Abstract
Simple SummaryDespite complete resection and adjuvant chemotherapy, the recurrence rate of early EGFR-mutated lung adenocarcinoma remains high. We hypothesized that patients with recurrence-related genetic alterations would have poor prognosis and analyzed the genetic profiles of 131 patients using next-generation sequencing (NGS) with a 207 cancer-related gene panel. As a result, we revealed several negative prognostic factors for recurrence, such as a large number of concomitant mutations and the existence of specific mutation subtypes. Targeted NGS analysis provides information on the prognosis of patients with resected EGFR-mutation lung adenocarcinoma and helps to identify patients with high relapse risks who require intensive chemotherapy or adjuvant EGFR-TKIs treatments.Targeted NGS, widely applied to identify driver oncogenes in advanced lung adenocarcinoma, may also be applied to resected early stage cancers. We investigated resected EGFR-mutated lung adenocarcinoma mutation profiles to evaluate prognostic impacts. Tissues from 131 patients who had complete resection of stage I–IIIA EGFR-mutated lung adenocarcinoma were analyzed by targeted NGS for 207 cancer-related genes. Recurrence free survival (RFS) was estimated according to genetic alterations using the Kaplan–Meier method and Cox proportional regression analysis. The relapse rate was 25.2% (33/131). Five-year RFS of stages IA, IB, II, and IIIA were 82%, 75%, 35%, and 0%, respectively (p < 0.001). RFS decreased with the number of co-mutations (p = 0.025). Among co-mutations, the CTNNB1 mutation was associated with short RFS in a multivariate analysis (hazard ratio: 5.4, 95% confidence interval: 2.1–14.4; p = 0.001). TP53 mutations were associated with short RFS in stage IB–IIIA (p = 0.01). RFS was shorter with EGFR exon 19 deletion (19-del) than with mutation 21-L858R in stage IB–IIIA tumors (p = 0.008). Among 19-del subtypes, pL747_P753delinS (6/56, 8.9%) had shorter RFS than pE746_A750del (39/56, 69.6%), the most frequent subtype (p = 0.004).
Highlights
Complete surgical resection is the standard treatment for early stage lung cancer
We evaluated the risk of recurrence based on co-occurring actionable mutations, the number of co-mutations, epidermal growth factor receptor (EGFR) mutation types, and EGFR exon 19 deletion (19-del) subtypes in resected EGFR-mutated lung adenocarcinomas
The adjuvant cytotoxic chemotherapy being provided to patients more susceptible to relapse was not effective in preventing recurrence
Summary
Complete surgical resection is the standard treatment for early stage lung cancer. The rate of recurrence is high and patients with recurrence eventually die of disease progression. The recurrence rate of patients with stage IB tumors is 20%, which is less than those of patients with stage II (40–60%) and IIIA (70–100%) tumors [5]. Tumor-stage distribution analysis shows that stage I tumors with low recurrence rates are much more prevalent than stage II and IIIA tumors, the number of patients with recurrence in stage I is not negligible [6]. It is an important unmet need to identify patients at high risk for recurrence in resected early stage EGFR-mutated lung adenocarcinoma
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