Integrated longitudinal circulating tumor DNA profiling predicts immunotherapy response of metastatic urothelial carcinoma in the POLARIS-03 trial.

Jingyu Zang, Ruiyun Zhang, Di Jin, Feng Xie, Akezhouli Shahatiaili, Guangyu Wu, Yue Zhang, Zhixin Zhao, Pan Du, Shidong Jia, Haige Chen, Guanglei Zhuang

The Journal of pathology 2023 Oct

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Non-invasive biomarkers for immunotherapy response remain a compelling unmet medical need. POLARIS-03 is a multicenter phase II trial to evaluate the safety and efficacy of toripalimab (anti-programmed cell death 1) in refractory metastatic urothelial carcinoma (mUC). We assessed the predictive utility of longitudinal circulating tumor DNA (ctDNA) analysis from a single-institution biomarker cohort. Twenty-seven mUC patients receiving toripalimab (3 mg/kg Q2W) at Ren Ji Hospital were enrolled. Serial plasma specimens were obtained at baseline and then every two cycles during treatment. The 600-gene panel (PredicineATLAS™) liquid biopsy assay was applied to probe somatic variants and cancer cell fraction (CCF). Low-pass whole genome sequencing was used to determine the copy number abnormality (CNA) score. Across the entire cohort, we observed different degrees of concordance between somatic aberrations detected by ctDNA and those inferred by matched tumor samples. Although the baseline CCF or CNA had limited predictive value, early ctDNA response at week 8 was associated with toripalimab efficacy and prolonged patient survival. Integrating CCF and CNA decrease achieved a superior accuracy of 90.5% in classifying responders and non-responders and predicted long-term benefit from toripalimab. Dynamic changes in the CCF and CNA in blood exquisitely reflected radiographic assessment of malignant lesions, including those with FGFR3-TACC3 gene fusion or microsatellite instability. This study demonstrates the feasibility and effectiveness of integrated longitudinal ctDNA profiling as a potential biomarker in mUC patients undergoing immunotherapy and supports further clinical evaluation of minimally invasive liquid biopsy assays for treatment stratification and therapy monitoring. © 2023 The Pathological Society of Great Britain and Ireland. © 2023 The Pathological Society of Great Britain and Ireland.

Citation

Jingyu Zang, Ruiyun Zhang, Di Jin, Feng Xie, Akezhouli Shahatiaili, Guangyu Wu, Yue Zhang, Zhixin Zhao, Pan Du, Shidong Jia, Haige Chen, Guanglei Zhuang. Integrated longitudinal circulating tumor DNA profiling predicts immunotherapy response of metastatic urothelial carcinoma in the POLARIS-03 trial. The Journal of pathology. 2023 Oct;261(2):198-209