Clinical, Pathologic, and Molecular Prognostic Factors in Patients with Early-Stage EGFR-Mutant NSCLC

• Published in: Clinical cancer research 2022-10, Vol.28 (19), p.4312-4321
• Main Authors: Jung, Hyun Ae, Lim, Jinyeong, Choi, Yoon-La, Lee, Se-Hoon, Joung, Je-Gun, Jeon, Yeong Jeong, Choi, Jae Won, Shin, Sumin, Cho, Jong Ho, Kim, Hong Kwan, Choi, Yong Soo, Zo, Jae Ill, Shim, Young Mog, Park, Sehhoon, Sun, Jong-Mu, Ahn, Jin Seok, Ahn, Myung-Ju, Han, Joungho, Park, Woong-Yang, Kim, Jhingook, Park, Keunchil
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - therapeutic use; Apolipoproteins - genetics; Apolipoproteins - therapeutic use; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Chemotherapy, Adjuvant; ErbB Receptors - genetics; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mutation; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors - therapeutic use; Retrospective Studies; RNA; RNA, Messenger; Small Cell Lung Carcinoma - pathology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-22-0879

In early-stage, EGFR mutation-positive (EGFR-M+) non-small cell lung cancer (NSCLC), surgery remains the primary treatment, without personalized adjuvant treatments. We aimed to identify risk factors for recurrence-free survival (RFS) to suggest personalized adjuvant strategies in resected early-stage EGFR-M+ NSCLC. From January 2008 to August 2020, a total of 2,340 patients with pathologic stage (pStage) IB-IIIA, non-squamous NSCLC underwent curative surgery. To identify clinicopathologic risk factors, 1,181 patients with pStage IB-IIIA, common EGFR-M+ NSCLC who underwent surgical resection were analyzed. To identify molecular risk factors, comprehensive genomic analysis was conducted in 56 patients with matched case-controls (pStage II and IIIA and type of EGFR mutation). Median follow-up duration was 38.8 months (0.5-156.2). Among 1,181 patients, pStage IB, II, and IIIA comprised 577 (48.9%), 331 (28.0%), and 273 (23.1%) subjects, respectively. Median RFS was 73.5 months [95% confidence interval (CI), 62.1-84.9], 48.7 months (95% CI, 41.2-56.3), and 22.7 months (95% CI, 19.4-26.0) for pStage IB, II, and IIIA, respectively (P < 0.001). In multivariate analysis of clinicopathologic risk factors, pStage, micropapillary subtype, vascular invasion, and pleural invasion, and pathologic classification by cell of origin (type II pneumocyte-like tumor cell vs. bronchial surface epithelial cell-like tumor cell) were associated with RFS. As molecular risk factors, the non-terminal respiratory unit (non-TRU) of the RNA subtype (HR, 3.49; 95% CI, 1.72-7.09; P < 0.01) and TP53 mutation (HR, 2.50; 95% CI, 1.24-5.04; P = 0.01) were associated with poor RFS independent of pStage II or IIIA. Among the patients with recurrence, progression-free survival of EGFR-tyrosine kinase inhibitor (TKI) in those with the Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) mutation signature was inferior compared with that of patients without this signature (8.6 vs. 28.8 months; HR, 4.16; 95% CI, 1.28-13.46; P = 0.02). The low-risk group with TRU subtype and TP53 wild-type without clinicopathologic risk factors might not need adjuvant EGFR-TKIs. In the high-risk group, with non-TRU subtype and/or TP 53 mutation, or clinicopathologic risk factors, a novel adjuvant strategy of EGFR-TKI with others, e.g., chemotherapy or antiangiogenic agents needs to be investigated. Given the poor outcome to EGFR-TKIs after recurrence in patients with the APOBEC mutation signature, an al