Long considered a “smoker’s disease,” lung cancer has, in recent years, shown an alarming increase in patients who have never smoked.1 Research published in the Journal of the National Cancer Institute demonstrated that the percentage of non-small cell lung cancer (NSCLC) cases diagnosed among never-smokers increased from 8% in 1993 to 14% in 2013.2 Many of these diagnoses are occurring in younger patients, including those who are otherwise healthy and physically active. The incidence of NSCLC among never-smokers appears to be higher among women, particularly those who are Asian.
In 2017, about 20% of patients who died from lung cancer in the United States had never smoked or used tobacco in any form.8 This equals roughly 30,000 fatal lung cancers among never-smokers. Although the increase in NSCLC among never-smokers may be attributable to environmental and genetic factors, more research is needed to explore this phenomenon and determine how to best address it, according to Brendon Stiles, MD, a thoracic and cardiac surgeon in New York who is affiliated with New York-Presbyterian Hospital.
We certainly appear to be finding more lung cancers in never-smokers,” Stiles told Healio. “For example, in the previous 3 years, almost 30% of the patients that our group operates on for lung cancer are people who have never smoked. However, it is controversial whether the actual incidence is increasing, or whether we are just finding more lung cancer in never-smokers due to an overall increase in the use of radiology studies and to an increased recognition of the disease in never-smokers.”
The increase in NSCLC among never-smokers coincides with a decrease in cancer deaths overall, driven partly by a decrease in lung cancer deaths.4 Among men, the rate of lung cancer deaths decreased 45% between 1989 and 2015, and in women, the incidence decreased 19% between 2002 and 2015.3 Moreover, between 2005 and 2014, the rates of newly diagnosed lung cancer cases fell by 2.5% per year in men and 1.2% per year in women. This gender disparity is indicative of tobacco use histories, with many women beginning to smoke much later than men and taking longer to quit.
Although these overall reductions in lung cancer may be partly due to greater success in smoking cessation efforts, Stiles cautioned against linking the disease exclusively to smoking.
“Certainly, decreases in tobacco usage should lead to decreases in lung cancer deaths; tobacco control and smoking cessation efforts are critical pieces of the lung cancer conversation,” he said. “However, these efforts don’t particularly help never-smokers with lung cancer and often lead to stigmatization of patients with the disease. It is important to recognize the fact that anyone with lungs can get lung cancer.”
Stiles also noted that the overall reduction in lung cancer deaths may also be related to earlier detection with CT screening programs or incidental detection of diagnoses.
As NSCLC is being increasingly identified in never-smokers, research has focused on risk factors that may be driving this phenomenon.
“We do know that there are risk factors for lung cancer other than smoking,” Stiles said. “These include radon and asbestos exposure, secondhand cigarette smoke, environmental causes including air pollution, other underlying lung diseases, and probably a genetic component that hasn’t been well-defined.”
The US Environmental Protection Agency reports that exposure to radon gas is the leading cause of lung cancer in nonsmokers.³ Approximately 21,000 annual deaths from lung cancer can be ascribed to radon gas exposure. Although radon gas is naturally present outdoors in nontoxic amounts, it can become condensed within homes built on soil with natural uranium deposits. Research also shows that lung cancer risk is highest among individuals who have lived for many years in a house contaminated by radon. Radon gas is not detectable under normal circumstances and can only be identified by testing a home.
Another significant risk factor for lung cancer among never-smokers is secondhand smoke, which is responsible for approximately 7,000 adult lung cancer deaths in the U.S. per year.³ Increased awareness of the dangers of secondhand smoke, as well as laws banning smoking in public places, have mitigated this risk. The American Cancer Society Cancer Action Network seeks to increase and reinforce these laws to minimize the dangers of secondhand smoke.
Although government and industry interventions have reduced workplace exposure to carcinogenic materials, some workplaces may still be sources of environmental hazards such as asbestos and diesel exhaust.3 Similarly, while the prevalence of indoor and outdoor air pollution is thought to be among the lowest in the U.S., air pollution nevertheless remains a risk factor for lung cancer in never-smokers.
Studies have also linked physical activity with lung cancer risk.5 In a hospital-based, case-control study of 660 patients with lung cancer and 1,335 controls, researchers found a significant association between lifetime physical inactivity and increased lung cancer risk (OR = 2.23; 95% CI, 1.77-2.81). This association was seen in both never-smokers (OR = 3; 95% CI, 1.33-6.78) and current nonsmokers (OR = 2.33; 95% CI, 1.79-3.02).
The genetic factors that drive NSCLC in never-smokers are also a major area of research.6 Women and never-smokers who carry a rare germline T790M mutation of the epidermal growth factor (EGFR) are at significantly higher risk of developing NSCLC compared to the average heavy smoker. Although this mutation is rare in the general population, it is identified in approximately one out of every 100 lung cancer cases. In a 2014 study, researchers assessed 14 members of a family carrying this germline mutation over five generations. This information was combined with data from a literature search on the topic.
Smokers who carried the T790M germline mutation had an OR of 0.31 for developing lung cancer vs. carriers who never smoked. Further, the incidence of the T790M mutation was disproportionately higher among never-smokers with lung cancer compared with the overall population of lung cancer patients.
Stiles said understanding the etiological differences between lung cancers in smokers and never-smokers is important for guiding treatment decisions.
