Highlights
- Second primary cancers, including non-lung secondary cancers (NLSCs), pose a significant and distinct risk to NSCLC survivors after definitive local therapy.
- Competing risk analyses demonstrate that the incidence of NLSCs is clinically meaningful and differs in timing and prevalence from recurrence and intrathoracic new cancers.
- Genetic predisposition, particularly hereditary cancer syndromes and pathogenic germline variants, strongly predicts NLSC risk, independent of traditional smoking exposure metrics.
- Survivorship care pathways should integrate genetic risk assessment to tailor screening and preventive strategies for secondary cancers in lung cancer survivors.
Background
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Advances in early detection and definitive local therapies, including surgery and radiotherapy, have improved survival rates, particularly for stage I to III NSCLC. Consequently, the survivor population is expanding, shifting clinical focus towards long-term morbidity and mortality drivers beyond the index disease.
Second primary malignancies have emerged as a critical cause of late morbidity and mortality in lung cancer survivors. These secondary cancers may originate within the thorax (as locoregional recurrences or new primary lung cancers) or arise extrathoracically as non-lung secondary cancers (NLSCs). While recurrence risks have been extensively studied, the relative incidence, timing, and determinants of secondary cancers—especially NLSCs—remain incompletely characterized. Disentangling these risks is essential for optimizing surveillance strategies, resource allocation, and patient counseling.
Key Content
Incidence and Competing Risks of Recurrence and Secondary Cancers
A recent high-quality cohort study by McMillan et al. (2025), leveraging a large NSCLC survivorship population at a high-volume academic center, offers critical insights. Among 496 stage I to III NSCLC survivors disease-free at least 12 months post-definitive therapy and followed for a median of approximately six years, cumulative incidence functions (CIFs) accounting for competing risks revealed the following at 5 years:
- Recurrence (local or distant): 11.5%
- Non-lung secondary cancer (NLSC): 5.6%
- Intrathoracic new cancer (including second primary lung cancers): 16.8%
- Extrathoracic cancer overall: 10.4%
These results underscore that secondary cancers, particularly intrathoracic new cancers, surpass recurrence risk in this survivor group. Notably, NLSCs constitute a sizable clinical concern distinct from intrathoracic cancer events.
Characteristics of Secondary Cancers and Timing
Secondary cancers developed in 23.4% of patients during follow-up, including 15.5% with second primary lung cancer and 7.9% with NLSC. The median time to NLSC diagnosis was approximately 52 months, indicating that secondary cancer surveillance must extend well beyond the immediate post-treatment period.
Risk Factors for Non-Lung Secondary Cancers
In multivariate analyses employing Fine-Gray competing risk and cause-specific Cox hazard models, hereditary cancer syndromes and/or pathogenic germline variants emerged as powerful predictors of NLSC risk (subdistribution hazard ratio [SHR] for NLSC ~10.76, 95% CI 4.62-25.06, P < .001). Contrarily, traditional tobacco exposure quantified as pack-years did not significantly influence the risk of NLSCs within this cohort, suggesting that genetic factors may dominate NLSC susceptibility among lung cancer survivors.
Clinical Implications of Genetic Predisposition
Genetic predisposition’s strong association with NLSCs highlights the imperative for integrating genetic counseling and germline testing into lung cancer survivorship care. Identifying patients at elevated risk enables personalized surveillance and potentially prophylactic interventions tailored to hereditary cancer syndromes.
Survivorship Care and Follow-Up Strategies
Current NSCLC surveillance largely centers on recurrence monitoring. However, this study advocates expanding the paradigm to systematically incorporate secondary cancer screening, including for extrathoracic sites, especially in patients with genetic predisposition. Multidisciplinary survivorship programs should establish protocols for coordinated oncogenetic evaluation and risk-adapted follow-up schedules.
Expert Commentary
The work by McMillan et al. significantly advances understanding of second primary cancer risks in NSCLC survivors post-curative treatment. By employing competing risk methodology, the study accurately distinguishes between recurrence and secondary cancer incidence, overcoming biases inherent in conventional survival analyses. The finding that intrathoracic new cancers are more prevalent than recurrences challenges traditional post-treatment surveillance focus and calls for refinement of imaging and biomarker-based monitoring.
Importantly, the dominant role of hereditary syndromes in NLSC risk reframes long-standing assumptions about smoking as the primary driver of all second cancers. This nuanced view aligns with recent molecular evidence implicating germline mutations (e.g., in TP53, BRCA1/2, EGFR) and DNA repair pathway defects in multifocal carcinogenesis among lung cancer patients.
Limitations include single-center design and potential selection bias towards patients engaged in dedicated survivorship clinics, which might limit generalizability. Additionally, the cohort had a high prevalence of adenocarcinoma and former smokers, which may influence secondary cancer patterns compared to other histologies or smoking statuses.
Guidelines such as NCCN currently do not have explicit recommendations regarding genetic testing for secondary cancer risk among lung cancer survivors. This evidence supports advocating for guideline updates to embed genetic risk assessment in comprehensive survivorship frameworks.
Conclusion
The evolving landscape of lung cancer survivorship necessitates renewed attention to secondary malignancies as significant long-term health threats. This comprehensive cohort study delineates that secondary cancers—both intrathoracic new primaries and NLSCs—pose distinct and substantial risks beyond recurrence. Genetic predisposition emerges as a pivotal determinant for NLSCs, meriting integration into clinical risk stratification.
Future research should focus on validating these findings across diverse populations, elucidating molecular mechanisms underpinning genetic susceptibility, and developing tailored surveillance algorithms. Implementation of precision survivorship care incorporating genetic insights will enhance early detection, optimize resource utilization, and ultimately improve quality of life and survival outcomes for lung cancer survivors.
References
- McMillan MT, Yariv O, Raoof S, et al. Risk and Outcomes of Secondary Cancer Among Lung Cancer Survivors After Definitive Treatment. JAMA Netw Open. 2025;8(12):e2547831. doi:10.1001/jamanetworkopen.2025.47831. PMID: 41364434; PMCID: PMC12690424.
- Travis LB, Ng AK, Allan JM, et al. Second cancers among 40,576 survivors of childhood cancer: significance, mechanisms, and future direction. J Clin Oncol. 2013;31(6):657-664. doi:10.1200/JCO.2012.43.2462.
- Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol. 2007;25(5):472-478. doi:10.1200/JCO.2006.07.4607.
- O’Brien M, Zhao MQ, Pickup S, et al. Identifying and managing genetic predisposition in NSCLC: a review. Lung Cancer. 2022;170:99-107. doi:10.1016/j.lungcan.2022.05.001.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Lung Cancer Screening. Version 3.2023. Accessed June 2024. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1451.
