Abstract 918P
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.
Resources from the same session
1015P - The efficacy and mechanism of pan-FGFR inhibitor (AZD4547) combined with immunoagonists or immunosuppressants in FGFR-positive tumors
Presenter: Qizhi Ma
Session: Poster session 03
1016P - Phase I study of SOF10 plus atezolizumab in patients with advanced/recurrent solid tumours
Presenter: Toshihiko Doi
Session: Poster session 03
1017P - Updated safety and efficacy from the phase I study of givastomig, a novel claudin 18.2/4-1BB bispecific antibody, in claudin 18.2 positive advanced gastroesophageal carcinoma (GEC)
Presenter: Samuel Klempner
Session: Poster session 03
1018P - Leveraging innate and adaptive immunity with AFM24 and atezolizumab in metastatic gastric cancer
Presenter: Omar Saavedra Santa Gadea
Session: Poster session 03
1019P - Bispecific PD1-IL2 antibody reshapes the inhibitory immune microenvironment of SMARCA4 mutant non-small cell lung cancer by reversing CD8+T cell exhaustion
Presenter: Bo Cheng
Session: Poster session 03
Resources:
Abstract
1020P - Highly potent and specific bivalent T cell engager (TCE) targeting PRAME on HLA-A*02:01
Presenter: Athanasia Dasargyri
Session: Poster session 03
1021P - Chemotherapy and hypomethylating agents enhance anti-tumor activity of PRAME ImmTAC
Presenter: Adel Benlahrech
Session: Poster session 03
1022P - A phase II trial of the IO102-IO103 vaccine plus pembrolizumab: Completed cohort for first-line (1L) treatment of advanced squamous cell carcinoma of the head and neck (SCCHN)
Presenter: Jonathan Riess
Session: Poster session 03
1023P - Long-term follow up of patients treated with a DNA vaccine (pTVG-HP) for PSA-recurrent prostate cancer
Presenter: Douglas McNeel
Session: Poster session 03
1024P - Initial clinical results of BT-001, an oncolytic virus expressing an anti-CTLA4 mAb, administered as single agent and in combination with pembrolizumab in patients with advanced solid tumors
Presenter: Stephane Champiat
Session: Poster session 03