“Never-smokers typically develop adenocarcinomas, whereas smokers can have adenocarcinoma, squamous cell carcinoma or small cell carcinoma,” he said. “Never-smokers often have cancers that are driven by well-defined molecular events, such as EGFR mutations, ALK rearrangements or ROS1 rearrangements… These ‘driver mutations’ can often be targeted by specific drugs that block their downstream activity and typically show better responses than chemotherapy.
“It is therefore critical that never-smokers with advanced NSCLC undergo molecular testing to determine the best treatment. Because these tumors are generally dependent upon one molecular event, never-smokers tend to have less total tumor mutation burden than smokers. Interestingly, this may make them less susceptible to immunotherapy.”
Asian women who have never smoked appear to be particularly affected by NSCLC.7 A meta-analysis of 5,137 lung cancer cases and 4,535 controls enrolled in 13 case-control studies and one cohort study from the Female Lung Cancer Consortium in Asia linked leucocyte CHrX mosaicism, especially chromosomal copy-number gains, to lung cancer development among Asian women.
While some data have been collected, Stiles said it is still not entirely clear why Asian women who are never-smokers have a higher risk for lung cancer.
“The reasons aren’t totally clear. In addition to different environmental exposures, genetic susceptibility may also play an important role,” he said. “Some have shown the association of certain genetic variants with the development of EGFR-mutated lung cancer, which most commonly occurs in Asian females.”
The US Preventive Task Force guidelines recommend yearly lung cancer screening with low-dose computed tomography in ever-smokers aged 55 to 80 years who have smoked 30 packs of cigarettes per year, as well as those who currently smoke.8 Patients who have stopped smoking for 15 years or more are not recommended for routine screening. Currently, there are no guidelines from any organization that recommend lung cancer screening among never-smokers. However, given the sharp increase in NSCLC in this population and the known risk factors besides smoking, a recent study assessed the benefit-harm tradeoff of screening never-smokers with varying levels of risk. The results showed that never-smokers with a RR of 15 could benefit from screening. However, the researchers noted that few never-smokers are expected to demonstrate RRs of 15 and, therefore, concluded that lung cancer screening is not beneficial in this population.
Blood-based assays could address the benefit-harm tradeoff of screening by simplifying the process. At ASCO 2018, researchers reported the outcomes of three prototype blood-based assays: targeted sequencing to detect 507 somatic mutations at 60,000X depth; whole-genome sequencing to detect changes in somatic gene copy number at 30 X depth; and whole-genome bisulfite sequencing of cell-free DNA to identify epigenetic changes at 30X depth.9 They showed that the whole-genome bisulfite sequencing assay detected 41% of early-stage lung cancer and 89% of late-stage lung cancer. The whole-genome sequencing test successfully identified 38% of early-stage lung cancer and 87% of late-stage lung cancer. The targeted blood assay identified 51% of early-stage lung cancer and 89% of late-stage lung cancer. All three tests demonstrated low rates of false-positive findings.
“A blood-based test for lung cancer screening is one of the Holy Grails of the field, but has proven challenging,” Stiles said. “Most screen-detected nodules are very small and may not spill a lot of protein or genetic material into the bloodstream. Additionally, if the genetic background of the tumor is unknown, one has to cast a very broad net to look for multiple mutations, which affects cost and efficiency of blood-based platforms.”
Stiles said blood-based assays are already being used clinically to detect EGFR mutations in patients with advanced cancer. However, he said these tests are usually most effective when cancer is already confirmed, and the clinicians have an idea of the mutations they need to identify.
“Significant progress is being made, particularly in detecting circulating cell-free DNA, which one day may be used to help determine lung cancer in screen-detected nodules, the vast majority of which are not cancer,” he said.
Newer drugs have been developed to target molecular changes and genetic mutations of NSCLC.10 In some patients, these targeted therapies may be more effective than chemotherapy and have milder adverse events. They are frequently used in later stages of lung cancer, either in conjunction with chemotherapy or alone. According to Stiles, these targeted treatments may be particularly useful for never-smokers.
“Many never-smokers who present with advanced lung cancer have driver mutations or rearrangements, such as EGFR, ALK or ROS1, which can be effectively targeted with these drugs,” he said.
EGFR inhibitors halt the signal that promotes tumor cell growth.10 Drugs in this class include erlotinib (Tarceva, Roche), afatinib (Gilotrif, Boehringer Ingelheim), gefitinib (Iressa, AstraZeneca), osimertinib (Tagrisso, AstraZeneca), and dacomitinib (Vizimpro, Pfizer). When cancer cells mutate intoT790M and EGFR inhibitors stop working, osimertinib can be used against this mutation. Meanwhile, drugs in the ALK inhibitor class include crizotinib (Xalkori, Pfizer), ceritinib (Zykadia, Novartis), alectinib (Alecensa, Genentech) and brigatinib (Alunbrig; Takeda Oncology, Ariad). At least some of these drugs may also be useful for patients with changes in the ROS1 gene.
Although cancer treatment presents certain challenges in most patients, Stiles said research indicates that never-smoker have fewer difficulties associated with treatment.
“As for patients with early-stage disease undergoing surgery, the literature is a bit conflicted,” he said. “Most research, however, shows that smokers have more complications related to treatment than do smokers.” – by Jennifer Byrne
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