Abstract 48: Molecular characteristics of HRAS mutated non-small cell lung cancer (NSCLC)
Authors: Trabolsi Asaad , Rodriguez Estelamari , Kareff Samuel Alexander , Korn Michael , Xiu Joanne , Liu Stephen , walker Philip , Ma Patrick , Mamdani Hirva , Nieva Jorge , Borghaei Hossein , Nabhan Chadi , Nagasaka Misako , puri Sonam , Lopes Gilberto 
Published: June 2022

Abstract
Background: Alterations in the RAS pathway have been linked to tumorigenesis, apoptosis, metabolism and angiogenesis. Mutations of KRAS in NSCLC are more frequent and better characterized, however, other family members such as HRAS remain under investigated and RAS remains a challenging therapeutic target. HRAS has been indirectly targeted with tipifarnib, a farnesyltransferase inhibitor rendering HRAS inactive in head and neck tumors. Here, we characterize the incidence, genomic landscape, and clinical context of HRAS alterations in NSCLC.
Methods: A total of 29,767 NSCLC tumor samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. MAPK activation was assessed using the MPAS gene expression signature. Wilcoxon, Fisher’s exact, or Dunnett’s tests were used to determined statistical significance (displayed as p value without and q value with multi-comparison correction). Overall survival was calculated from date of tissue collection to last contact from insurance claims data and used for Kaplan-Meier analysis. Comparisons were conducted between HRAS mutated tumors and the entire NSCLC general cohort (GC).
Results: HRAS mutations (Hm) were detected in 128 of 29767 NSCLC samples (0.4%) and were significantly enriched in older patients (median age, 71 vs. 69 years; q&lt;0.01) and squamous histology (57.8% vs 21.8%, q&lt;0.0001) compared to GC. Smoking status was not associated with HRAS mutational status (p=0.19). The most prevalent loci of hotspot mutations in Hm tumors were G13 (42.2%), followed by Q61 (33.6%) and G12 (21.1%). HRAS was not prognostic for overall survival (HR = 1.06, 95% CI [0.83-1.35], p=0.64), but for HRAS G13 mutant subset of NSCLC there was a trend towards worse prognosis (HR = 1.31, 95% CI [0.91-1.88], p =0.14). Hm-positive tumors harbored significantly more PIK3CA mutations (16.9% vs 5.5%, q&lt;0.05) but less KRAS (3.2% vs 27.4%, q&lt;0.05) and EGFR mutations (0.8% vs 11.9%, q&lt;0.05) compared to GC. In addition, Hm displayed dMMR/MSI deficiency (2.6% vs 0.7%, p &lt;0.05) more frequently, but had a comparable percentage of TMB-H tumors (34.2% vs 40.2%, p = 0.16) and similar median PD-L1 expression (54.7% vs 60.3%, p = 0.21) when comparing to GC. Lastly, MAPK pathway activation score was relatively higher in Hm compared to GC (-0.26 vs -0.42) with Q61 being the highest group (0.04 vs -0.42, p = 0.37).
Conclusions: HRAS mutations are detectable but uncommon events in NSCLC and significantly enriched in squamous histology. HRAS mutations often occur with PIK3CA co-mutations and trended towards higher activation of MAPK pathway and MSI-H frequency. This warrants further investigation on possible clinical applications of HRAS pathway inhibitors and utility of immune checkpoint inhibitors for this subset of NSCLC.
Citation Format: Asaad Trabolsi, Estelamari Rodriguez, Samuel Alexander Kareff, Michael Korn, Joanne Xiu, Stephen Liu, Philip walker, Patrick Ma, Hirva Mamdani, Jorge Nieva, Hossein Borghaei, Chadi Nabhan, Misako Nagasaka, Sonam puri, Gilberto Lopes. Molecular characteristics of HRAS mutated non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 48.