GRACE :: Lung Cancer


Part 2: Lung Cancer Is Not Your Fault, Even If You Smoked


Read Part 1

Smoking is the most common cause of lung cancer – 85% of lung cancer patients have smoked at some point in their lives (or, stated another way, 15% of lung cancer patients have never smoked).  While quitting smoking certainly decreases the risk of getting lung cancer, more than half of lung cancer happens in people who have quit.  

Reason #3 to not blame the lung cancer patient:

Luckies adNicotine is really, really addictive.Asthma cigs ad

After passing step one of my medical boards, my father decided to take me to Las Vegas to celebrate and for some father/son bonding. On our first night, he awoke in a cold sweat. As a burgeoning doctor, freshly woken from sleep, I was ready for action, “Dad, do you have chest pain?” “Can you breathe?” “What’s going on?” My father, almost 20 years after quitting smoking, had awoken with a dream of having a cigarette. Nicotine is that addictive. For a while, scientists had believed that it was the second most addictive chemical known to mankind, but many now rank it ahead of heroin. As anyone who has known addiction in their lives or the lives of someone they’ve cared about, addiction takes choices away.

While I’m sharing personal stories, I will admit that I smoked a cigarette in college. Some people, like me, smoked one cigarette, found nothing pleasing in the experience, and stopped. Other people have a very different experience—they find cigarettes pleasurable. Maybe they try a cigarette in their teens socially, perhaps after a few drinks. For a while they’re social smokers, never buying their own. Then, over time, they find that they’re craving the cigarettes. After a breakup or some other stressful experience, they smoke more. Pretty soon, they have a habit, and wake up one day, reach for a cigarette, and realize that they are an addicted smoker.

The tobacco industry has supported this process. Big Tobacco historically advertised to children. They promoted an image of smoking as cool. They misrepresented and even lied regarding the health effects of smoking cigarettes. The delivery of nicotine per cigarette and its speed of administration are more tightly controlled than many pharmaceutical products. Simply put, cigarettes are delivery devices for a harmful drug that, for reasons of American culture and law, are legal.  

Legally, you must be 18 years of age to purchase cigarettes in the US. But, in reality, teenagers find access to cigarettes fairly easily. Many teenagers are addicted to these harmful products long before they are smart enough to reject them; quitting later isn’t so easy. 

In America, we have a strong culture of personal responsibility, but the reality of nicotine addiction does not support this idea—personal choice, at best, is very incomplete when addictive substances are at play. I think that we can all agree that we should educate our children and teenagers about the harms of cigarettes and give them the coping skills to reject them. I think that we can all agree that smokers should be motivated to quit and that the medical system should give them all the counseling and medicines that can help. But, no matter how much we endorse empowerment of individuals to never start smoking or for smokers to quit, we cannot ignore the hard data that suggests that there are powerful forces at work other than personal choice.

Reason #4 to not blame the lung cancer patient:

A Non-Smoking WomanStigma hurts the patient (smoker or not) and it hurts efforts against lung cancer.

Stigma occurs when society views a person or group as inferior or disgraced because of some characteristic.  In other stigmatized diseases, stigma has been shown to negatively affect patients and health outcomes and some data demonstrates the same in lung cancer. Stigma also negatively affects public efforts to fight lung cancer. Although a nonsmoking woman has greater chance of dying of lung cancer than of breast cancer, lung cancer receives $1,337 in research funding per death while breast cancer receives $16,850 per death. More Americans will die this year of lung cancer than colon cancer, breast cancer and prostate cancer combined. America  (correctly) recognizes that breast cancer is a terrible disease — in October, the pink ribbon is everywhere. But where is the white ribbon in November?

And, if we want to talk about stigmatized and invisible smoking-associated cancers, dear reader, can you tell me what color the head and neck cancer ribbon is? Don’t feel bad if you don’t know; I didn’t know either until I started treating head and neck cancer patients — it’s red and white striped. Simply stated, efforts against breast cancer are popular; companies want to associate themselves with efforts against breast cancer because it improves their images. In contrast, fighting lung cancer, head and neck cancer, and other smoking related cancers is less popular, at least in part, because patients are blamed for their disease. A large survey of the general public found that 59 percent believed that lung cancer patients were at least partially to blame for their cancer. Despite the poor funding described above for efforts against lung cancer, only 12 percent of Americans choose it among cancers to deserve greater support.

