Original articleClinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study
Introduction
During the past decade, molecular characterization of tumors has been associated with improved outcomes and quality of life of patients with cancer.1 Previous studies2, 3, 4, 5, 6, 7 have evaluated the clinical utility of molecular tests carried out on tumor tissue. This approach has several limitations including technical failure due to poor quality or inadequate tissue quantity and risks of complications related to biopsy procedure.8 Moreover, while the tissue biopsy may provide information about the genomic landscape of a specific tumor site, it does not allow to capture tumor heterogeneity which is hallmark of metastatic cancer.9, 10, 11
Because of the rapid development of high-throughput technologies such as next-generation sequencing, it is now possible to characterize the molecular profile of circulating tumor DNA (ctDNA).12,13 ctDNA profiling is noninvasive and representative of the whole molecular landscape of the patient’s tumor,14,15 challenging then the limitations of tissue biopsy. Accumulating evidence has emphasized the potential of ctDNA to detecting and monitor cancer16, 17, 18 and to identify mechanisms of resistance to anticancer agents.19
We have recently reported a systematic comparison of ctDNA versus tissue sequencing which showed the capacity of ctDNA for capturing clinically relevant alterations to guide therapy in patients with cancer with high accuracy and rapid turnover results.20 However, no study has prospectively evaluated the benefit of ctDNA profiling to guide therapy in patients with cancer and the outcome of patients with advanced cancer treated with ctDNA-matched therapy as recommended by a multidisciplinary tumor board (MTB).
We report here the largest prospective study addressing these specific questions in patients with advanced solid tumors.
Section snippets
Study design and procedure
Patients were included in the ongoing precision medicine study STING (NCT04932525, Gustave Roussy). Patients were eligible if they presented a locally advanced, unresectable, or metastatic solid tumor. All genomic results were discussed during a weekly molecular multidisciplinary board. All patients provided written consent for the genomic analyses. This study was approved by the Institutional Review Board (Institute Gustave Roussy).
Genomic analysis
Genomic analysis was performed for each patient using the
Patient characteristics
The Consolidated Standards of Reporting Trials (CONSORT) diagram of the study is illustrated in Figure 1. A total of 1772 patients with metastasis were included from December 2020 to November 2021 at Gustave Roussy (Villejuif, France). Their characteristics are summarized in Table 1. Their median age was 63 years [interquartile range (IQR) 54-71 years] and most patients (n = 1531, 86%) were in good general condition [Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1] when
Discussion
We report hereby the largest study investigating the clinical utility of ctDNA profiling for tailoring therapy in patients with advanced solid cancer. Our results showed that genomic profiling of ctDNA with a large panel is feasible in the routine setting and allows the obtention of relevant molecular information in almost all patients (94%, 1659/1772) with a turnaround time of 12 days only. This is in contrast to tissue profiling analysis for which the rate of technical failure is >15% and the
Acknowledgements
We are grateful for Laetitia Millier, Zsofia Balogh, Pascale Conan, Laetitia Soullier, Tasnim Heddoui and to all the precision medicine team of Gustave Roussy for their help.
Funding
This work was supported by Fondation Gustave Roussy (no grant number).
Disclosure
AI received research grants from Astra Zeneca, Bayer, BMS, Chugai, Merck, MSD, PharmaMar, Novartis, and Roche; personal fees from Epizyme, Bayer, Lilly, Roche, and Springworks. BB received grants from AstraZeneca, Pfizer, Eli Lilly, Onxeo, Bristol Myers
References (31)
- et al.
Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial
Lancet Oncol
(2015) - et al.
Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle
Ann Oncol
(2014) - et al.
Liquid versus tissue biopsy for detecting actionable alterations according to ESCAT in patients with advanced cancer: a study from the French National Center for Precision Medicine (PRISM)
Ann Oncol
(2022) - et al.
A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
Ann Oncol
(2018) - et al.
Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support
J Biomed Inform
(2009) - et al.
The REDCap consortium: building an international community of software platform partners
J Biomed Inform
(2019) - et al.
RECIST 1.1-Update and clarification: from the RECIST committee
Eur J Cancer
(2016) - et al.
Precision oncology: a clinical and patient perspective
Future Oncol
(2021) - et al.
High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial
Cancer Discov
(2017) - et al.
Copenhagen prospective personalized oncology (CoPPO)-clinical utility of using molecular profiling to select patients to phase I trials
Clin Cancer Res
(2019)
The molecular analysis for therapy choice (NCI-MATCH) trial: lessons for genomic trial design
J Natl Cancer Inst
Cancer therapy directed by comprehensive genomic profiling: a single center study
Cancer Res
Initiative for molecular profiling and advanced cancer therapy (IMPACT): an MD Anderson Precision Medicine study
JCO Precis Oncol
Application of cell-free DNA for genomic tumor profiling: a feasibility study
Oncotarget
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing
N Engl J Med
Cited by (21)
Molecular Tumor Boards: On the evolution of species
2024, European Journal of CancerCost of high-throughput sequencing (NGS) technologies: Literature review and insights
2024, Bulletin du CancerWGS/WES-RNAseq compared to targeted NGS in oncology: is there something to unlock?
2023, Annals of OncologyClinical utility of plasma ctDNA sequencing in metastatic urothelial cancer
2023, European Journal of Cancer
- †
These authors contributed equally to this work.