Next Generation Sequencing and Clinical Outcomes of Lung Adenocarcinomas Treated With Stereotactic Body Radiation Therapy

Abstract

Genetic aberrations in lung adenocarcinomas (LAC) are well characterized and clinical outcomes have been influenced by the development of targeted therapies for driver mutations. However, little is known regarding the impact of genetic alterations on the efficacy of radiation therapy. We sought to determine the frequency and association of genomic mutations with clinical outcomes for early-stage LAC treated with stereotactic body radiotherapy (SBRT). Under an IRB approved protocol, the records of 242 consecutive early-stage lung cancer patients treated with SBRT at 4 academic sites were reviewed. Inclusion criteria included LAC histology with adequate tumor sample for successful use of SNaPshot or TruSight mutation testing panel and FISH lung cancer panel. Univariable (UVA) analyses were performed to identify characteristics associated with local recurrence (LR), regional recurrence (RR), and metastatic recurrence (MR). Additionally, Kaplan-Meier analysis (KM) was performed to compare clinical endpoints. Ninety-eight LACs (40.5%) were identified, of which 45 patients (46.0%) had genetic testing performed. The following aberrations were seen: KRAS (20.0%), ALK rearrangement (8.9%), Her2 (6.7%), BRAF (2.2%), SMAD4 (4.4%), EGFR (15.6%), MET amplification (17.8%), STK11 (2.2%), RET rearrangement (2.2%), p53 (15.6%), and PTEN (2.2%). Notably no patients had mutations of AKT1, IDH-1, IDH-2, NRAS, P13KCA, or ROS1 rearrangement. Median follow-up was 10.6 months (1.1 months – 36.0 months), median total delivered radiation dose was 50 Gy (48 Gy – 60 Gy), median radiation dose per fraction was 10 Gy (7.5 Gy – 20 Gy), and median number of fractions of 5 (3-8). KRAS mutation was associated with worse LR (HR = 3.64, 95% CI 1.05-12.65, P < 0.05). MET amplification was associated with worse RR (HR = 4.64, 95% CI 1.54-14.03, P < 0.01) and MR (HR = 3.73, 95% CI 1.24-11.23, P = 0.02). On KM, 1-year local control rates for KRAS mutated patients was 63.5% compared to 96.0% for KRAS wild-type patients (P = 0.02). 1-year regional control and metastatic control for MET amplified patients was 38.1% and 68.6% compared to 87.5% and 85.4% for MET wild-type patients respectively (both P < 0.01). Our series is the first to quantify genetic mutations in early-stage LAC patients undergoing SBRT. We found that KRAS mutation was associated with worse LR and MET amplification was associated with worse RR and MR. These results need to be further validated in a prospective setting.