A suggestion for refocussing our attention

I suggest that lung cancer patients should not be asked if they smoked—it is irrelevant because neither smokers nor nonsmokers deserve lung cancer or should be blamed for it. If you have been touched by lung cancer, consider doing something about it. Consider joining your local advocacy organization—in North Carolina I’m a big fan of the Lung Cancer Initiative and on a national level, there are many fine organizations to join. Better yet, if you think that we do good work here at GRACE, consider donating to us! 

Regardless, I’d like to spend less time on blame and more time on real action.

Part 1: Lung Cancer Isn’t Your Fault, Even If You Smoked


Smoking is the most common cause of lung cancer; 85% of lung cancer patients have smoked at some point in their lives (or, stated another way, 15% of lung cancer patients have never smoked).  While quitting smoking certainly decreases the risk of getting lung cancer, more than half of lung cancer happens in people who have quit. 

From Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, “Cigarette Smoking Among Adults -  United States, 2006”, November 9,2007/56(44): 1157-1161, Table 2

Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, “Cigarette Smoking Among Adults – United States, 2006”, November 9,2007/56(44): 1157-1161, Table 2

Reason #1 to not blame the lung cancer patient:

He or she may have never smoked.  I just visited a very young patient of mine while he was dying at home of lung cancer.  He never smoked.

Reason #2 to not blame the lung cancer patient:

The smoking may not have caused the cancer.

Smoking is not the only cause of lung cancer.  Other causes include occupational carcinogen exposure, radon, and outdoor air pollution.  There are probably other, as yet undiscovered, causes. 

I’ll add a cause that is rarely directly discussed: an (un)healthy dose of bad luck. The majority of active smokers and former smokers do not get lung cancer.  Cigarette smoke contains numerous chemicals that can cause mutations, or changes in the DNA of cells. Some DNA codes for important proteins—mutations to these areas of DNA have the potential to cause cancer.  Other parts of DNA are “junk” that don’t actually code for anything.  While there is active research into why some people get cancer from cigarette smoking and others don’t, the luck of having these mutations in “junk” regions or in important ones surely plays a major role. 

Jared Weiss Horizontal

Dr. Jared Weiss (Courtesy of UNC Lineberger)

Smokers and nonsmokers have similar chances of developing smoking-unrelated lung cancer. Scientists now believe that non-smoking related lung cancers tend to be biologically simpler—they have one or two “driving” mutations that transform a healthy lung cell into a lung cancer cell (for example, EGFR or EML4/ALK).  In contrast, smoking-related cancers may have more mutations that together contribute to transforming that healthy lung cell into a cancerous one.  But, there is absolutely nothing about smoking, even heavy smoking, that protects a person against a smoking-unrelated lung cancer.

This last point is important not only for how we think or feel about people with lung cancer, it also has a very important practical consequence for medical practice. All patients with metastatic non-squamous non-small cell lung cancer (the type that might have mutations that can be treated with targeted therapies such as erlotinib or crizotinib) deserve molecular testing, regardless of how much they smoked. 

In my practice, I have found several patients with EGFR mutation (treatable with erltotinib or afatinib) and at least 1 with EML4/ALK (treatable with crizotinib) amongst patients with a smoking history.  Statistically, patients who have smoked a lot may have a lower probability of having such mutations, but there is still a real chance, and I feel strongly that these patients deserve testing. 

Part 2:

Nicotine versus heroin.


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


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



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.

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The EML4-ALK Mutation Enters the Lung Cancer Clinic


Dr. Pinder previously summarized the early story of the newly identified EML4-ALK mutation in NSCLC, which traces back only a couple of years. Amazingly, in that short time, treatments targeting this mutation have already been identified and administered to patients who are benefiting from these novel agents at this very moment. Still, one of the leading issues with this story of progress is that the EML4-ALK mutation appears to be present in less that 5 percent of the overall NSCLC population, so people may ask how valuable this discovery really is.

That really depends on a couple of factors. First, screening for an EML4-ALK mutation will be much more appealing and feasible if we have some hints of which pateints are more or less likely to have one of these mutations. Second, we need to have a treatment that helps the people we screen who have the ALK mutation.

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