Lung cancer is currently the most common cancer worldwide. In most countries, lung cancer is also the most malignant form of tumor with the lowest survival rates. As of 2018, in most countries worldwide, lung cancer is the primary cancer-related cause of death. A staggering 1.8 million deaths from lung cancer in both sexes combined were recorded in 2018 globally. In the USA lung cancer mortality peaked at 159,292 in 2005 but has since decreased by 6.5% to 148,945 in 2016.
The five-year survival rate for lung cancer in the U.S.A. as of 2015 is 18.6 percent, much lower than other types of cancers such as colorectal (64.5 percent), breast (89.6 percent) and prostate (98.2 percent). When the disease is diagnosed at an early stage, the survival rate of lung cancer can be as high as 56 percent. Unfortunately, most lung cancer patients are rarely, if ever, diagnosed at an early stage. As a result of the spreading of the malignancy, more than half of lung cancer patients die within one year of being diagnosed. The 5-year survival rate regardless of stage is only 15% among lung cancer patients.
The latest statistics provided by the World Cancer Research Fund International revealed a total of 2,093,876 new cases of lung cancer being diagnosed in 2018 for both sexes worldwide. Prevalence of lung cancer was the highest among men worldwide, representing 15.5% (1,368,524 new cases) of the total number of new cases diagnosed in 2018. Lung cancer ranked number 3 for women, representing 8.8% of the total number of new cancer cases diagnosed in 2018, or 725,352 new cases in lung cancer alone, worldwide.
When individuals stop working due to cancer this represents a loss to society in the loss of productivity. The National Institutes of Health estimated that annual costs for the care of lung cancer in the U.S.A. reached $13.4 billion in 2015. Loss of earnings/productivity due to early death from lung cancer in the U.S.A adds another $21.3 billion in costs in 2015. In other countries, including Ireland, lung cancer is responsible for the highest productivity loss for cancer-related mortality.
Projected productivity loss for cancer-related mortality 2011-2030 in Ireland
[Source: Alison Pearce, Cathy Bradley, Paul Hanly, Ciaran O’Neill, Audrey Alforque Thomas, Michal Molcho and Linda Sharp Projecting productivity losses for cancer-related mortality 2011 – 2030 BMC Cancer. 2016 Oct 18;16(1):804.PMCID: PMC5069877 DOI: 10.1186/s12885-016-2854-4]
In the past, lung cancer was regarded as a disease for the elderly as the disease was found mostly in men over 50 years old, between the ages of 60-75 years. About 75% of lung cancer cases were attributed in part to tobacco smoking, with a higher estimate of 85% to 90% for the U.S.A. Compared to people who do not smoke, men who smoke are 23 times more likely to develop lung cancer, whereas women are 13 times more likely. Duration of smoking is considered to be the strongest determinant of lung cancer risk in smokers.
Ever since the early 1950’s when the carcinogenic effects of tobacco smoke on the lung were repeatedly shown in scientific studies, the rate of tobacco smoking began to decline sharply after the recognition by public health regulatory authorities in the mid-1960’s. In the U.S.A., the self-reported adult smoking rates peaked in 1954 at 45%, and remained at around 40% or more through the early 1970’s. The average rate of smoking across the decades began falling from 40% in the 1970s to 32% in the 1980s, 26% in the 1990s, and 24% since 2000. In 2008, the percentage of U.S. adults saying they smoked cigarettes was only 21%, a decrease of more than 50% from the peak at 45% in 1954.
PER CAPITA CONSUMPTION OF CIGARETTES AMONG ADULTS 18 YEARS AND OLDER FROM 1900 – 2004 IN THE U.S.A.
[SOURCE: THE NATIONAL ACADEMY PRESS, ENDING THE TOBACCO PROBLEM: A BLUEPRINT FOR THE NATION (2007) https://www.nap.edu/read/11795/chapter/4]
Despite the dramatic reduction of close to 50% in smoking rates between 1975 to 2004 in the U.S.A., the age-adjusted cancer incidence rates for lung cancer actually INCREASED by 6.3 percent from 52.2 per 100,000 in 1975 to 55.5 per 100,000 in 2011.
Even though the development of lung cancer is attributed mainly to smoking, approximately 25% of lung cancer incidences worldwide are not related to tobacco use. Lung cancers in never-smokers account for over 300,000 deaths worldwide each year.
Striking differences in the epidemiological, clinical and molecular characteristics of lung cancers arising in never-smokers versus smokers have been identified, suggesting that they are separate entities. Never smokers are people who have smoked less than the equivalent of 100 cigarettes in their entire lifetime. Lung cancer in never-smokers affect females more than males. It is estimated that 53% of all women with lung cancer worldwide compared to 15% of men, are never-smokers. In the U.K. 67% of never-smokers who underwent lung cancer surgery from 2008 to 2014 were females.
Lung Cancer Age‐Adjusted Incidence Rates by Sex, 1975‐ 2011
[Source: National Cancer Institute. SEER Cancer Statistics Review, 1975‐20011 Credit: American Lung Association Epidemiology and Statistics Unit Research and Program Services Division, Trends in Lung Cancer Morbidity and Mortality November 2014 https://www.lung.org/assets/documents/research/lc-trend-report.pdf]
Distinct clinical, pathological and biological features of lung cancer in never-smokers are also observed, in that small-cell lung cancer that is highly correlated with smoking is quite rare in never-smokers; and lung cancer in never-smokers is almost exclusively made up of non-small-cell lung cancer, with a predominance of adenocarcinoma over squamous cell carcinoma in the ratio of around 8:1 in Europe. Studies before 1990 also confirmed the observation that adenocarcinoma was most common among lung cancer in never-smokers.
