The question of "who should be tested?" for an epidermal growth factor receptor (EGFR) mutation and potentially other molecular markers is among the most timely questions in lung cancer management today. The field has changed dramatically since the initial description of the mutation, associated with a high probability of an impressive and often prolonged response to EGFR tyrosine kinase inhibitor (TKI) therapy, back in 2004. For several years after that, mutations had been known to be neither absolutely necessary (occasional patients would have phenomenal responses despite not having a mutation identified) nor sufficient (response rates to EGFR TKIs among patients with an EGFR mutation have been in the 65-75% range, not 100%) to see a gratifying response. Moreover, it was also known that certain clinical/demographic characteristics, such as being Asian, female, a never-smoker, and having an adenocarcinoma or bronchioloalveolar carcinoma (BAC) tumor histology was associated with a higher probability of a significant response to EGFR TKIs as well, and that these characteristics are associated with a higher probability of having a lung cancer with an activating EGFR mutation (it has been clarified in the last few years that particular mutations in exons 19 and 21 are far more common than others and are the ones most consistently associated with a dramatic response, as discussed in Dr. Pennell's terrific review of the subject).

Though I had previously felt there to be a potential role to be played by "clinical selection" of patients who might be best served by starting with an EGFR TKI inhibitor, such as for a never-smoker presenting with a lung adenocarcinoma, or potentially anyone with a BAC, the IPASS trial clearly illustrated that EGFR mutation status was a reliable means of selecting which patients are better served by prioritizing an EGFR TKI over standard chemotherapy, while clinical selection failed: as I described in my post "Confessions of a Former Clinical Selector", the trial highlighted that even Asian never-smokers with a lung adenocarcinoma did better with chemotherapy than an EGFR TKI if they didn't have an EGFR mutation.

Since then, multiple trials have confirmed that while a difference in overall survival (OS) hasn't been clearly demonstrated, patients with an EGFR mutation have a very significantly improved progression-free survival (PFS) after starting an EGFR TKI compared with standard chemotherapy. Accordingly, testing for EGFR mutations has become far more common, though not a uniform practice. The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC) now call for EGFR mutation testing in all patients who don't have a squamous NSCLC tumor (since mutations are known to be unlikely -- though are still seen rarely -- in patients with a squamous tumor). Surveys of oncologist practices in the US over time have shown that more oncologists are testing than previously, but only perhaps a third to 40% of patients are being tested, and the probability of someone being tested having an EGFR mutation is about 40%, quite a bit higher than the 10-15% prevalence of the EGFR mutation among NSCLC patients in North America. This means that oncologists are being selective about who to test, and they're focusing on patients who have a higher probability of testing positive.

So at this point, a central question is how well these clinical variables predict for an EGFR mutation, if doctors are pre-screening. The group at Memorial Sloan Kettering Cancer Center focused on this question in reviewing the frequency of an activating EGFR mutation (exons 19 or 21) among 2142 consecutive lung adenocarcinoma patients between early 2002 and late 2009. As they had previously described, smoking status wasn't as pure a factor as as we sometimes describe it to be: the probability of an EGFR mutation was 52% among their never-smokers (302/580), but it was 15% in former smokers (181/1218) and even 6% in current smokers (20/344). They also found that while EGFR mutations were more commonly identified in women than men (26% vs. 19%), this still translated to about a third of EGFR mutations being identified in men.

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This is interesting work, though not surprising to me. I believe that what it highlights is that it's a mistake to use overly simplistic rules based on generalities of who will have an EGFR mutation: you see them in some ex-smokers and even current smokers, though less commonly than in never-smokers; and men have them too, just less commonly than women. It's important to note, however, that ALL of the numbers of EGFR mutation detection rates here are higher than you see in many other North American series, and I believe this is because MSKCC is a place with a more unique, enriched population. Essentially since the time that EGFR mutations have been identified, they've focused intensely on them and have attracted many patients either with a proven mutation or with a higher probability of having one, serving as a Mecca for EGFR mutation work and attracting a population around that. Though some of the same principles could apply to work done at Washington University in St. Louis or the University of Chicago, I think the numbers reported from MSKCC are higher than you see elsewhere.

To me, a leading question is whether mutation testing should be done automatically on people with a NSCLC histologic subtype such as large cell, which has been studied in too small numbers to say that it'll show a prevalence of EGFR mutation definitely in range with adenocarcinoma vs. squamous. At the same time, I think it's important to recognize that many patients don't have enough tumor tissue readily available and that there isn't evidence that giving an EGFR inhibitor as maintenance therapy or second line treatment leads to a worse survival than you'd get if giving it as first line therapy. Because of this, I think it's still important to remember that, even though some people, including some experts, sound very authoritative when they declare that everyone needs to be tested, there isn't actual evidence that it makes a difference in how well people will actually do or how long people live, as long as they get their opportunity to get the treatment. Still, this work highlights that we can't oversimplify rules about who's going to have an EGFR mutation, and it underscores that some people you might not expect could get a terrific benefit from an EGFR inhibitor. Moreover, these principles will also likely apply to other molecular targets and treatments down the line.