Exploring loco-regional heterogeneity in head and neck squamous cell carcinoma within the ART DECO trial

Background Head and neck squamous cell carcinoma (HNSCC) can be cured by radical radiotherapy, often in combination with chemotherapy.

Approximately half of people treated in this way are cured, but there is currently no way to predict who will be cured and who will not. Patients with disease that has spread to the local lymph nodes are less likely to be cured.

Those patients who relapse have limited treatment options and very poor clinical outcomes, reflecting a significant unmet clinical need.

HNSCC remains a less well-studied cancer, with the biology underpinning radiotherapy resistance and lymph node metastasis in HNSCC largely unknown.

Large genomics studies have revealed the importance of tumour heterogeneity in other cancer types but there are few data available for HNSCC.

An early study of HNSCC in TCGA data suggested patients with a greater index of heterogeneity have a worse outcome (Mroz et al 2015 PLoS Med), inviting the hypothesis that greater subclonal diversity could be a factor in poorer outcome despite radical radiotherapy.

Aims We hypothesise that clonal evolution drives loco-regional progression in HNSCC, leading to regional lymph node metastases and sub clonal diversity that increases resistance to radical radiotherapy.

We aim to characterise the genomic differences between primary HNSCC and local lymph node metastases collected in ART DECO, a large phase III trial of radiotherapy in HNSCC, generating preliminary data for a larger translational study that will include clinical outcomes.

Methods First, we will assess tumour evolution in matched primary tumour and lymph node metastases by exome sequencing tumour tissue collected in the ART DECO trial, a negative study of radiotherapy dose escalation in locally advanced HNSCC.

This will allow comparison of copy number and mutation profiles between matched pairs to look at genomic changes that could precipitate loco-regional spread. Secondly, we will infer the sub clonal architecture in the matched pairs.

This will allow assessment of the mutational signatures at a clonal and subclonal level, enabling comparison to see if genomic drivers of diversity differ between primary and regional metastases, and between different subclones.

Lastly, we plan to conduct an exploratory analysis of neoantigens and neoantigen binding in the context of the observed immune cell infiltrate.

How the results of this research will be used This will potentially break new ground in the understanding of HNSCC lymph node metastases and provide proof of principle for a larger translational analysis of the ART DECO trial.