番茄社区

Fine particulate matter from the combustion of fossil fuels seemed to trigger non-small cell lung cancer (NSCLC) in never-smokers through a process of tumor promotion, according to a study on the etiology of EGFR-mutated disease presented at the annual congress of the European Society for Medical Oncology.

In this exclusive 番茄社区 video, Nicholas Rohs, MD, of the Icahn School of Medicine at Mount Sinai in New York City, discusses the results of this study.

Following is a transcript of his remarks:

So this was a dataset presented by [Charles] Swanton, PhD, and his team about the driver of mutant non-small cell lung cancer. And what they were looking at was environmental exposures and how they may have triggered cancers.

So they looked at something called PM2.5 or particulate matter levels, and we know that small particles are what get into your lungs and cause irritation. It can cause long-term illnesses. But really, there's been a lack of direct relationship to lung cancer, and definitely mutated lung cancers, for this particulate matter. So I thought this was a really interesting study.

Historically, we've always thought about the cancer progression of carcinogens leading to mutations in DNA, which then leads to a driver gene activation and cancer progression. But many carcinogens that they've tested in mouse models have not really triggered these DNA mutations. And what was found is that some normal tissues can harbor EGFR, KRAS or similar mutations.

So this was actually a throwback to data from the 1940s [Isaac] Berenblum did looking at something called a two-step process, where you talked about an initiator and a promoter, and that these two steps may be what helps the evolution of cancer. So the study team did a really interesting approach to this.

They wanted to make three points. First they looked at the geographic relationships between cancers and this PM2.5. And they looked at a couple of different cancers -- larynx, anal cancers, mesothelioma cancers -- but particularly they saw not just lung cancers, but EGFR-positive lung cancers did have a very strong geographic relationship to the level of PM2.5 exposures or this air pollution. They looked in the U.K., they looked in South Korea, they looked in Taiwan, and globally, and they continued to see a relatively fair relationship between this particular exposure and this type of cancer.

So then they had to go try and prove causation. So they looked at mouse models. So again, a little bit less direct clinical exposure, but really interesting stuff. And they induced EGFR and KRAS mutations in these mouse models. And then they exposed them over many weeks to this particulate matter. And they found that after inducing these mutations and then exposing to the particulate matter, that actually did increase tumor formation.

So this is how they're showing in this model that there really does seem to be some link about these two different steps, the initiator and the promoter.

Another interesting thing that they pointed out was they looked at interleukin-1β, which is an inflammatory cytokine. And we know that tumors can trigger a lot of inflammatory situations, but what they found is they extrapolated from actually the CANTOS trial, which is a cardiovascular trial where they looked at a drug canakinumab in prevention of cardiovascular issues.

And they found actually in that dataset that the population had less lung cancer. So really interesting dataset asking a lot of questions. So they thought that maybe that this may be part of the process as well.

And then they did high-sensitivity genetic mutation [testing] on healthy lung tissue. And they found that about 50% of the time they could find a KRAS mutation in healthy lung tissue. And about 15% of the time they found an EGFR mutation in healthy tissue, which I kind of thought was really amazing data. Very interesting. And we know these tumors or these mutations can come throughout the process of aging toxic exposures, but it's really interesting to see that level of expression. So they're getting these cancers without that classic mutagenic signature that we expect.

So really, again, I thought that this was a really thought-provoking dataset. This is a question I get a lot in my clinic: I'm healthy, I don't smoke, how do I have this tumor? And a lot of these patients are EGFR-positive non-small cell lung cancer patients. So at least now I have some sort of dialogue to go with that. This may be some of the cause for their tumors. And I think it's really thought-provoking -- hopefully will help us reverse-engineer some more therapies and work on prevention.

As the author said, we have no choice in the air we breathe. I think this is a big call-out for us to fight for improved air quality. And as I say, the only risk factor we need for lung cancer is lungs. So breathing in this air can trigger this. So I think that there's this, hopefully gonna drive a lot more research in this area to help us understand the underpinning causes of these diseases. And again, hopefully to translate into more effective therapies and prevention.

Comment