Cancer Progress and Priorities: Lung Cancer.

Abstract

In the United States, lung cancer is the second most common diagnosed cancer and the leading cause of cancer-related death. Although tobacco smoking is the major risk factor accounting for 80% to 90% of all lung cancer diagnoses, there are numerous other risk factors that have been identified as casually associated with lung cancer etiology. However, there are few causally linked risk factors for lung cancer diagnosed among never smokers, which, if considered a unique reportable category, is the 11th most common cancer and the 7th leading cause of cancer-related death. Lung cancer survival has only marginally improved over the last several decades, but the availability of screening and early detection by low-dose CT and advances in targeted treatments and immunotherapy will likely decrease mortality rates and improve patient survival outcomes in the near future.Globally, lung cancer has been the most common diagnosed cancer for the last several decades (1, 2). In 2018, there was an estimated 2.1 million new lung cancer diagnoses accounting for 12% of the global cancer burden (1, 2). Among men, lung cancer remains the most common cancer diagnosis with approximately 1.37 million diagnoses in 2018, with the highest incidence rates in Micronesia (54.1 per 100,000), Polynesia (52.0 per 100,000), Central and Eastern Europe (49.3 per 100,000), and Eastern Asia (47.2 per 100,000). Among women, incidence rates are generally lower than men with approximately over 725,000 new lung cancer diagnoses in 2018. Geographic variations in incidence rates differ for women compared with men (Fig. 1A and B), which are attributed to historical differences in cigarette smoking. Among women, the highest incidence rates occur in North America (30.7 per 100,000), Northern Europe (26.9 per 100,000), and Western Europe (25.7 per 100,000).In the United States, lung cancer is the second most common cancer in men after prostate cancer and the second most common cancer in women after breast cancer (3, 4). In 2019, an estimated 228,150 new cases of lung cancer are expected. The incidence rate among men is 71.3 per 100,000 and for women it is 52.3 per 100,000. Although the incidence rate has been declining in men since the mid-1980s, incidence rates did not start declining for women until the mid-2000s because of historical sex-specific differences of smoking uptake and cessation. The decline in incidence has gained momentum in the past decade with rates decreasing from 2011 to 2015 by nearly 3% per year in men and 1.5% per year in women. Geographically, lung cancer incidence is higher in the Midwest, East, and South with the highest rates observed in the South for both men and women (Fig. 2A and B).The global geographical patterns in lung cancer–related deaths closely follow those in incidence because of poor survival and the high fatality rate of this disease (Fig. 3A and B). Worldwide, lung cancer is the leading cause of cancer-related death in men and the second-leading cause in women. In 2018, an estimated 1.8 million deaths occurred (1.2 million in men and 576,100 in women), accounting for 1 in 5 cancer-related deaths worldwide (1, 2). The geographic variations by country/region between men and women are largely attributed to historic patterns in tobacco smoking and maturity of the tobacco epidemic (2).In the United States, lung cancer is the leading cause of cancer-related death among both men and women (3, 4). In 2019, an estimated 142,670 deaths are expected to occur, or about 23.5% of all cancer-related deaths. The mortality rate among men is 51.6 per 100,000 and 34.4 per 100,000 for women. Because of reductions in smoking, the lung cancer–related death rate has declined 48% since 1990 in men and by 23% since 2002 in women. From 2012 to 2016, the death rate dropped by about 4% per year in men and 3% per year in women. Geographically, lung cancer mortality follows a pattern similar to incidence, including the highest rates observed in the South (Fig. 4A and B).Despite substantial improvements in survival in recent years for most other cancer types in the United States, there have only been small improvements in 5-year survival among patients diagnosed with lung cancer (Fig. 5). This lack of improvement is primarily because the majority of patients are diagnosed with late-stage disease where the survival rates are dismal (Fig. 6). The 5-year relative survival rate for all lung cancers [non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) combined] is 19%, and the 5-year survival is higher for NSCLC (23%) than SCLC (6%; refs. 3, 4).Despite the high mortality rates and poor survival outcomes associated with a lung cancer diagnosis, the next generation of targeted therapies and the emergence of immune checkpoint inhibitors have demonstrated durable long-term survival in subsets of patients. As such, these therapies may hold the key in improving lung cancer patient outcomes leading to curable lung cancer among early-stage diagnoses and a chronic and manageable disease for patients with advanced and metastatic disease.Lung cancer tumors are divided into two broad histologic categories: NSCLC and SCLC. NSCLC represents more than 80% to 85% of lung cancers of which approximately 40% are adenocarcinoma, 25% to 30% are squamous cell carcinoma, and 10% to 15% are large cell carcinomas (Fig. 7; refs. 5–7). Bronchioloalveolar carcinoma (BAC) was a distinct histologic classification representing a subgroup of adenocarcinomas and has been replaced with adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive adenocarcinoma of the lung (8). Other less common histologic subtypes include adenosquamous carcinoma, pleomorphic sarcomatoid carcinoma, large-cell neuroendocrine carcinoma, and carcinoid tumor.Among women, adenocarcinoma has been the most frequently diagnosed histologic subtype since at least the 1970s (Fig. 8A). Among men, the incidence rate of lung adenocarcinoma has been on the rise since the 1970s, and the incidence rate for lung adenocarcinoma surpassed squamous cell carcinoma around 1994 (Fig. 8B). The incidence rate for squamous cell carcinomas has been on the decline since the early 1980s. This temporal shift in histologic diagnoses is largely attributed to the widespread use of filtered cigarettes and increasing amounts of tobacco-specific nitrosamines in tobacco (9). Regarding the former, earlier in the 20th century, most mass-produced cigarettes were nonfiltered, which discouraged deep inhalation and combusted tobacco smoke exposed primarily in the trachea and bronchus, resulting in observed higher rates of squamous cell carcinoma diagnoses especially among men (10). When filtered cigarettes were introduced, combusted tobacco smoke dispersed deeper into the respiratory tree due to deeper inhalation resulting in adenocarcinomas with a more peripheral distribution (11). The introduction of so-called “light” filtered cigarettes and changing tobacco blends, which decreased nicotine but increased nitrates and N-nitrosamines, had the paradoxical effect of increasing, rather than decreasing, lung cancer risk due to promotion of deeper and more frequent inhalation of combusted tobacco smoke (10, 11).Although the binary division of lung cancer into NSCLC and SCLC is still widely applied and relevant, advances in genomic profiling has resulted in a paradigm shift whereby lung cancers are also characterized and classified by tumor biomarkers and genetic alterations, such as gene expression, mutations, amplifications, and rearrangements (Table 1), that are critical to tumor growth and survival and can be exploited with specific targeted agents or immune-checkpoint blockades (12–14).Although the terms