Somatic copy number variation as a prognostic marker for recurrence in never‐smokers with early‐stage lung adenocarcinoma

Lung cancer in never-smokers has a distinct genomic profile characterized by lower tumor mutational burden, more tumor-promoting mutations, and fewer somatic copy number variations (CNVs) compared to smokers. While CNVs are linked to poor outcomes in advanced-stage cancer, their role in early-stage lung adenocarcinoma remains unclear. In a cohort of 210 treatment-naive never-smokers with early-stage lung adenocarcinoma, hierarchical clustering of CNVs identified three distinct groups: CNV low (n = 86 [41%]), CNV moderate (n = 75 [36%]), and CNV high (n = 49 [23%]). CNV low tumors had minimal CNV burden, CNV moderate tumors exhibited loss of heterozygosity in chromosomes 3, 9, 13, 15, and 18, and CNV high tumors showed genome-wide amplifications and whole-genome doubling. Recurrence occurred in 42 patients (20%), with a significantly lower 5-year cumulative incidence in the CNV low group (14% [95% CI, 7%-25%]) compared to the CNV moderate (31% [95% CI, 18%-44%]) and CNV high group (48% [95% CI, 27%-66%]) (p = .004). Adjusted hazard ratios for recurrence were 2.30 (p = .074) and 2.65 (p = .037) for CNV moderate and CNV high, respectively. These findings suggest CNV status is an independent predictor of recurrence, with CNV low tumors being associated with the most favorable prognosis.