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Ranking of Molecular Alterations in HNSCC According to ESCAT Classification Provides Targeted Therapy Information

The ESMO ESCAT classification can be used to guide in the selection of patients with head and neck squamous cell carcinoma for targeted treatment strategies in clinical studies
09 Feb 2021
Molecular Oncology
Head and Neck Cancers

Using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) investigators were able to rank the level of evidence of recurrent actionable molecular alterations found in head and neck squamous cell carcinoma (HNSCC) to aid in the prioritisation of treatment. Gregoire Marret of the Hopital Europeen Georges Pompidou in Paris, France and co-investigators detailed the identification of clinically relevant actionable molecular alterations in HNSCC that may be effectively treated with matched targeted therapy on 19 January 2021 in the JCO Precision Oncology.

For assessment of the efficacy of drugs matching specific molecular alterations, the investigators searched ClinicalTrials.gov, PubMed, and abstracts presented at major scientific meetings including ASCO, ESMO, and AACR for the results of clinical studies performed in HNSCC; in the absence of clinical studies in HNSCC, they searched for preclinical and in silico data. Ranking of molecular alterations in different tiers (I-V and X) according to ESCAT, was done by assessing the strength of evidence in clinical studies.

They identified actionable alterations in 33 genes. The investigators classified activating mutations, oncogenic fusions, and/or amplifications occurring in HNSCC for oncogenes or deep deletions, and inactivating mutations for tumour suppressor genes into several different pathways.

Molecular alterations of ESCAT tiers I and/or II

The most compelling actionable molecular alterations in HNSCC according to ESCAT ranking include HRAS-activating mutations, microsatellite instability (MSI), high tumour mutational burden (TMB), NTRK fusions, CDKN2A-inactivating alterations, and EGFR amplification. Few molecular alterations in HNSCC were classified in tiers I (HRAS - IB; MSI - IC; NTRK - IC) and II (CDKN2A - IIA; EGFR - IIA) according to ESCAT.

HRAS in the MAPK pathway was identified as the most frequently altered gene among the three RAS family members showing activating mutations in HNSCC with a frequency of 6.3%. HRAS-activating mutations were ranked in tier IB due to the efficacy of tipifarnib in patients with HNSCC and HRAS-mutation.

In the DNA repair pathway, MSI has an incidence of 1.2% in HNSCC. High TMB ≥10 mutations per megabase occurs in 20% of patients with HNSCC. MSI-High tumours display a very large number of mutation-associated neoantigens that have increased sensitivity to PD-1 blockade.  

NTRK oncogenic fusions have an incidence of 0.2%. Both TMB and NTRK fusions were ranked in tier IC due to approvals of PD-1 and tyrosine kinase inhibitor (TRK) tissue-agnostic agents.

In regards to the cell cycle pathway, CDKN2A-inactivating alterations were reported in 53.8% of patients with HNSCC. CDKN2A-inactivating alterations and EGFR amplification were ranked in tier IIA because of the efficacy of palbociclib (CDK4/6 inhibitor) and afatinib (TKI) in these respective molecular subgroups in retrospective analyses of clinical studies.

In the tyrosine kinase receptor pathway, EGFR is commonly amplified in 10.7% of HNSCC patients and afatinib has demonstrated efficacy in treatment of these patients.

Investigation of the PI3K/AKT/mTOR pathway revealed molecular alterations in several genes, including PIK3CA gene (34.5% incidence), which were ranked in tier IIIA because of the clinical benefit reported in other tumour types, whereas molecular alterations in IGF1R (1.0%) and TP53 (72%; DNA repair pathway) genes were ranked in tier IVA and tier V, respectively.


The investigators described six clinically relevant actionable molecular alterations occurring in HNSCC that may be effectively treated with matched targeted therapy.

They advise that this classification should be applied in sequencing reports and tumour boards in order to avoid missing patients harbouring targetable genetic alterations, as well as to avoid over-interpretation of hypothetical targets.

Furthermore, they concluded that, in addition to inherent limitations of the ESCAT, several issues need to be considered in the context of precision medicine, including the challenges of tumour heterogeneity and the emergence of resistance mechanisms.

The authors underscored that the development and updating of such classification in the translation of molecular findings to clinical benefit is critical for the successful implementation of precision cancer medicine.

No external funding for this study was disclosed.


Marret G, Bieche I, Dupain C et al. Genomic Alterations in Head and Neck Squamous Cell Carcinoma: Level of Evidence According to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). JCO Precision Oncology 2021;5:215-226.

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