The results from the largest study investigating the clinical utility of circulating tumour DNA (ctDNA) profiling for tailoring treatment in patients with advanced solid tumours show that genomic profiling of ctDNA with a large panel is feasible in the routine setting and allows to obtain relevant molecular information in almost all patients with a turnaround time of 12 days only. This is in contrast with tissue profiling analysis for which the rate of technical failure is more than 15% and the median time to obtain results frequently more than 30 days due the delay in recovering archival tumour tissue. The clinical utility of ctDNA based molecular profiling in patients with advanced cancer is illustrated by the identification of at least one actionable target in up to 60% of patients and by the favourable 36% objective response rate among the patients treated with a ctDNA matched therapy and evaluable for tumour response. The findings are reported by Prof. Antoine Italiano of the Gustave Roussy – Cancer Campus in Villejuif, France and colleagues on 25 January 2023 in the Annals of Oncology.
The authors wrote in the background that due to the rapid development of high-throughput technologies such as next-generation sequencing, it is now possible to characterise the molecular profile of ctDNA; ctDNA profiling is non-invasive and representative of the whole molecular landscape of the tumour, challenging the limitations of tissue biopsy. Accumulating evidence has emphasized the potential of ctDNA to detect and monitor cancer and to identify mechanisms of resistance to anti-cancer agents.
The same team of investigators has recently reported a systematic comparison of ctDNA versus tissue sequencing which showed the capacity of ctDNA for capturing clinically relevant alterations to guide treatment with high accuracy and rapid turnover results. However, no study has evaluated prospectively the benefit of ctDNA profiling to guide treatment and the outcome in patients with advanced cancer treated with ctDNA matched therapy as recommended by a molecular tumour board. The latest report reflects the findings from the largest prospective study that addressed these specific questions in patients with advanced solid tumours.
Genomic analysis was performed by using the Foundation One Liquid CDx Assay (324 genes, tumour mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a molecular tumour board. Actionable targets were classified by ESCAT tier leading to molecular-based treatment suggestions wherever it was possible. All patients were included in the STING precision medicine study and provided informed consent for liquid biopsy and data analysis.
Between December 2020 and November 2021, 1772 patients with metastatic solid tumours 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 (18%), high TMB (13%), PIK3CA mutations (8%), ERBB family pathway alterations (7%), PTEN alterations (5%), FGFR alterations (4%) and MET activations (0.7%).
The molecular tumour board recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (78%), off label/compassionate use (10%), approved drug (6%) and early access programme (6%). In total, 122 patients (21%) were treated. Among the 107 evaluable patients, 4% had complete response, 33% had partial response, 25% had stable disease and 38% a progressive disease as best response. Median progression-free survival was 4.7 months (95% confidence interval [CI] 2.7-6.7) and median overall survival 8.3 months (95% CI 4.7-11.9).
The authors concluded that ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies. They commented that 13% of patients were not treated with matched therapy just because eligibility criteria of relevant clinical trials required that the molecular aberration was identified through tissue sequencing. These results advocate for higher flexibility of inclusion criteria which should consider ctDNA results as robust as tissue-based profiling.
The study was funded by Fondation Gustave Roussy.
Bayle A, Belcaid L, Aldea M, et al. Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study. Annals of Oncology; Published online 25 January 2023. DOI: https://doi.org/10.1016/j.annonc.2023.01.008