The most troubling aspect in the diagnosis and treatment of lung cancer in never-smokers worldwide is that the demographics now include younger patients in their 20s, 30s, and 40s, instead of the traditional mean age of 70 at diagnosis.
Compared to smokers, the carcinogenesis of lung adenocarcinoma in never-smokers is more complicated. Many factors may cause the development of lung cancer in never-smokers, the major contributors are considered to be:
Environmental Tobacco Smoke (ETS)
Environmental Tobacco Smoke (ETS) is defined as “sidestream smoke from the smoldering tobacco between puffs and exhaled mainstream smoke from the smoker.” The link between ETS and lung cancer was first reported in 1981. In 1992, the Environmental Protection Agency published a review on the effects of ETS on lung cancer and indicated that ETS is associated with increased risk for lung cancer. However, in 2005 a large population study involving over 500,000 volunteers by the European Prospective Investigation into Cancer (EPIC) and Nutrition, an ongoing multi-centre prospective cohort study designed to investigate the relationship between nutrition and cancer, revealed that there is no statistically significant hazard in the development of lung caner from exposure to ETS. The current evidence seems to suggest that ETS plays a modest role in the development of lung cancer in never-smokers.
Radon is a naturally occurring radioactive gas produced by uranium decay in the earth’s crust. It emits alpha particles, decaying to polonium and bismuth. indoor levels can be quite variable depending on soil composition, building foundations and ventilation. Radon can accumulate to unsafe levels in basements and lower building levels. Radon exposure in underground workplaces is regulated in the U.S.A. Radon exposure is considered to be the second leading cause of lung cancer after tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers.
Occupational exposure to carcinogens is estimated to account for 5–10% of lung cancers. Of these, asbestos is the most common. The risk for lung cancer from asbestos exposure is dependent on both fiber type and dose, as larger chrysotile fibers can be cleared from the lungs more rapidly than amphibole fibers. Studies that did not detect increased lung cancer mortality from nonoccupational asbestos exposure involved populations that were predominantly exposed to chrysotile fibers. In general, it is believed that nonoccupational exposure to asbestos may not have a significant role in increasing mortality from lung cancer in never-smokers.
Infection & Inflammation
Damage to the lungs from inflammation and infection is often implicated in tumorigenesis. Pre-existing lung disease like tuberculosis increases odds ratio up to 1.76 for the development of lung cancer, regardless of smoking status. Chronic inflammatory lung diseases also confer additional risks for cancer development. However, the majority of lung cancer patients who are never-smokers do not have a history of active interstitial lung disease.
Inherited Genetic Susceptibility
A positive family history of lung cancer has been found to be a risk factor in several registry-based studies that have reported a high familial risk for early-onset lung cancer. Family history of lung cancer is correlated with increased risk in the development of lung cancer in both smokers and never-smokers. For never-smokers, genetic influences would explain the increased risk in the younger age group.
Genetic Risk Factors
Lung cancer in never-smokers is almost exclusively made up of NSCLC (non-small-cell lung cancer), with a predominance of adenocarcinoma. NSCLC patients often show metastasis to major organs such as liver (33–40%), brain (15–43%), kidney (16–23%), adrenal glands (18–38%), bone (19–33%), and abdominal lymph nodes (29%). The difficulty in treating primary tumors and related metastatic secondary mutations accounts for the poor prognosis of NSCLC. The 5-year survival rate for advanced NSCLC patients remain stubbornly below 5%.
Scientists now believe that genes may be involved in the increased susceptibility to adenocarcinoma in young never-smokers, especially in the gender disparity as the incidence of lung cancer in never-smokers worldwide indicate a female predominance. 53% of females who develop lung cancer are never-smokers while only 15% of male lung cancer patients never smoked, and the incidence of lung cancer in women can vary by 30-fold even in countries reported to have low prevalence of female smoking.
The higher incidence of lung cancer in female never-smokers has led scientists to explore gender-dependent hormones in the development of lung cancer. It has been observed that women who received anti-estrogen therapies showed a reduction in lung cancer incidence while women placed on hormonal replacement therapy showed increased risks for NSCLC.
Although lung cancer in never-smokers share molecular features that are typical in tobacco-related carcinogenesis, the presence of unique genetic and epigenetic markers indicate that a different but possibly overlapping carcinogenic pathway is responsible for the development of lung cancer in never-smokers.
Specific genetic mutations have been associated with a higher prevalence of adenocarcinomas in never-smokers. Those genes include EGFR, PTEN, ALK, ROS1, and RET; whereas a different set of genetic mutations in smokers have been identified. These genes are K-RAS, TP53, BRAF, STK11, and JAK2/3. Mutations and hypermethylation of p16 and LGALS4 are also implicated in progression of lung cancer in smokers.
Different Frequencies of Oncogenic Drivers in Never-smoking vs. Smoking Non-Small Cell Lung Cancer
[Shin Saito, Fernando Espinoza-Mercado, Hui Liu, Naohiro Sata, Xiaojiang Cui, and Harmik J. Soukiasian, Current status of research and treatment for non-small cell lung cancer in never-smoking females, Cancer Biol Ther. 2017; 18(6): 359–368. doi: 10.1080/15384047.2017.1323580]
As a result of dedicated efforts committed to the control of tobacco use, smoking prevalence and lung cancer mortality have decreased over the past several decades in the USA. However, tobacco smoking remains the major cause for lung cancer, whereas different carcinogens as well as genetic influences could be involved for different groups of never-smokers. With ever increasing understanding of the mechanisms behind the pathogenesis of lung cancer for smokers and never-smokers, it is anticipated that successful treatment can be tailored for the individual patient based on the presence or absence of critical molecular alterations.