Genomic Alterations in Head and Neck Squamous Cell Carcinoma: Level of Evidence According to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT)

Abstract

Development of high-throughput technologies helped to decipher tumor genomic landscapes revealing actionable molecular alterations. We aimed to rank the level of evidence of recurrent actionable molecular alterations in head and neck squamous cell carcinoma (HNSCC) on the basis of the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) to help the clinicians prioritize treatment. We identified actionable alterations in 33 genes. HRAS-activating mutations were ranked in tier IB because of the efficacy of tipifarnib (farnesyltransferase inhibitor) in HRAS-mutated patients with HNSCC (nonrandomized clinical trial). Microsatellite instability (MSI), high tumor mutational burden (TMB), and NTRK fusions were ranked in tier IC because of PD-1 and TRK tyrosine kinase inhibitors tissue-agnostic approvals. CDKN2A-inactivating alterations and EGFR amplification were ranked in tier IIA because of the efficacy of palbociclib (CDK4/6 inhibitor) and afatinib (tyrosine kinase inhibitor) in these respective molecular subgroups in retrospective analyses of clinical trials. Molecular alterations in several genes, including PIK3CA gene, were ranked in tier IIIA because of clinical benefit in other tumor types, whereas molecular alterations in IGF1R and TP53 genes were ranked in tier IVA and tier V, respectively. The most compelling actionable molecular alterations in HNSCC according to ESCAT include HRAS-activating mutations, MSI, high TMB, NTRK fusions, CDKN2A-inactivating alterations, and EGFR amplification.

Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma

“…Patients with HNSCC, who have failed standard first-line therapies, have limited therapeutic options and may benefit from new targeted therapies. Marret et al ranked recurrent molecular alterations in HNSCC on the basis of the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and identified six of 33 actionable alterations as the most clinically relevant: HRAS activating mutations, high microsatellite instability (MSI-H), high tumor mutational burden (TMB-high), NTRK fusions, CDKN2A inactivating alterations, and EGFR amplifications [ 77 ].…”

“…In HNSCC the incidence of TMB-high, defined as ≥10 mutations per megabase (mut/Mb), is around 20% and the incidence of MSI-H is 1.2% [ 77 ]. TMB-high and MSI-H status has been correlated with the response to checkpoint blockade in basket trials which led to the tissue-agnostic FDA approval of pembrolizumab for advanced solid tumors meeting these criteria [ 81 , 82 ].…”

Involvement of the p53‐p16/RB pathway control mechanism in early‐stage carcinogenesis in head and neck squamous cell carcinoma

“…HRAS mutations occur in 4%-8% of patients with recurrent or premetastatic HNSCCs. 42 Tipifarnib is a farnesyl transferase inhibitor that blocks HRAS function. A single-arm, open-label phase II study of tipifarnib was evaluated in patients with HRAS mutation with high variant allele frequencies (20%).…”

“…HRAS mutations occur in 4%–8% of patients with recurrent or premetastatic HNSCCs 42 . Tipifarnib is a farnesyl transferase inhibitor that blocks HRAS function.…”

Head Neck Squamous Cell Cancer Genomics: Oncogenes, Tumor Suppressor Genes and Clinical Implications

“…European Society for Medical Oncology (ESMO) has a designed a scale (ESCAT) to guide the clinician to select a novel targeted drug with highest potential of efficacy in an HNSCC patient. The most Accordingly, compelling actionable molecular alterations in HNSCC included HRAS activating mutations (tipifarnib, farnesyl transferase inhibitor), MSI, high TMB (for immune check point inhibitors), NTRK fusions (TRK tyrosine kinase inhibitors), CDKN2A inactivating alterations (CDK 4/6 inhibitors) and EGFR amplification (afatinib) [63].…”