Data from Clinical, Pathologic, and Molecular Prognostic Factors in Patients with Early-Stage EGFR-Mutant NSCLC
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 
Published: April 2023

<div>AbstractPurpose:<p>In early-stage, <i>EGFR</i> mutation–positive (<i>EGFR</i>-M<sup>+</sup>) 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 <i>EGFR</i>-M<sup>+</sup> NSCLC.</p>Experimental Design:<p>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 <i>EGFR</i>-M<sup>+</sup> 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 <i>EGFR</i> mutation).</p>Results:<p>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 (<i>P <</i> 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; <i>P <</i> 0.01) and <i>TP53</i> mutation (HR, 2.50; 95% CI, 1.24–5.04; <i>P =</i> 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; <i>P =</i> 0.02).</p>Conclusions:<p>The low-risk group with TRU subtype and <i>TP53</i> wild-type without clinicopathologic risk factors might not need adjuvant EGFR-TKIs. In the high-risk group, with non-TRU subtype and/or <i>TP 53</i> 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 alternative adjuvant strategy might be needed.</p></div>