Lung Cancer in People Who Have Never Smoked
After decades of viewing lung cancer as almost exclusively a smoking-related disease, cases in people who have never smoked are becoming more visible. Specialists now recognize lung cancer in people who have never smoked as a “biologically distinct entity.” Lung cancer in people who have never smoked is now considered to be the fifth most common cause of cancer death globally. As tobacco smoking declines worldwide, lung cancer clinicians are spending more of their time tending to people who have never smoked. There is more than a proportional rise going on with evidence suggesting “a genuine absolute increase” in cases of lung cancer in people who have never smoked. It is not clear why, but researchers are beginning to piece things together – with the goal of helping people well before they reach an advanced stage of disease.
Most lung cancer cases are still caused by smoking. In the United States, people who have never smoked account for around 12 percent of cases. In Asia, they represent 30 percent or more. For reasons that are unclear, women account for two-thirds of never-smokers with the disease. Many national cancer registries do not contain reliable data on smoking status, which makes it difficult to discern trends in lung cancer in people who have never smoked. Where data do exist, they often indicate a rising trend. Studies in Singapore and China reveal an increase in early-onset lung cancer, especially in women. In the United States, diagnoses are increasing in Asian American women, and possibly in Hispanic women.
The reasons for this rise are not fully clear. Unlike smoking-related lung cancer, which is driven by tobacco carcinogens that leave a distinct pattern of mutations in the genome, lung cancer in people who have never smoked lacks a universal mutational marker of disease. Lung tumors in people who have never smoked have at least one of a handful of non-inherited gene alterations, which vary by geography. In Taiwan, for example, nearly half of women who have never smoked and are diagnosed with the disease have a mutation in the EGFR gene. Scientists are making progress towards understanding the environmental risks that might be driving these mutations. Exposure to second-hand smoke, counterintuitively, accounts for only a small minority of cases; one US study linked it to around six percent of tumors. Another cause is exposure to radon – a naturally occurring radioactive gas that percolates from the ground in certain areas. In Asia, links have been found with consumption of Aristolochia, a type of herb used in traditional Chinese medicine, and with indoor cooking with coal.
Other potential factors include inhalation of microplastics and consumption of ultra-processed food. Scientists in Canada are looking at 174 possibly important exposures that might be linked to lung cancer in people who have never smoked. In an analysis of whole-genome sequencing and environmental data from more than 1,000 people with lung cancer, scientists identified a strong link between levels of air pollution and numbers of lung cancer-causing mutations, mirroring previous findings. They also found a molecular signal of disease – independent of air pollution – but they have yet to identify its source. This mysterious signature is shared across people, but we don’t know what the underlying mechanism is.
Lung cancer in people who have never smoked is particularly high in Asian women, and further study is needed to understand why this is occurring. Suggestions include differences in immune function, hormonal influences, and how the body metabolizes carcinogens. Scientists found links between women’s reproductive history and their risk of lung cancer. Generally speaking, the more times that a person has given birth, the lower their lung cancer risk. Research has also suggested that giving birth for the first time at an older age is also associated with lower risk.
In an analysis of paired tumor and tissue samples from around 100 people in Taiwan, researchers found that lung cancer in women, aged 60 years and younger, who have never smoked showed higher levels of mutations arising from internal biological processes. In older women, however, mutation patterns were more consistent with environmental exposures. Work is ongoing to understand these complexities. Scientists at Stanford University in California just completed data collection for a study that will compare the genetic and environmental factors of more than 500 Asian women with lung cancer who have never smoked with similar participants without the disease. They are looking to find what it is that predisposes them to cancer.
Lung cancer survival depends mostly on the stage of the disease at the time of diagnosis. Surgery can often treat early stages, but it is usually not an option after the cancer has spread. Advanced cancers are often treated with targeted therapies when a specific gene alteration is driving the disease, including tumors driven by non-inherited changes. Many of these genes encode proteins involved in cellular signaling that, when mutated, become locked into a permanent “on” state, causing uncontrolled proliferation. Targeted drugs inhibit these signals, usually by binding to the proteins and shutting off the signal. Dozens of these drugs exist, and the latest generation has really remarkable outcomes, according to an oncologist at The Ohio State University in Columbus. According to him, twenty years ago, the median survival for people with metastatic lung cancer treated with chemotherapy was about eight months after diagnosis. By contrast, the median survival time – the point at which 50 percent of participants are still alive – has yet to be reached in people treated with an oral therapy that targets one of the most common mutations seen in people with lung cancer who have never smoked. According to the oncologist, it is likely close to 10 years.
Currently, most people with lung cancer who have never smoked are diagnosed at late stages. One reason is that physicians do not think of lung cancer as a possibility in younger people with a cough. Another issue is that national screening guidelines in most countries still focus on those with a history of heavy smoking.
One workaround is to take advantage of data contained in computed tomography (CT) scans done for other reasons, such as evaluating abdominal pain or after a car accident. Scientists examined thousands of CT scans conducted in a hospital in Ohio in 2018 for any reason and identified nearly 700 people with lung nodules that could indicate cancer. More than half of these people did not receive appropriate follow-up for the nodules when they were first recorded. Due to these findings, the hospital began using an artificial-intelligence tool to review every CT scan – regardless of the reason it was taken – for lung nodules. Now, more lung cancer cases are being detected through that program than they are through formal lung cancer screening.
More-deliberate screening also shows promise. Doctors at the National Taiwan University in Taipei performed CT scans every year for eight years on more than 12,000 non-smokers who had certain other lung cancer risk factors. They detected the disease in around two percent of the people they screened – and the vast majority were at potentially curable early stages. Using these results, in 2022 they persuaded the authorities in Taiwan to implement a nationwide screening program for people who have never smoked and who have a family history of lung cancer. Singapore and Hong Kong soon followed suit. South Korea is now considering a similar approach.
Doctors hope to refine screening eligibility by developing biomarkers to identify other high-risk individuals. Even broader screening is also under discussion. Last November, researchers reported that only 35 percent of people with lung cancer currently meet US screening criteria. They projected that expanding eligibility to people aged 40-85 regardless of smoking history could increase the detection rate to 94 percent, potentially preventing at least 26,100 annual deaths at an estimated cost of about $100,000 per life saved.
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