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Therapy Testing in a Spheroid-based 3D Cell Culture Model for Head and Neck Squamous Cell Carcinoma
Published on: April 20, 2018
Longitudinal Circulating Tumor DNA Profiling as a Biomarker for Response and Resistance in Platinum-Refractory Head
Wonyoung Choi1,2, Jong-Ho Lee1,3, Junsun Ryu1,4
1Center for Rare Cancers, National Cancer Center, Goyang, Korea.
Purpose:
Immune checkpoint inhibitors (ICIs) are the standard treatment for platinum-refractory head and neck squamous cell carcinoma (HNSCC). This study aimed to characterize genomic alterations, monitor dynamic changes in circulating tumor DNA (ctDNA) associated with treatment response, and identify novel alterations linked to resistance through serial ctDNA profiling.
Materials And Methods:
Patients with platinum-refractory HNSCC receiving nivolumab were enrolled. ctDNA was analyzed using FoundationOne Liquid CDx at baseline, 6 weeks after treatment, and at disease progression.
Results:
A total of 36 patients were enrolled, and 33 were evaluable for ctDNA. The most frequent baseline alterations were TP53 (75.8%), followed by TERT (27.3%), NOTCH1 (24.2%), CDKN2A (12.1%), and CCND1 (12.1%). Of 27 patients with measurable lesions, 5 achieved a partial response with a response rate of 18.5%. Dynamic ctDNA profiling revealed all responders had marked reductions in both the sum of variant allele frequencies (sumVAF) and the maximum variant allele frequencies (maxVAF) across detected mutations. A decrease in sumVAF or maxVAF correlated with longer treatment durations, and patients with a >50% decrease in either sumVAF or maxVAF showed significantly longer progression-free survival. Additionally, serial profiling identified de novo mutations in 17 patients, detected during stable disease or progression.
Conclusion:
Serial ctDNA analysis provides a noninvasive tool for monitoring treatment response and detecting emerging resistance in HNSCC treated with ICIs. A significant reduction in ctDNA at 6 weeks was associated with improved clinical outcomes and warrants validation in larger, prospective studies to define its role as a predictive biomarker in HNSCC.
Insights
Serial ctDNA profiling in head and neck cancer (HNSCC) patients treated with immune checkpoint inhibitors (ICIs) can predict treatment response. A significant decrease in circulating tumor DNA (ctDNA) levels at 6 weeks indicates better outcomes.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Immune checkpoint inhibitors (ICIs) are a standard treatment for platinum-refractory head and neck squamous cell carcinoma (HNSCC).
- Monitoring treatment response and identifying resistance mechanisms are crucial for optimizing HNSCC therapy.
Purpose of the Study:
- To characterize genomic alterations in platinum-refractory HNSCC.
- To monitor dynamic changes in circulating tumor DNA (ctDNA) in response to ICI treatment.
- To identify novel alterations associated with treatment resistance using serial ctDNA profiling.
Main Methods:
- Patients with platinum-refractory HNSCC receiving nivolumab were enrolled.
- Circulating tumor DNA (ctDNA) was analyzed at baseline, 6 weeks, and disease progression using FoundationOne Liquid CDx.
- Genomic alterations and variant allele frequencies (VAFs) were assessed.
Main Results:
- TP53, TERT, NOTCH1, CDKN2A, and CCND1 were the most frequent baseline alterations.
- A partial response (18.5%) was observed in 5 out of 27 evaluable patients.
- Responders showed significant reductions in sumVAF and maxVAF; decreased ctDNA levels correlated with longer treatment duration and improved progression-free survival.
- De novo mutations were detected in 17 patients during disease progression.
Conclusions:
- Serial ctDNA analysis is a noninvasive tool for monitoring ICI treatment response and detecting resistance in HNSCC.
- A significant reduction in ctDNA at 6 weeks is associated with improved clinical outcomes.
- Further validation in prospective studies is needed to establish ctDNA as a predictive biomarker in HNSCC.
