Sharon Begley died of complications of lung cancer on Jan. 16, just five days after completing this article. She was a never-smoker.

Breast cancer wouldnt have surprised her; being among the 1 in 8 women who develop it over their lifetime isnt statistically improbable. Neither would have colorectal cancer; knowing the risk, Mandi Pike definitely planned to have colonoscopies as she grew older.

But when a PET scan in November 2019 revealed that Pike, a 33-year-old oil trader, wife, and mother of two in Edmond, Okla., had lung cancer she had been coughing and was initially misdiagnosed with pneumonia her first reaction was, but I never smoked, she said. It all seemed so surreal.

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Join the club. Cigarette smoking is still the single greatest cause of lung cancer, which is why screening recommendations apply only to current and former smokers and why84% of U.S. women and 90% of U.S. men with a new diagnosis of lung cancer have ever smoked, according to a study published in December in JAMA Oncology. Still, 12% of U.S. lung cancer patients are never-smokers.

Scientists disagree on whether the absolute number of such patients is increasing, but the proportion who are never-smokers clearly is. Doctors and public health experts have been slow to recognize this trend, however, and now there is growing pressure to understand how never-smokers disease differs from that of smokers, and to review whether screening guidelines need revision.

Since the early 2000s, we have seen what I think is truly an epidemiological shift in lung cancer, said surgeon Andrew Kaufman of Mount Sinai Hospital in New York, whose program for never-smokers has treated some 3,800 patients in 10 years. If lung cancer in never-smokers were a separate entity, it would be in the top 10 cancers in the U.S. for both incidence and mortality.

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A 2017 study of 12,103 lung cancer patients in three representative U.S. hospitals found that never-smokers were 8% of the total from 1990 to 1995 but 14.9% from 2011 to 2013. The authors ruled out statistical anomalies and concluded that the actual incidence of lung cancer in never smokers is increasing. Another study that same year, of 2,170 patients in the U.K., found an even larger increase: The proportion of lung cancer patients who were never-smokers rose from 13% in 2008 to 28% in 2014.

It is well-documented that approximately 20% of lung cancer cases that occur in women in the U.S. and 9% of cases in men, are diagnosed in never-smokers, Kaufman said.

To a great extent, this is a function of straightforward math, said epidemiologist Ahmedin Jemal of the American Cancer Society. Fewer people smoke today than in previous decades 15% in 2015, 25% in 1995, 30% in 1985, 42% in 1965. Simply because there are fewer smokers in the population, out of every 100 lung cancer patients, fewer will therefore be smokers. And that means more of them will be never-smokers.

There are also hints that the absolute incidence of lung cancer in never-smokers has been rising, said oncologist John Heymach of MD Anderson Cancer Center. Some data say it has, but other data say no. The stumbling block is that old datasets often dont indicate a lung cancer patients smoking status, Heymach said, making it impossible to calculate what percent of never-smokers in past decades developed lung cancer.

Jemal, however, cautions that it is not the case that a never-smoker has a greater chance of developing lung cancer today than never-smokers did in the past.

Current cancer screening guidelines recommend a CT scan for anyone 50 to 80 years old who has smoked at least 20 pack years (the equivalent of one pack a day for 20 years, or two packs a day for 10 years, and so on) and who is still smoking or quit less than 15 years ago. Screening is not recommended for never-smokers because the costs of doing so are deemed greater than the benefits, Jemal said; thousands of never-smokers would have to be screened in any given year to find one lung cancer.

Still, low-dose CT can catch lung cancer in a significant number of never-smokers. A 2019 study in South Korea diagnosed lung cancer in 0.45% of never-smokers, compared to 0.86% of smokers. The researchers urged policymakers to consider the value of using low-dose CT screening in the never-smoker population.

It used to be that the high-risk group for whom CT screening is recommended was the vast majority of lung cancer patients, Heymach said. But now that so many lung cancer cases are in nonsmokers, there is absolutely a need to reevaluate the screening criteria.

Researchers are trying to improve screening by reducing the incidence of false positives when CT finds lung nodules or an old scar that you got 20 years ago, he said. Those dont pose a threat but have to be biopsied to ascertain that. Screening never-smokers would also be more efficient than it is today if we could identify who, among nonsmokers, are at higher risk, he said.

