Elsevier

Annals of Oncology

Volume 34, Issue 4, April 2023, Pages 389-396
Annals of Oncology

Original article
Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study

https://doi.org/10.1016/j.annonc.2023.01.008Get rights and content

Highlights

  • ctDNA sequencing is increasingly used in clinical practice to characterize genomic tumor profile.

  • We report here the largest study evaluating the clinical value of ctDNA profiling in patients with advanced cancer.

  • ctDNA sequencing with a large is an efficient approach to detect actionable alterations in patients with advanced cancer.

Background

Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors.

Patients and Methods

Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible.

Results

Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively.

Conclusions

ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

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

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    These authors contributed equally to this work.

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