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never-smoker NSCLC

Molecular Markers in Lung Cancer

The Inherited T790M EGFR Mutation and Risk of Familial Lung Cancer

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Here’s the pdf for this presentation: Inherited T790M EGFR Mutation


The Perils of Molecular Oncology: Mutations Aren’t Everything, or at Least They’re Not Infallible

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Every few months I see a patient who reminds me of the fallability of mutation testing.

One of the brightest rays of hope in the management of lung cancer and much of cancer care in the last decade has been the transition toward treatment guided by the presence or absence of particular molecular markers like EGFR mutations, ALK or ROS1 rearrangements, and potentially others being studied now.  However, I’d like to sound a note of caution about focusing too much on the results of a test. Specifically, I have seen a few patients, including one in the last couple of days, who highlight how tragic it would be for us to limit the use of the oral EGFR tyrosine kinase inhibitor (TKI)  Tarceva (erlotinib) to patients who are tested and have an EGFR mutation.

To backtrack, over the last few years it has become clear that most of the people who are major beneficiaries of an EGFR TKI are those with an activating EGFR mutation. We’ve also seen several studies that show that in the minority of advanced NSCLC patients whose tumors have an activating EGFR mutation, an EGFR TKI is extremely likely to be more effective than chemo as first line treatment.  Tarceva had already been approved by the FDA as a second or third line treatment for a broad range of molecularly unselected patients (no EGFR mutation requirement) based on a randomized trial that showed a 2 month survival benefit overall, so the question was whether when you take out the profound benefit seen in a minority, there’s still enough benefit in the “EGFR wild type” patients (no activating mutation) to have it be worth treating such patients with Tarceva.  

Though there are many who minimize the value of Tarceva in patients with EGFR wild type, the evidence indicates that such patients still receive an approximately 1.5-2 month improvement in median overall survival with it, so I routinely recommend Tarceva as a second or third line therapy after initial chemo in patients who test negative for an EGFR mutation. Most of the benefit is in the form of prolonged stable disease or at most a minor response, which can still translate to living a few months longer. In the back of my mind, as well, is the possibility that a small minority of such patients will respond extremely well, reminiscent of what we’d expect to see in someone with an EGFR mutation — because we know that the response rate to Tarceva in tested, EGFR wild type patients is low, but it’s not zero.  Continue reading


Dr. Alice Shaw on Clinical Factors Associated with Molecular Markers

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I’m happy to bring you now the second part of the Santa Monica webinar, developed with the LUNGevity Foundation, on “Molecular Markers in Advanced NSCLC: Who to Test and What to Test For?“, in which I was joined by Drs. Charles Rudin (Johns Hopkins University in Balimore, MD), Alice Shaw (Massachusetts General Hospital in Boston, MA), David Spigel (Sarah Cannon Cancer Center in Nashville, TN), and Glen Gloss (University of Ottawa in Ontario, Canada).  

In this short podcast, Dr. Alice Shaw reviewed the frequencies of different molecular markers in advanced NSCLC as a function of patient sex, smoking status, race, and tumor histology.  This work is very interesting, of course, because if we only do molecular marker studies of people with an adenocarcinoma or never-smokers, we not only won’t ever find potentially relevant mutations in people with other histologies and those with a smoking history, but we won’t have any good idea of the probabilities of finding them either.

Here is the podcast in audio and video formats, as well as the transcript and figures.

Molecular Markers SM Pt 2 Shaw on Markers by Clin Factors Audio Podcast

Molecular Markers SM Pt 2 Shaw on Markers by Clin Factors Transcript

Molecular Markers SM Pt 2 Shaw on Markers by Clin Factors Figs

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Who to Test for an EGFR Mutation or ALK Rearrangement: Filtering Based on TTF-1 Status

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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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Prevalence of EGFR Mutations in Patients with Adenocarcinoma: Moving Beyond Never-Smokers

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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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World Lung Conference Day 2, 7/5/2011

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iaslc1

Plenary Session: Lung Cancer in Never Smokers

The day started if with Dr. Thun from the American Cancer Society. He reviewed environmental factors contributing to Lung Cancer in never smokers. He started by reminding us that although only 10% of lung cancer deaths in men and 15-20% of lung cancer deaths in women are due to nonsmoking cancer, the burden of suffering caused by non-smoking lung cancer is actually rather high. If non-smoking lung cancer were treated as its own disease, separate from smoking-driven lung cancer, it would rank eighth among the most common fatal cancers in America! He reviewed environmental factors known to cause lung cancer: secondhand smoke, radon, asbestos, certain metals, some organic chemicals, radiation, air pollution, tubercoulosis, and other chronic inflammatory conditions. Others exposures likely also play a role, but have yet to be proven: human papilloma virus and chronic inhalation of cooking fumes and incense. Indoor air pollution from cooking, coal burning, and smoking men may explain the extraordinarily high rate of nonsmoking lung cancer among women in some areas of Northern China.

Dr. Pierre Massion of Vanderbilt took the stage second to talk about the molecular pathogenesis of never smokers. He reminded us of the different histologic tendencies of never smokers—less SqCC, more adenocarcinoma including the multiple subtypes once called BAC. He reviewed genes associated with susceptibility including cyp1a1, gstm1, xrcc1, gpc5, and fam38b. He pointed out the role of genetic differences in key molecules in inflammatory pathways: IL-1b, IL6, and IL1RN. Finally, insults from the environment may be expressed differently based on variations in genetic susceptibility.

Dr. Massion then used the figure, reproduced below, from Pao et al, Lancet Oncology 2011 to remind us how far we have come in understanding the molecular drivers in nonsmoking cancer:

pao-mutations1

Studies have shown particular genomic signatures in never smokers. But not only is the DNA changed, but DNA modifiers (epigenetics) are also changed and we have defined specific genes whose expression is modified.

