The Genomic Landscape and Prognostic Impact of KRAS, STK11, and SMARCA4 Mutations and Co-Mutations on Survival Outcomes in Non-Small Cell Lung Cancer

Non-small lung cancer (NSCLC) accounts for 85% of lung cancer cases, and Kirsten rat sarcoma viral oncogene homolog (KRAS), Serine/Threonine Kinase 11 (STK11), and SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations and co-mutations have been increasingly recognized for their potential prognostic significance. However, clear knowledge gaps remain regarding which treatments should be selected for patients who present clinically with KRAS/STK11 or KRAS/SMARCA4 co-mutations, as outlined in Chapter 1. Despite significant clinical development advancements in immunotherapy and targeted therapy, a deeper understanding of the influence of these genomic subtypes is necessary to refine precision medicine strategies for clinicians who manage and treat lung cancer patients. Moreover, the five-year survival rates from 2014-2020 remain low for lung cancer patients, with a five-year survival rate of approximately 27% for all stages combined. This dissertation aimed to investigate the genomic landscape of KRAS, STK11, and SMARCA4 mutations and co-mutations in NSCLC while assessing their prognostic impact on patient survival outcomes. Given the mixed findings in the current literature regarding treatment analyses with specific genomic co-mutations subtypes, this cohesive work integrated two extensive critical reviews (Chapters 2 & 3) and a real-world evidence (RWE) multivariate analysis (Chapter 4) utilizing the AACR GENIE BPC database to evaluate the survival outcomes of these aforementioned mutations and co-mutations. The critical review in Chapter 2 highlighted the clinical studies that have elucidated the potential prognostic and predictive implications of KRAS mutations, STK11 mutations, or KRAS/STK11 co-mutations when treating metastatic NSCLC across various types of treatments (e.g., immune checkpoint inhibitors [ICIs]). Overall, KRAS mutations were associated with poor prognoses and were determined to be a valid but weak prognostic biomarker among patients diagnosed with NSCLC. In addition, KRAS mutations in NSCLC showed mixed results as a predictive clinical biomarker for immune checkpoint inhibitor treatment. Concerning STK11 mutations, the studies in this review demonstrated that they are prognostic and show mixed results as predictive biomarkers for ICI therapy. However, KRAS/STK11 co-mutations in NSCLC may predict primary resistance to ICI. The critical review in Chapter 3 investigates the impact of SMARCA4 mutations on survival outcomes in NSCLC through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. Moreover, this NSCLC review consistently reported statistically worse treatment-related overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT) and KRAS G12C inhibitors. The multivariate analysis in Chapter 4 evaluated the prognostic implications of KRAS and SMARCA4 mutations, including their co-mutations and their impact on NSCLC patients by utilizing real-world evidence. The retrospective analysis was conducted using the AACR GENIE Biopharma Collaborative (BPC) NSCLC 2.0 dataset among 659 NSCLC patients with KRAS or SMARCA4 class 1 or class 2 mutations. Neither SMARCA4 class was associated with worse survival outcomes than KRAS-mutated patients (p = .438 & .720). Patients harboring KRAS/SMARCA4 class 1 co-mutations had significantly worse overall survival compared to those with KRAS mutations alone (HR=3.23, p < .001). In contrast, KRAS/SMARCA4 class 2 co-mutations did not significantly impact survival compared to KRAS-mutated patients (HR= 1.34, p = .205). In this analysis, KRAS/SMARCA4 class 1 co-mutations were associated with significantly worse survival outcomes compared to KRAS-mutated patients in NSCLC. This dissertation contributes significantly to healthcare genomics by expanding and advancing the role of genomic subtypes in NSCLC prognosis while providing critical insights for clinicians managing and treating cancer patients (Chapter 5). For future direction, pre-specified survival analysis in clinical trials should be considered for the following co-mutations: KRAS/STK11, KRAS/SMARCA4 (class 1 vs class 2), KRAS/KEAP1, and KRAS G12C vs. KRAS non-G12C. In conclusion, the findings from this dissertation emphasize the necessity of routine genomic profiling to refine precision medicine strategies and establish the role of KRAS/SMARCA4 class 1 and KRAS/STK11 co-mutations as potential prognostic and predictive biomarkers in NSCLC.