Unveiling the molecular and clinical risk landscape of second primary lung cancer in resected non-small cell lung cancer

Background

Lung cancer (LC) survivors have a 4–6-fold higher risk of developing a second primary LC than the general population. In prospective multicenter studies, 15–17 % of patients undergoing surgical resection for LC develop a second malignancy, often in the lung, with risk persisting beyond 5 years. We characterized its incidence and risk factors, including genetic mutations, in a large retrospective cohort.

Methods

This study retrospectively analyzed 5,274 patients undergoing complete resection for non-small cell lung cancer at the National Cancer Center Hospital Tokyo between 2011 and 2023. Second primary LCs were identified using the Martini and Melamed criteria. We estimated cumulative incidence with the Fine–Gray competing–risk method, treating death as a competing event, and calculated sub–distribution hazard ratios (SHRs).

Results

The median follow-up was 4.4 years (range: 0–12). Overall, 365 (6.9 %) patients developed a second primary LC at a median interval of 4.1 years. Cumulative incidence from surgery was 0.7 % at 1 year, 6.1 % at 5 years, and 15.1 % at 10 years. Multivariate analysis identified heavy smoking history ([SHR]: 1.47, 95 % confidence interval [CI]: 1.07–2.30, p = 0.02), first status of multiple primary lung cancer (MPLC), defined as ≥ 2 synchronous tumors at baseline (SHR: 1.88, 95 % CI: 1.25–2.85, p = 0.002), and higher consolidation-to-tumor ratio (CTR) (SHR: 2.40, 95 % CI: 1.67–3.47, p < 0.001) as independent risk factors. Among 1,292 (24.5 %) patients assessed for genetic mutations, 699 (13.2 %) harbored at least one clinically targetable driver mutation; however, mutation status did not affect risk of second primary LC (p = 0.46).

Conclusions

Heavy smoking history, first status of MPLC, and higher CTR increase the risk of second primary LC; mutation status does not. Patients with these features require intensified, long-term surveillance.