Coexisting driver alterations in non-small cell lung cancer: Prevalence, clonal architecture, and impact on survival and progression.

Coexisting driver mutations in non-small cell lung cancer (NSCLC) can influence tumor biology, therapeutic response, and patient outcomes, yet these implications remain underexplored. 5420 NSCLC cases from QEII Health Sciences Centre were analyzed. Major driver variants were assessed, and clinical and survival data were analyzed. KRAS mutations were the most common variants, followed by EGFR, with higher variant frequency found in females. Coexisting driver mutations were found in 3.9% of tumors analyzed, with higher proportion in females. KRAS was the most frequent co-mutated driver (67%), and the most common combination of coexisting mutations was KRAS and PIK3CA (35%). 57.3% of tumors with coexisting alterations had at least one actionable variant. Clonality analysis demonstrated KRAS and EGFR as major initiating drivers, while PIK3CA, AKT1 and IDH1 were mostly secondary events. EGFR + KRAS mutations were associated with worse overall survival compared to patients with KRAS mutations only, in both early (HR: 2.58, 95% CI [1.45-13.05], p = 0.0091) as well as advanced-stage cohorts (HR: 3.23, 95% CI [2.27-18.60], p = 0.0008). Similar outcomes were observed compared to EGFR mutations in early (HR: 4.14, 95% CI [1.99-23.27], p = 0.0025) and advanced-stage cohorts (HR: 3.37, 95% CI [2.50-20.75], p = 0.0006). However, presence of KRAS + PIK3CA or EGFR + PIK3CA co-mutations did not impact prognosis in early-stage but was associated with worse outcomes in advanced-stage. Driver mutations coexist in NSCLC at various stages and can have a significant impact on prognosis. Comprehensive genomic profiling, investigating all oncogenic alterations including coexisting variants, is important for effective therapeutic management.