Abstract 2408: Comprehensive genomic profiling of ctDNA reveals distinct genomic signatures and therapeutic implications for immunotherapy response in advanced head and neck cancer
Authors: Bharde Atul , Noronha Vanita , Ratnaparkhi Mrunal , Patil Vijay , Jadhav Bhagwat , Prajapati Sangeeta , Choughule Anuradha , Chandrani Pratik , Haldar Sumit , Moubeen Fauzul , Menon Nandini , Hariramani Kanchan , Basavalingegowda Madhura , Ramesh Aarthi , Khandare Jayant , Chaturvedi Pankaj , Shafi Gowhar , Prabhash Kumar 
Published: March 2024

Abstract
Background: Head and Neck Cancer (HNC) is highly prevalent malignancy in Southeast Asia. We investigated comprehensive genomic profiling (CGP) of ctDNA, aimed to compare genomic landscapes between responders (R) and non-responders (NR) to immunotherapy among advanced HNC patients.
Methods: An observational study, ctDNA was evaluated in 69 advanced HNC patients both at the baseline (BL) and during follow up (FL). OncoIndx® CGP was used to identify patient-specific genomic alterations in the ctDNA cohort. Raw sequence alignment and variant calling were performed using iCare® software. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier statistics.
Results: Total 250 mutations, encompassing pathogenic (P), likely pathogenic (LP), and variants of unknown significance (VUS), were identified at BL. In FL samples a slight decrease in the overall number of mutations was observed. Loss-of-function (LOF) KMT2C, MSH6 mutations, and activating HNF1α mutations were consistently present at comparable frequencies in BL and FL samples, exhibiting ubiquity across immunotherapy R and NR populations (F test, P 0.00063, OR 13). The variants did not demonstrate statistically significant association with PFS and OS. Most prevalent variants at follow-up emerged from tumor suppressor genes TP53, BRIP1, STAT5B, NF1, suggesting their potential role as therapy-resistant variants. PFS and OS were notably lower for patients with TP53 + BRCA pathway variants compared to their wild-type counterparts (median PFS TP53 + BRCA pathway mutated 2.7 months vs wt 9.1 months, HR = 4.1; median OS TP53 + BRCA pathway mutated 4.7 months vs 12.8 months for wt, HR 7.7). Similarly STAT5B carriers compared to the wild-type STAT5B-bearing population. Multivariate analysis further confirmed the independent role of TP53 + BRCA pathway and STAT5B variants as determinants for worst outcome (P 0.006, HR2.5). Population with prevalent TP53 and STAT5B LOF variants exhibited a strong negative correlation with the PD-L1 score compared to the population with their wild-type counterparts (P 0.03). Average scores for genome-wide homologous recombination deficiency (HRD), bTMB, and loss of LOH were low at BL and FL and did not correlate with the PD-L1 score. Interestingly, bTMB was low for the cohort, Tumor fraction (TF) emerged as an independent prognosticator for OS and PFS.
Conclusions: ctDNA revealed distinct genomic signatures in R and NR populations at BL and FL. Significant prevalence of TP53, BRIP1, STAT5B, and NF1 in the NR population suggest a potential role in conferring immunotherapy resistance. Genomic signatures, TMB and TF impacted survival of immunotherapy responders. Integrating CGP into SOC protocol may help in identifying therapy resistance in advanced HNC patients who did not respond to initial treatment.
Citation Format: Atul Bharde, Vanita Noronha, Mrunal Ratnaparkhi, Vijay Patil, Bhagwat Jadhav, Sangeeta Prajapati, Anuradha Choughule, Pratik Chandrani, Sumit Haldar, Fauzul Moubeen, Nandini Menon, Kanchan Hariramani, Madhura Basavalingegowda, Aarthi Ramesh, Jayant Khandare, Pankaj Chaturvedi, Gowhar Shafi, Kumar Prabhash. Comprehensive genomic profiling of ctDNA reveals distinct genomic signatures and therapeutic implications for immunotherapy response in advanced head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2408.