918P - Deciphering the molecular drivers behind locoregional progression, intratumoral heterogeneity, and clonal evolution in locally advanced head and neck cancer

Background

LAHNSCC exhibits high heterogeneity. Molecular mechanisms of lymph node (LN) and lung metastases (LM) remain unclear and intratumor heterogeneity (ITH), a key factor in treatment failure is not fully understood.

Methods

Between January 2017 and September 2022, we included 152 LAHNSCC treated with definitive chemoradiation. At baseline and relapse, we collected tumor tissue (TT) and blood samples. WES was conducted on DNA obtained from TT, plasma (ctDNA) and white blood cells, followed by analysis using an in-house bioinformatics pipeline targeting oncogenic somatic variants. Tumor evolution (TE) and ITH were evaluated by comparing molecular profiles from baseline to relapse across plasma and tumor samples.

Results

Our analysis covered 37 cases meeting quality criteria. Top 3 mutated genes were TP53, KMT2D, and NOTCH1. We identified 5 pathogenic germline variants in 13.5% of cases, emphasizing actionable mutations in BRCA2, CHK2, and KIT. In terms of ITH, WES of baseline TT and matched ctDNA found low concordance (median 11.8%), with up to 67% of oncogenic mutations exclusively detected in ctDNA. Relapse analysis showed low agreement between TT ctDNA (median concordance 12.4%), with up to 58% of oncogenic mutations identified solely in ctDNA. For TE, comparing baseline ctDNA to relapse ctDNA showed even lower concordance (10.3%,) with up to 50% of oncogenic mutations exclusively detected at relapse. Moreover, genes related to the serine-threonine kinase pathway were notably enriched, with pathogenic mutations in PI3K-mTORC2, ATM-CHK2 playing potential role in progression. Unlike patients facing LM, those with LN relapse revealed potential drivers of LN metastasis, showing significant enrichment in the IL6-STAT3-JAK pathway (p=0.00234) and RHOU GTPase cycle pathway (p=0.00027), alongside subclonal mutations in genes like TNFAIP (p<0.0001).

Conclusions

Our data confirms high ITH in LAHNSCC, with many actionable mutations exclusively detected in plasma compared to TT. ctDNA analysis at relapse highlights key pathways, suggesting that WES of ctDNA may unveil therapeutic avenues overlooked in TT. IL6-STAT3-JAK and RHOU GTPase emerge as drivers of locoregional progression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

G. Bruixola: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, MSD, Bristo Myers Squibb. All other authors have declared no conflicts of interest.