Molecular Markers in Lung Cancer
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.
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:
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.
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. (Click on image to enlarge)
Here is the continuation of my conversation with Dr. Nasser Hanna, lung cancer expert at Indiana University and all-around good guy (not part of his official title). Here we discuss a patient of mine who combines the challenges of managing stage IIIA N2 NSCLC with the issues of how to potentially integrate an EGFR inhibitor for an Asian never-smoker, particularly in a setting where we don’t yet have good data.
At the tail end of the case, we also take a bit of a detour in discussing the question of whether the order of therapy matters as much as getting in the right therapies over time, specifically with regard to trying to prioritize chemo vs. an EGFR inhibitor.
Dr. West: This case is of a 54 year old lifelong never smoking Asian woman who was involved in a motor vehicle accident and went to the emergency room and she had a chest x-ray there followed immediately by a CT of the neck and chest. She had a 2.4 centimeter right upper lobe spiculated mass and she also had several lucencies in her C2 verterbral body, very non-specific appearing. She had musculokeletal injuries in her sternum and actually a pelvic fracture.
She subsequently had a PET scan that showed the right upper lobe mass had an SUV of 4.5. Other findings were consistent with trauma, nothing suggestive of hiler or mediastinal uptake, nor any distant disease.