Understanding Lung Cancers in Never Smokers: Epidemiology, Genomic Features and Implications for Treatment

Lung cancer, often associated with smoking, is increasingly seen in individuals who have never smoked. These lung cancers in never smokers (LCINS) display unique characteristics - from their epidemiology to their genetic makeup - which demand tailored diagnostic and treatment strategies. This article will explore the science behind LCINS, its distinct aspects, and how this knowledge influences patient care.

Epidemiology of Lung Cancers in Never Smokers

The prevalence of LCINS is on the rise, with some studies revealing a significant increase in cases from 1990-1995 to 2011-2013. By 2023, LCINS is estimated to be the fifth most common cause of cancer-related deaths worldwide. This trend could be attributed to a complex interplay between genetic risk and environmental exposures, although the specifics are still under investigation.

Distinct Histological and Genomic Features

LCINS is not just epidemiologically distinct but also exhibits unique histological and genomic features. Histologically, LCINS often presents differently from smoking-related lung cancers, making their diagnosis a careful process. Genomically, LCINS is enriched for targetable oncogenic alterations, which may offer opportunities for personalized treatments. However, it also has a low tumour mutational burden and low rates of PD-L1 positivity, influencing its response to certain therapies.

Implication for Diagnosis and Treatment

These distinctive characteristics of LCINS necessitate unique approaches to diagnosis and treatment. For instance, the low tumour mutational burden and low rates of PD-L1 positivity may affect the efficacy of immune checkpoint inhibitors, a type of cancer therapy that unleashes the body's immune system to fight cancer cells. These factors need to be considered when planning treatment strategies for LCINS.

Real-World Implications and Future Research

Recent studies have shed light on the prevalence of non-actionable mutations in patients with advanced non-small cell lung cancer (aNSCLC) who initiated first-line immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy. The most prevalent mutations were TP53, KRAS, CDKN2A/B, and STK11. Interestingly, fast progressors were significantly more likely to harbor STK11, KEAP1, and CDKN2A/B mutations, while long-term survivors showed a significantly lower prevalence of these mutations. These findings may help in the development of predictive biomarkers and more effective treatment strategies.

The increasing prevalence and distinctive characteristics of LCINS underscore the need for continued research in this area. Understanding the unique epidemiology, histology, and genomics of LCINS could lead to more effective diagnostic tools and targeted treatments, improving outcomes for this unique group of patients. In the meantime, increased awareness of LCINS among both clinicians and the public is vital to ensure early detection and appropriate treatment.