HRAS Mutations Define a Distinct Subgroup in Head and Neck Squamous Cell Carcinoma

Abstract

PURPOSE In head and neck squamous cell carcinoma (HNSCC), HRAS mutation is a new actionable oncogene driver. We aimed to evaluate HRAS mutational variants, comutation profile, and survival outcomes of this molecularly defined population. METHODS We leveraged four deidentified patient data sets with HRAS-mutant HNSCC, MD Anderson Cancer Center, Kura Oncology, Inc trial, Foundation Medicine, and American Association for Cancer Research GENIE v.12. Patient demographic information and clinical courses were extracted, when available, in addition to HRAS mutation type and co-occurring mutations. Survival outcomes were analyzed (Kaplan-Meier method). RESULTS Two hundred forty-nine patients with HRAS-mutant HNSCC were identified from the four data sets. Median age ranged from 55 to 65 years, with a higher frequency in male patients (64%); the majority of HRAS-mutant HNSCC occurred in human papillomavirus–negative HNSCC. HRAS mutation patterns were similar across data sets; G12S was the most common (29%). Treatment responses to tipifarnib were not codon-specific. Compared with wild-type, significantly co-occurring mutations with HRAS were Casp8 (Fisher's exact test, P < .00013), TERT ( P < .0085), and NOTCH1 ( P < .00013). Analysis of clinical courses from the MD Anderson Cancer Center and Kura Oncology, Inc data sets demonstrated poor clinical outcomes with a high rate of recurrence following primary definitive treatment (50%-67% relapse < 6 months) and short disease-free survival (4.0 months; 95% CI, 1.0 to 36.0) and overall survival (OS; 15.0 months; 95% CI, 6.0 to 52.0). Use of tipifarnib in this data set demonstrated improved OS (25.5 months; 95% CI, 18.0 to 48.0). CONCLUSION Oncogenic mutations in HRAS occur in 3%-4% of HNSCC, with G12S being the most frequent. Without targeted therapy, patients with HRAS-mutant HNSCC had poor clinic outcomes; observable trend toward improvement in OS has been noted in cohorts receiving treatments such as tipifarnib. The comutation pattern of HRAS-mutant in HNSCC is distinct, which may provide insight to future therapeutic combination strategies.

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors

“…HRASmt status was associated with poorer clinical outcomes in HNSCC, and no difference in OS was observed between the different HRAS codon mutations. Similar findings were recently reported for 249 HRASmt HNSCC samples with median diseasefree survival (DFS) of 4.0 months and OS between 15 and 25.5 months [20], which were slightly longer than those observed in our cohort. This confirms the aggressive clinical nature of HRASmt HNSCC, as has been observed previously [37].…”

“…With inhibitors for TP53wt HRASmt UC under development [29], our results provide further evidence for targeting HRASmt UC. Finally, the alterations observed in our HNSCC cohort echo a previously reported dataset in which CASP8, TERT, and NOTCH1 were also frequent co-mutations in HRASmt HNSCC, while CCND1 had higher amplification in HRASwt compared to HRASmt [20] (Figure 2). However, we also report a significantly increased co-occurrence of HRASmt with CTCF and FAT1 mutations (Figure 2).…”

“…This estimate is slightly lower than previously described [9]. However, the disease-specific prevalences reported in this study of 3.0% in UC, 2.82% in HNSCC, and 1.05% in melanoma mirror the literature [18][19][20][21].…”

Farnesyl-transferase inhibitors show synergistic anticancer effects in combination with novel KRAS-G12C inhibitors

“…This widely used method provides a quantitative definition of drug interactions ( CI = 1 additive effect, CI > 1 antagonistic and CI < 1 synergistic effect). We first investigated sotorasib, which is already approved for clinical treatment of KRAS-G12C lung adenocarcinoma, in combination with tipifarnib, an FTi that was recently granted Breakthrough Therapy Designation for treatment of HRAS mutant head and neck squamous cell carcinoma [ 31 ]. To test combinational therapy, we first tested three KRAS-G12C mutant cell lines: H358 a sotorasib sensitive; SW1573, a sotorasib-resistant and a novel patient-derived cell line, PF139.…”

Effect of Harvey Rat Sarcoma Virus Mutation in Oral Squamous Cell Carcinoma and Its Influence on Different Populations: A Systematic Review

“…It was also found that in all cohorts, the most common mutation encountered was G12S, which was 25% in MDACC, 30% in Kura, 26% in the FMI data set, and 41% in AACR Project GENIE v.12 cohort, respectively. Other than codon 12 and codon 13, codon 61 was also frequently reported for mutation which was presented as 31% in the MDACC, 11% in Kura, 27% in the FMI data set, and 20% in AACR Project GENIE v.12 cohort [ 29 ].…”