sutent and Nexavar (never-smoker and/or BAC, right?); are there others?
Thanks for any info you can provide!–Neil
neilb
Neil,
I don’t know of any trial outside of EGFR inhibitors that has done a never-smoker subgroup analysis. Why? Recognition of smoking status only began in earnest in the past 3-5 years, and it’s been picking up speed every year. Back in 2005, I suggested that I speak on smoking status when I was invited to a national conference with a fairly undefined topic, and at that time I think it was one of the first talks I know of that was dedicated to this topic. Now it’s a staple in many lung cancer conferences and there are a handful of lung cancer specialists with this as a research focus. But I think it all really emerged from the recognition that never-smokers seemed to be especially likely to respond and live longer with EGFR inhibitors. Up until then, most clinical trials were not in the habit of recording smoking history. Now they do. But I think there has been such skepticism that smoking status would have a relationship with outcomes on conventional chemo that it still hasn’t emerged as a reported subset that I can recall. The only thing I can say is that the TRIBUTE trial that compared chemo/placebo to chemo/tarceva looked at a never-smoker subset, and it showed that never-smokers on chemo/placebo had the same survival you’d expect for a general population on chemo (chemo/tarceva did much better, but I think that this was entirely driven by the tarceva and that they would have done as well or better without concurrent chemo).
There are still remarkably few trials for never-smokers, at least that I know of. I’m running one through SWOG that is now activated throughout the US, a single arm trial of avastin/tarceva concurrently. I have the sutent and sorafenib trials. I’m thinking about developing others. There is a separate arm on a trial of HKI-272, the irreversible EGFR inhibitor, that has completed enrollment but for which we have no results reported yet. There is also a CALGB randomized phase II trial for never-smokers or light former smokers (up to 10 pack-years and quit at least one year before enrollment), in which 180 patients are randomized between tarceva alone or carbo/taxol/tarceva concurrently — I think this should give a clear answer about the value of concurrent chemo and EGFR TKI, even if it’s not a huge trial.
There is a gap in time from generating interest and asking the question, to developing trials, to enrolling and following patients, and then reporting data. Even the EGFR trials and all of the work up to now has been retrospective analyses, not prospective trials. In the years it takes to go from idea to results, we’re now at a point where trials are moving through enrollment and then toward reporting. Expect a lot more information on this topic over the next couple of years, and perhaps new things to discuss as early as ASCO 2008 (early June).
-Dr. West
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