Analysis of tumor genomic pathway alterations using broad-panel next-generation sequencing in surgically resected lung adenocarcinoma

Purpose: The majority of broad-panel tumor genomic profiling has used a gene-centric approach, although much of that data is unused in clinical decision making. We hypothesized that a pathway-centric approach using next-generation sequencing (NGS), combined with conventional clinicopathologic features, may better predict disease-free survival (DFS) in early stage lung adenocarcinoma. Experimental Design: Utilizing our prospectively maintained database, we analyzed 492 patients with primary, untreated, completely surgically resected lung adenocarcinoma. Ten canonical pathways were analyzed using broad-panel NGS. The correlations of DFS and number (and type) of pathway (NPA) were analyzed using the Kaplan–Meier method and log-rank test. Associations between altered pathways and clinicopathologic variables, as well as identification of actionable therapeutic strategies were explored. Results: Median NPA for the cohort was two (range, 0–5). Smoking status, solid morphologic appearance on preoperative CT, maximal standardized uptake value, pathologic tumor size, aggressive histologic subtype, lymphovascular invasion, visceral pleural invasion, and positive lymph nodes were significantly associated with NPA (P < 0.05). Of 543 actionable genetic alterations identified, 455 (84%) were within the RTK/RAS pathway. A total of 86 tumors had actionable therapeutic genomic alterations in >1 pathway. On multivariable analysis, higher NPA was significantly associated with worse DFS (HR, 1.31; P ¼ 0.014). Conclusions: NPA and specific pathway alterations are associated with clinicopathologic features in patients with surgically resected lung adenocarcinoma. Cell cycle, Hippo, TGFb, and p53 pathway alterations are associated with poor DFS. Finally, NPA is an independent risk factor for poor DFS in our cohort.