Abstract 5211: Somatic copy number variation as prognostic marker for recurrence in never-smokers with early-stage lung adenocarcinoma
Authors: Stijn Vanstraelen, Allison Reiner, Brooke H. Mastrogiacomo, Kay See Tan, Joseph Dycoco, Bernard J. Park, Prasad S. Adusumilli, Matthew J. Bott, David R. Jones, Gaetano Rocco
Journal: Cancer Research (2024)

Abstract Objective: Lung cancer in never-smokers has a distinct genomic profile with low tumor mutation burden, more tumor promotor mutations and fewer somatic copy number variations (CNV) than smokers. CNVs have shown to be associated with poor outcome in advanced stage disease. However, the relationship between CNV and clinicopathologic features on prognosis in early-stage lung cancer is undefined. To address this knowledge gap, we assessed the impact of CNV on recurrence in never-smokers who underwent curative resection for pathological stage I-II lung adenocarcinoma using an integrated genomic and clinicopathological analysis. Methods: We analyzed a cohort of 210 never-smokers with stage I-II lung adenocarcinoma treated from 2014 to 2022 who met the inclusion criteria (no neoadjuvant therapy, pathological stage I-II, complete resection, next-generation sequencing available). The patient cohort was stratified using unsupervised hierarchical clustering of arm-level CNVs. We assessed cumulative incidence of recurrence (CIR) between CNV groups using competing risk regression analysis, adjusting for SUVmax, pathologic stage, lymphovascular invasion, IASLC grade, and tumor mutation burden. Results: Of the 210 patients, 159 patients were female (76%), and patients were primarily from Caucasian (n=140, 67%) or Asian decent (n=50, 24%). Based on arm-level CNV clustering, the cohort was stratified into three groups: CNV low (n=86, 41%), CNV moderate (n=75, 36%) and CNV high (n=49, 23%). The CNV low tumors were characterized by a low CNV burden. Conversely, the CNV moderate tumors primarily exhibited gains in chromosomes 1q, 5p and 7p, along with loss of heterozygosity in chromosome 9p, 9q and 13. CNV high tumors were characterized by whole-genome doubling. Whole-genome doubling was significantly more common in CNV high tumors (n=33, 66%) compared to CNV low (n=2, 2.3%) and CNV moderate tumors (n=2, 2.7%) (p&amp;lt;.001). EGFR (n=145, 69%) and TP53 (n=61, 29%) were the most frequently altered genes, with EGFR alterations being significantly more prevalent in CNV high tumors (n=41, 84%) compared to CNV low tumors (n=46, 53%) (p&amp;lt;.001). In total, 42 patients (20%) developed recurrences. The CIR was lower in the CNV low group (5y-CIR, 14%, 95%CI: 6.5%-25%) compared to the CNV moderate (5y-CIR, 31%, 95%CI: 18%-44%) and CNV high group (5y-CIR, 48%, 95%CI: 27%-66%) (p=.004), with adjusted hazard ratios of 2.3 (95%CI: 0.93-5.71; p=0.074) and 2.65 (95%CI: 1.07-6.60; p=.037), respectively. The CIR for locoregional (n=11, 5%) and distant recurrence (n=31, 15%) remained lower in the CNV low group compared to the combined CNV moderate &amp; high groups (Gray test p=.020 and p=.049, respectively). Conclusion: In never-smokers who underwent curative treatment of pathological stage I-II lung adenocarcinoma, copy number status seems a predictor of recurrence, with CNV low tumors associated with the best prognosis. Citation Format: Stijn Vanstraelen, Allison Reiner, Brooke H. Mastrogiacomo, Kay See Tan, Joseph Dycoco, Bernard J. Park, Prasad S. Adusumilli, Matthew J. Bott, David R. Jones, Gaetano Rocco. Somatic copy number variation as prognostic marker for recurrence in never-smokers with early-stage lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5211.