Natural history of curatively resected stage IB-IIIA EGFR mutation (+) NSCLC: Clinicopathologic and molecular prognostic factors (ROOT-EGFR-ADJ).
Authors: Jung Hyun Ae , Jeon Yeong Jeong , Kim Jhingook , Park Sehhoon , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil 
Published: June 2021

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Background: Surgery is the primary therapy for patients with early-stage NSCLC. However, five-year recurrence rates were 45%, 62%, and 76% for pathologic stage (pStage) IB, II, and III respectively. In the ADARUA study, adjuvant osimertinib significantly improved DFS in patients with completely resected EGFR mutation (+) NSCLC. Though marked improvement of DFS is encouraging, OS is not mature yet and several questions remain unanswered; Does this DFS benefit translate to cure? Do all patients need to receive adjuvant Osiemrtinib? In order to address these questions we reviewed the clinical records of pStage IB-IIIA EGFR mutant NSCLC. Methods: From January 2008 and August 2020, total 2,340 patients with pStage IB-IIIA, non-SQ NSCLC underwent curative surgery at Samsung Medical Center. Using innovative in-house algorithm to retrieve medical big data-based cohort called ROOT (Realtime autOmetically updated data warehOuse in healTh care) detailed clinical data were analyzed to investigate any prognostic factors of recurrence. In order to identify any molecular prognostic factors, we did a comprehensive genomic analysis (WTS/WES)in a subset of patients with matched case-control. Results: Total 1,811 patients with pStage IB-IIIA, non-SQ EGFR mutation (+) NSCLC were included (367 patients : no EGFR mutation test). Median follow-up duration was 38.8 (range: 0.5 -156.2). Patient demographics; Deletion 19 was 52.7%, L858R was 47.3%. Female was 64.7% and never smoker was 72%. Stage IB, IIA, IIIA was 50.4%, 26.5%, and 23.2%. Among them, 6.7% of pStage IB, 72.8% of pStage II, and 88.7% of pStage IIIA received adjuvant chemotherapy. Median DFS were 74.0 months (95% CI 63.2-84.8), 48.6 months (95% CI: 40.2-57.0), and 22.4 months (95%: 19.5-25.3) for pStage IB, II, and IIIA, respectively. The median OS were 132.1 months (95% CI: 101.3-162.8), 124.3 months (95% CI: 61.8-186.9), and 82.1 months (95% CI: 71.2-93.1) for pStage IB, II, and IIIA, respectively. In univariate analysis, pStage, poorly differentiation, histologic subtype (micropapillary, solid), lymphatic invasion, vascular invasion, and pleural invasion were related with high recurrence rate statistically. In multivariate analysis, pStage, vascular invasion, and pleural invasion were related with recurrence statistically. To detect molecular factors, 76 patients performed the matched case -control (included pStage, type of EGFR mutation, and sex) analysis (WES/WTS). Conclusions: This study showed that the median DFS of pStage II-IIIA EGFR mutation (+) NSCLC was 31.9 months. With approximately 55% of patients with pStage II-IIIA EGFR mutation (+) NSCLC experienced recurrence at the 3rd year, we need to find the appropriate subset who need 3-year adjuvant osimertinib by comprehensive predictive marker for cure. Updated and detail exploratory biomarker outcome will be presented at the annual meeting.