Cancer doctors already know part of the answer: women. Worldwide, 15% of male lung cancer patients are never-smokers. But fully half of female lung cancer patients never smoked. And women never-smokers are twice as likely to develop lung cancer as men who never put a cigarette to their lips.

Beyond sex, nothing stands out as a single large risk factor that, if we only got rid of it, we would solve the problem of lung cancer in never-smokers, said Josephine Feliciano, an oncologist at Johns Hopkins University School of Medicine. But air pollution, radon, family history of lung cancer, [and] genetic predispositions all play a role. Chronic lung infections and lung diseases such as chronic obstructive pulmonary disorder (COPD) also seem to increase risk.

None of those, with the possible exception of genetics and indoor pollution (cooking fires in some low-income countries), affect women more than men. So whats going on?

At least one biotech believes that biological differences between lung cancer in never-smokers and smokers merits a new drug, and one that might be especially effective in women. A different disease needs a different drug, said co-founder and CEO Panna Sharma of Lantern Pharma. In fact Lantern, which is developing a drug for lung cancer in female never-smokers, believes that disease is so different it recently tried to convince the U.S. Food and Drug Administration to designate it an orphan disease, said Sharma.

Called LP-300, the Lantern drug increased overall survival from 13 months to more than 27, compared to chemotherapy alone, in female nonsmokers, in a small trial. It targets molecular pathways that are more common in female nonsmokers than in any other group, said Sharma, targeting the mutations EGFR, ALK, MET, and ROS1 (common in never-smokers) directly and boosting the efficacy of other drugs that attack them, such as erlotinib and crizotinib. Lantern plans a larger trial this year.

Smokers tumors tend to have more mutations overall, thanks to mutagen-packed cigarette smoke attacking their lungs, but scientists have developed more drugs for never-smokers lung tumors than for smokers. For instance, EGFR and ALK mutations are more common in never-smokers. (Mandi Pike had the EGFR mutation, which was relatively fortunate: A drug targets it, and she has been cancer-free since November.)

The targeted drugs bollix up each mutations cancer-causing effects. KRAS mutations are more common in smokers lung tumors, and there are no KRAS drugs. (A KRAS drug for lung cancer is imminent, though, said thoracic oncologist Ben Creelan of Moffitt Cancer Center in Tampa, Fla.)

According to national guidelines, lung cancer in never-smokers should be treated the same as in smokers, said Creelan. But I think we should reconsider this, he said.

Because never-smokers have fewer tumor mutations, its harder to find them. So he said clinicians should be more aggressive about looking for actionable mutations in these patients. I keep looking for a mutation until I find something important, he said, adding that doctors might need better biopsy material or to use a different sequencing method in never-smokers.

In a cruel twist, the breakthrough drugs that take the brakes off immune cells, which then attack the tumor, are less effective in never-smokers lung cancer than in smokers. The reason seems to be that smokers tumors have more mutations, said Mount Sinais Kaufman; the mutations often cause the tumor cells to have molecules on their surface that the immune system perceives as foreign and revs up to attack. Never-smokers tumors have few, if any, of those come and get me molecules. Immune cells therefore ignore them.

In smokers, conversely, with more mutations, there is more for the immune system to recognize as bizarre and foreign, and so to provoke an attack, Creelan said.

In contrast, never-smokers tumors are more likely to respond to targeted drugs, and as a result to be in remission for a long time or even cured. Thats because with fewer mutations, never-smokers tumors are more likely to have an oncogene addiction, Heymach explained: They are propelled by only one mutation. The plethora of mutations in smokers tumors means that there is usually a back-up cancer driver if a targeted drug eliminates cells with only one. When a tumor has more and more mutations, blocking one is less likely to have an impact, Heymach said. But in nonsmokers, it can.

Heymach called for more funding to study lung cancer in never-smokers. It is an area thats underserved and deserves more investment, Heymach said. It should be commensurate with the public health threat it represents.

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A growing share of lung cancer is turning up in never-smokers - STAT

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