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Update on Evidence of CALGB 30406 Trial: Chemo/EGFR Inhibitor vs. EGFR Inhibitor Alone in Never-Smokers

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Just prior to ASCO, I mentioned the early results of the Cancer and Leurkemia Group B (CALGB — Group A long-since defunct) 30406 trial. This study enrolled 181 people with advanced lung adenocarcinoma who had either never-smoked or had a rather minimal smoking history of 10 “pack-years” or fewer, and who were randomized to receive the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) alone or in combination with standard chemo of carboplatin and Taxol (paclitaxel) as first line treatment. The idea of this trial was that the selection of patients by the clinical factor of smoking status was meant to enrich for a higher probability of such patients having an EGFR mutation, and it had also been recognized that never-smokers (less than 100 cigarettes in their lifetime) or “oligo-smokers” (oligo meaning few, so the term means those ex-smokers who had a light smoking history but didn’t qualify as never-smokers) in many clinical trials of EGFR inhibitors appeared to be the greatest beneficiaries of an EGFR inihibitor like Tarceva or Iressa (gefitinib). At the same time, there was reason to question whether combining chemo with an EGFR inhibitor might provide additional benefit, have no effect, or might even be detrimental.

calgb-30406-schema

(click on image to enlarge)

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Assessing the Causes of Lung Cancer in Never-Smokers

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The following is the edited transcript and figures from a webinar presentation made by Dr. Heather Wakelee, medical oncologist and Associate Professor at Stanford Cancer Center, on Never-Smokers and Gender Differences in Lung Cancer.

The real question, of course, is why do people get lung cancer who have never smoked? We don’t really know. We think it could be related to second hand smoke, and perhaps it’s happening in childhood even more so. It might be from vehicle exhaust, and a lot of work is being done there. Cooking fumes have been the culprit in several studies, especially in poorly ventilated kitchens. Occupational exposures including paint in a recent analysis. Radon exposure is a big risk and something especially in the mountain states, people look at radon levels in their house and important, and that can be a thing to test for.

There are a lot of environmental toxins, such as asbestos and arsenic, and then there’s a family risk. It’s much, much lower when we talk about cancer risks like colon cancer families and breast cancer families. It’s not of that magnitude, but there certainly are families where lung cancer tends to run in the family. We see this especially when the lung cancer is diagnosed very early, there’s been a hint that certain genes might be related to family lung cancer — but we have a lot of work still to do on that.

Overall, though, we don’t quite know the reasons why people get lung cancer, but we are starting to understand more about what has happened on a molecular basis, especially in people who never smoked but develop lung cancer.lung-adenocarcinoma-genetics (Click on image to enlarge)

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Expert Round Table with Drs. Hensing & Jackman: Molecular Markers & Sequence of Therapy for An Asian Never-Smoker with Advanced Lung Adenocarcinoma

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The third and final part of my conversation with Drs. Tom Hensing from North Shore Health System in Chicago and David Jackman from Dana Farber Cancer Institute in Boston covered a presentation of an Asian never-smoking woman with an advanced lung adenocarcinoma, the demographic picture most closely associated with potentially but not necessarily having an EGFR mutation or ALK rearrangement.

We cover the question of whether, in someone with a significant probability of one of these particular molecular markers, it’s worth obtaining tissue and delaying treatment to tailor treatment on the basis of these results. We also discuss the range of options for maintenance therapy in someone who has many alternatives for continuing one or more agents from the first line setting or switching to a new treatment. Finally, we turn to the question of managing treatment for a patient who has a prolonged response to an EGFR inhibitor and then develops an acquired resistance to that therapy.

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Changing Clinical Practice: The Evidence that Convinced Me Many People with Advanced NSCLC Should Have Up Front Molecular Testing

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The question of which patients to test for an EGFR mutation, and when, has become one of the most timely and rapidly changing ones in lung cancer. The IPASS trial was a landmark study that definitively illustrated that molecular testing overshadows clinical selection for EGFR tyrosine kinase inhibitor (TKI)-based therapy, demonstrating that the 60% of Asian never-smoker or light former smoking patients with advanced lung adenocarcinoma on this trial that had an activating EGFR mutation demonstrated a significantly higher response rate and progression-free survival (PFS) with the EGFR tyrosine kinase inhibitor (TKI) Iressa (gefitinib) than with standard chemotherapy (carboplatin/Taxol (paclitaxel) in this particular study). In contrast, the 40% of patients with the same clinical characteristics on this trial but without an EGFR mutation had a significantly better response rate and PFS with standard chemotherapy. Overall survival (OS) results were preliminary and revealed the same mutation-dependent trends, though they were not significantly different in the approximately one third of patients who had tumor tissue available for mutation testing.

My take on this work was that there was now compelling evidence that clinical selection of patients to receive chemotherapy vs. EGFR-based first line therapy is most definitely inferior to molecular selection, but this was just one study and a retrospective analysis of mutation status in only a limited subset of patients, and perhaps the trend of an OS difference could be reduced if we work to ensure that patients all get access to the same agents over time.

Essentially, the question to me was that even if some patients are better served by receiving one treatment vs. another, and this can largely be predicted by the presence or absence of an EGFR mutation, does it really matter whether the optimal treatment for that particular patient is given first line or second line? Does order of treatment matter if everyone gets the opportunity to receive the same treatments over time? A few very recently presented studies corroborate the findings from IPASS in a population identified by prospective EGFR mutation testing and lead me to be newly convinced that, at least for patients with an adenocarcinoma or those with little or no smoking history, order of treatment can make a meaningful difference, so it’s ideal to do molecular testing before starting systemic therapy.

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