Exposure to Occupational Carcinogens and Non-Oncogene Addicted Phenotype in Lung Cancer: Results from a Real-Life Observational Study

Background/Objectives: Lung cancer (LC) remains one of the most lethal malignancies worldwide, with both environmental and occupational exposures contributing to its incidence. While oncogene-addicted tumors—defined by single driver mutations—have garnered attention due to their therapeutic implications, less is known about the mutational landscape of tumors potentially arising from occupational exposure to carcinogens. This real-life observational study aimed to assess whether previous occupational exposure to lung carcinogens correlates with distinct LC phenotypes, particularly non-oncogene addicted (nOA) profiles. Methods: A total of 199 LC patients were enrolled across two specialized oncology centers in Northern Italy between 2021 and 2023. Each participant underwent detailed occupational history reconstruction and molecular characterization using next-generation sequencing. Patients were stratified into non-exposed (NE), low-exposed (LE), and high-exposed (HE) categories based on standardized questionnaires and sector-specific assessments. Results: While no significant differences were found in histological subtypes across exposure groups, a notable association emerged between high occupational exposure and nOA phenotypes in adenocarcinoma patients. Logistic regression models—adjusted for age, sex, and smoking habits—confirmed that HE patients had a significantly higher likelihood of developing nOA tumors (OR=3.07; 95% CI: 1.16–8.11; p=0.023). This association weakened but persisted after adjusting for smoking habits by using pack-years of smoking. Timing of exposure also played a potential role: exposures occurring 5–10 years before diagnosis were associated with increased nOA risk, although not statistically significant. Conclusions: These findings suggest that occupational exposures may contribute to more complex and therapeutically challenging LC phenotypes. Recognizing occupational history in the diagnostic pathway may offer prognostic insights and support compensation assessments. Further studies are warranted to validate these results and explore targeted prevention strategies for occupational lung cancer.