Thyroid transcription factor-1 (TTF-1) is a protein seen on the surface of thyroid cells, but also on about 70-75% lung adenocarcinomas and only a small minority (~10%) of squamous cell NSCLC tumors.  In fact, the presence of TTF-1 on a NSCLC tumor provides a good hint for the pathologist that this is an adenocarcinoma.  It’s an immunohistochemical (IHC) test that is done on the vast majority of lung cancers, and there’s some new information that suggests it may also be useful for predicting which patients are especially unlikely to have an EGFR mutation or ALK rearrangement.  This is especially important as we are now faced with a question of whose tissue to send for these particular tests, especially if this decision involves obtaining another biopsy.

A few months ago, a group from Seoul, Korea published their results on the correlation between ALK positivity in a series of 221 patients with lung adenocarcinoma and other clinical and pathologic features.   In this somewhat selected group of Asian patients with an adenocarcinoma, 45 (20% had an ALK rearrangement, and this population skewed toward being younger than other patients (49 vs. 61), but didn’t differ in smoking status (about half were never-smokers in both groups for this population) or gender distribution, but they did have two striking features.  ALK rearrangements were mutually exclusive with an EGFR mutation (they were never seen in the same patient), and there were no patients with an ALK rearrangement who tested negative for TTF-1 expression.

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Here’s the second talk from our recent webinar, partnering with LUNGevity Foundation to cover the ASCO Highlights in Lung Cancer, and this talk followed after the presentation by Dr. Mary Pinder on highlights in SCLC, early stage NSCLC, and mesothelioma and covered developments in advanced NSCLC.   Dr. Nasser Hanna, an international leader in the field from Indiana University, summarized the most important new data in this arena.

Below you’ll find links to the audio and video versions of the podcast, as well as the transcript and figures from his talk.

hanna-asco-2011-highlights-advanced-nsclc-audio-podcast

hanna-asco-2011-highlights-advanced-nsclc-transcript

hanna-asco-2011-highlights-advanced-nsclc-figures

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Podcast: Play in new window | Download

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.

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The following is laden with personal opinion as much as actual evidence.  Feel free to take it or leave it.

In my last post, I introduced the key questions we’re facing in my own institution, and many other oncologists and their own hospitals are doing the same thing: which patients do we now routinely test for molecular markers in their lung cancer tumors, and what markers do we request?  Here’s an outline of the questions where there’s still back and forth, and why:

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Continued from part 1

Dr. West: You have a huge portion of your patients who have an EGFR mutation and we know that over time patients develop acquired resistance. So how do you approach the patients who have a great response initially, have a known EGFR mutation, and then you see that slipping away at slow progression? Do you continue the EGFR inhibitor?  Do you add something to it?  Do you change the dose? How do you approach that?

Dr. Mok: I think this is one area where we still have a lot to learn.  First of all, let’s define resistance, or progression. If you use the Jackman criteria (Jackman, J Clin Oncol 2010), that still incorporates the RECIST criteria, which mean if the lesion that has increased by about 30%, then it’s progression. But then one factor we didn’t look into was in the rate of progression within this definition. The second concern is about the occurrence of a new lesion that’s also progression. Now, whether this is directly applicable to a targeted like Tarceva or another EGFR TKI or not, I have some doubts, because simply from your experience and my experience, some of these patients get a new nodule, but they can take a long time to grow and the patient lives a normal life. And we also know the fact that if we take them off the TKI, the disease can progress rapidly. So some of these are slow progressors, then we just keep them on a TKI. Read the rest of this entry »

A few weeks ago I had the chance to speak with Dr. Tony Mok, who is a professor in the Department of Clinical Oncology at the Prince of Wales Hospital in Hong Kong and the Chairman of the Hong Kong Cancer Therapy Society.

He is also the principal investigator and lead author for the pivotal Iressa Pan ASian Study (IPASS), which was published in the New England Journal of Medicine in the fall of 2009.  I started by telling him that I consider that study to be arguably the most influential over the last 5-10 years in the field of lung cancer, because it highlighted that molecular predictive factors trump clinical markers in determining who is likely to do best with a targeted therapy, specifically an EGFR tyrosine kinase inhibitor like Iressa (gefitinib) or Tarceva (erlotinib).  Here’s the first part of our conversation about what we’ve learned about how best to use these EGFR inhibitors and the potential differences in practice between Asia and the US.

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