Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer

Introduction: Patients with metastatic EGFR-mutant NSCLC inevitably have disease progression while on tyrosine kinase inhibitor (TKI) therapy. Co-occurring tumor suppressor gene (TSG) alterations have been associated with poor outcomes, however, detailed analyses of their impact on patient outcomes are limited. Methods: Patients with EGFR-mutant NSCLC treated with EGFR TKIs who had tumor genomic profiling were included. Alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1, and PTEN) were used to stratify the cohort into the following three subgroups: patients with tumors harboring a TP53 mutation plus a mutation in at least one additional TSG (TP53^mut/TSG^mut), those having a TP53 mutation without additional TSG mutations (TP53^mut/TSG^wt), and those with TP53^wt. Patient characteristics and clinical outcomes were assessed in two independent cohorts. Results: A total of 101 patients from the Yale Cancer Center and 182 patients from the American Association for Cancer Research Project GENIE database were included. In the Yale cohort, TP53 mutations were identified in 65 cases (64%), of which 23 were TP53^mut/TSG^mut and 42 were TP53^mut/TSG^wt. Although the presence of a TP53 mutation was associated with worse outcomes, the additional TSG alteration in TP53^mut tumors identified a subset of patients associated with particularly aggressive disease and inferior clinical outcome in both the Yale and the GENIE cohorts. Specifically, in the Yale cohort for patients receiving first-line TKIs, those with TP53^mut/TSG^mut tumors had shorter progression-free survival (PFS) and overall survival (OS) than TP53^mut/TSG^wt (PFS: hazard ratio [HR] = 2.03, confidence interval [CI]: 1.12–3.69, p < 0.01, OS: HR = 1.58, CI: 0.82–3.04, p = 0.12) or TP53^wt cases (PFS: HR 2.4, CI: 1.28–4.47, p < 0.001, OS: HR = 2.54, CI: 1.21–5.34, p < 0.005). Inferior outcomes in patients with TP53^mut/TSG^mut tumors were also found in those receiving osimertinib as second-line therapy. Similar findings were seen in patients in the GENIE cohort. Conclusions: Patients with TP53^mut/TSG^mut tumors represent a patient subgroup characterized by an aggressive disease phenotype and inferior outcomes on EGFR TKIs. This information is important for understanding the biological underpinnings of differential outcomes with TKI treatment and has implications for identifying patients who may benefit from additional therapeutic interventions beyond osimertinib monotherapy.