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Second primary lung cancers (SPLC) may be more common than previously known, with up to 1 in 6 survivors developing SPLC, but research is limited.

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Although early detection of lung cancer through increased screening has improved survival rates, it has created new challenges. As more patients survive, there is an increased risk of developing secondary cancers.

Authors of a study published in the Journal of Thoracic Oncology discuss the surveillance, diagnosis, and management challenges of second primary lung cancer (SPLC), noting that its incidence may be higher than previously thought, with up to 1 in 6 survivors developing SPLC within 5 years.

Robert C. Rintoul, PhD, and colleagues note that emerging genomic approaches could help differentiate SPLC from metastases of the first primary cancer, which is crucial for proper patient management. Their review also highlights the need for updated classification methods and the potential role of early detection biomarkers, particularly blood-based ones, in identifying SPLC.

Assessing Risk and Patterns

“The etiology and epidemiology of SPLC are complex, reflecting the evolving epidemiological patterns of lung cancer,” noted the authors.

SPLC can be classified as either metachronous, occurring 1 year or more after the first primary lung cancer, or synchronous, appearing at the same time as or within 12 months of the first diagnosis.

Despite the recognition of SPLC for more than 50 years, small sample sizes have limited detailed analyses. Population-based research has provided valuable insights, with data indicating that lung cancer survivors have a significantly higher risk—up to 4 to 6 times greater—of developing SPLC compared to the general population. This elevated risk persists for at least a decade after the first diagnosis, especially in patients who smoke.

Smoking remains the leading cause of lung cancer, and many patients continue to smoke even after their initial diagnosis. Studies have shown that the risk of SPLC is comparable to that of smokers among never-smokers who develop lung cancer, suggesting that factors beyond smoking may also play a significant role. This highlights the need for further research to better understand the underlying causes of SPLC in both smokers and non-smokers.

Age at the time of the first primary lung cancer diagnosis also significantly impacts SPLC risk, authors found. Studies indicate that the risk varies widely depending on age, with those aged 60 to 64 years at the highest risk. This contrasts with younger patients under 50 years, who have a lower risk, and older patients above age 85, whose risk is also relatively lower, which suggests that the risk of SPLC is influenced by age and survival duration after the first diagnosis. Additionally, the histologic type of the initial lung cancer influences SPLC risk. The evolving epidemiology of lung cancer underscores the need for updated diagnostic and management strategies for SPLC.

Recent studies have applied next-generation sequencing alongside traditional histopathology to differentiate independent primary lung tumors from intrapulmonary metastases. The TRACERx study used whole exome sequencing to reveal distinct clonal origins in tumors, reclassifying presumed metastatic disease as synchronous primary lung cancer and vice versa. Integrating genomic profiling with radiologic and histologic assessment highlights the need for more tailored treatment strategies.

Early Detection Biomarkers

Early detection biomarkers hold the potential to identify SPLC. These biomarkers have been explored in various clinical settings, such as screening high-risk populations, diagnosing and monitoring minimal residual disease, and evaluating indeterminate lung nodules.

Blood-based liquid biopsies, particularly circulating tumor DNA (ctDNA), show the most promise among these. ctDNA analysis can reveal genetic mutations and alterations associated with cancer, offering insights into the genomic landscape of malignancy.

While ctDNA has shown potential in identifying first primary lung cancers, its sensitivity for early detection remains a challenge, especially for early-stage cancers with low ctDNA levels. Multi-modal approaches combining ctDNA with other biomarkers or machine learning algorithms are being explored to improve diagnostic accuracy.

Current studies are investigating the potential of these biomarkers in lung cancer survivors, aiming to enhance early detection of SPLC. However, translating biomarkers developed for primary lung cancer to the SPLC setting remains uncertain, and large, well-characterized cohorts are needed to advance this field.

“In addition to the clinical complexities, it is essential to consider the impact of SPLC on health care systems and the associated health economics,” said the authors. “As the incidence of SPLC increases, driven by longer patient survival and changes in risk factors, healthcare resources may come under increased pressure because of increased imaging and follow-up requirements.”

Key Takeaways

• The incidence of second primary lung cancer (SPLC) may be higher than previously thought, with up to 1 in 6 survivors developing SPLC within 5 years.
• While SPLC has been recognized for more than 50 years, small sample sizes have limited analysis.
• Recent studies have used next-generation sequencing with histopathology to differentiate independent primary lung tumors from intrapulmonary metastases.
• Current research is assessing potential biomarkers in lung cancer survivors to enhance early detection of SPLC.