Circulating tumor DNA Clearance as a Predictive Biomarker of Pathologic Complete Response in Patients with Solid Tumors Treated with Neoadjuvant Immune-Checkpoint Inhibitors: a Systematic Review and Meta-Analysis.
C Valenza, E F Saldanha, Y Gong, P De Placido, D Gritsch, H Ortiz, D Trapani, F Conforti, C Cremolini, S Peters, J Mateo, V Subbiah, H A Parsons, A H Partridge, G Curigliano
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Abstract
Background: In patients with solid tumors undergoing neoadjuvant immune checkpoint inhibitor (ICI) therapy, identifying biomarkers to predict pathologic complete response (pCR) preoperatively could enhance treatment modulation. Circulating tumor DNA (ctDNA) clearance is a potential predictor of pCR, though its analytical and clinical validity has yet to be established. This systematic review and meta-analysis aims to assess the role of ctDNA clearance as a predictor of pCR in patients with solid tumors treated with neoadjuvant ICIs.
Materials and methods: A systematic search of PubMed, EMBASE and conference proceedings up to 5 August 2024 was carried out to identify phase 1b, 2 or 3 clinical trials investigating ctDNA clearance and pCR in patients with solid tumors and detectable ctDNA, undergoing neoadjuvant therapy with ICIs. Using a bivariate model, we estimated the pooled sensitivity and specificity of ctDNA clearance in predicting pCR, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR), with 95% Confidence Intervals (CI).
Results: Thirteen trials involving 380 patients with detectable ctDNA at baseline were included. ctDNA was assessed with a tumor-informed approach in 11 (85%) trials. Overall, 38% of patients achieved pCR and 73% had ctDNA clearance before/at the surgery. Pooled sensitivity was 0.98 (95% CI: 0.86, 1.00), specificity was 0.53 (95% CI: 0.37, 0.69), PLR was 2.09 (95% CI: 1.48, 2.93), NLR was 0.04 (95% CI: 0.01, 0.26), DOR was 57.36 (95% CI: 8.12, 405.12). Significant heterogeneity was observed across studies (I2 ∼70% for all metrics), indicating considerable variability in the diagnostic performance.
Conclusion: The lack of ctDNA clearance may identify patients unlikely to have a pCR. Instead, the confirmatory power of ctDNA clearance is limited by low specificity and high heterogeneity due to the variability of the assays, and warrants further study. Therefore, clinicians should not rely on the use of ctDNA clearance to inform treatment decisions in the neoadjuvant setting.
期刊介绍：
Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine.
The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings.
Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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