In a recent review published in Nature Reviews Clinical Oncology, scientists discussed the development of lung cancer in individuals who have never smoked (LCINS).
This review particularly focussed on this disease's genetic and environmental factors and outlined the available diagnostics and treatments.
Study: Lung cancer in patients who have never smoked — an emerging disease. Image Credit: SewCreamStudio/Shutterstock.com
Prevalence of lung cancer
Although smoking rates have been decreasing for several decades, smoking-related lung cancers account for the majority of lung cancer diagnoses in the USA. Globally, in every ethnic group, lung cancer is the leading cause of cancer-related deaths.
A recent study indicated a rapid increase in LCINS cases, particularly among younger age groups and women.
In 2023, more than 20,000 deaths linked to LCINS have been recorded. It has become the fifth most common cause of cancer-related mortality worldwide.
Epidemiological, histological, and molecular features of LCINs
Studies have indicated a distinct difference in histological and epidemiological aspects of LCINS from smoking-related lung cancers. For instance, LCINS commonly manifests in women and individuals with Asian ancestry. Hispanic female patients who have never smoked have been diagnosed with non-small-cell lung cancer (NSCLC).
Previous studies have shown that non-smoking women from East Asia are more vulnerable to lung cancer, which suggests that genetic and/or environmental factors other than tobacco smoking contribute to the incidence of the disease.
The average age for LCINS and smoking-related lung cancer diagnosis is almost the same; however, the younger age group exhibited a marginally higher incidence of LCINS.
Unlike smoking-related lung cancers, LCINS are almost exclusively lung adenocarcinoma (LUAD).
This group has exhibited molecular and genomic uniqueness from smoking-related lung cancers with a high level of targetable oncogenic alterations in key pro-survival signaling pathways that include ALK rearrangements and EGFR mutations.
Mostly, lung squamous cell carcinoma (LSCC) and small-cell lung cancer (SCLC) are robustly associated with smoking.
These typically develop in the central airways, most accessible to tobacco smoke. Experimental results have indicated that SCLC arising in LCINS requires differential treatment than smoking-related SCLC.
Interestingly, histological studies fail to differentiate between LUADs occurring in the presence or absence of tobacco smoke. No differential adverse prognostic features, such as visceral pleural invasion, lymphovascular invasion, and tumor spread through airways, were found between the two LUAD samples.
Radiographical features of molecular subtypes of LUAD have been analyzed. These studies have shown that ALK-rearranged LUADs are typically centrally located and linked with large pleural effusions, lacking a pleural tail.
In the case of metastatic spread linked to molecular drivers, patients with NSCLCs were found to possess EGFR mutations or ALK rearrangements.
In comparison to smoking-related lung cancers, LCINS have significantly lower tumor mutational burden (TMB) in coding and non-coding regions. Genomic profiling revealed that KRAS and BRAF driver mutations are mainly linked with tobacco smoking with a higher TMB.
The absence of immune-checkpoint inhibitors (ICI) response associated with LCINS and NSCLCs could contribute to alterations in EGFR or ALK that lowers TMB burden.
Risk factors for LCINS
Several large-scale genome-wide association studies (GWAS) identified common polymorphisms associated with lung cancer risk. Besides genetic factors, second-hand smoking (SHS) and radon exposure significantly contribute to LCINS development.
However, it must be noted that SHS-associated lung cancers exhibit similar types of tumors to those of never-smoking patients. There was no difference in EGFR, ALK, BRAF, KRAS, HER2, and PIK3CA alterations.
Tobacco carcinogen metabolites have been detected in the blood and urine samples of never-smoking individuals exposed to SHS. Household exposure to SHS is more significant than public exposure for developing LCINS.
Poor air quality with high particulate matter and chemical pollutants can contribute to the incidence of lung cancer. Fumes and particulate matter produced due to the burning of wood, charcoal, and crop residue in household settings contribute to indoor air pollution.
Exposure to diesel exhaust, silica, and welding fumes independently increases the risk of lung cancer. Individuals are often exposed to these carcinogens due to their occupation.
Exposure to asbestos increases the risk of bronchogenic carcinoma and pleural mesothelioma. Individuals working in construction, mining, shipbuilding, and firefighting are exposed to military asbestos products, which enhances the risk of developing lung cancer.
Diagnosis and management of LCINS
Many diagnostic and management strategies have been applied to LCINS based on multiple targetable somatic alterations.
The National Comprehensive Cancer Network (NCCN) Guidelines have recommended guidelines to test for oncogenes: EGFR, ALK, ROS1, KRAS, RET, BRAF, MET, HER2, and NTRK for NSCLC detection.
DNA-based next-generation sequencing (NSG) and whole exome sequencing (WES) techniques have been formulated for the same.
NCCN guidelines for NSCLC have largely outlined LCINS management. The efficacy of EGFR tyrosine kinase inhibitors (TKIs) therapy, followed by local consolidative treatment, has been assessed recently.
Adjuvant osimertinib treatment has received approval for treating patients with completely resected stage IB–IIIA EGFR-mutant NSCLC.
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