Multi-gene ctDNA profiling effectively matches patients with advanced cancer to targeted therapies

Results from two trials as part of a programme incorporating liquid biopsy into precision oncology workflows at the Institute Gustave Roussy, Villejuif, France, are presented at the ESMO Congress 2024 (Barcelona, 13–17 September) showing that comprehensive circulating tumour DNA (ctDNA) analysis of liquid biopsies effectively matches patients with advanced cancer to targeted therapies (Abstract 1177P).

Analysis of ctDNA offers rapid and dynamic insights into tumour evolution and mechanisms of resistance to therapy without the need for invasive, archival tissue biopsies. Since December 2020, the Gustave Roussy Cancer Profiling (STING) trial has evaluated over 7,000 patients, with an additional 1,500 patients evaluated through the prospective biomarker trial, Implementing Precision Medicine in Community Hospitals (PRISM-POrTAL), averaging 50 liquid biopsy analyses per week. A molecular tumour board (MTB) evaluated patient samples, identifying actionable genomic alterations in 56% (3,869/7,037) of patients in the STING trial, with matched therapies proposed for 57% (2,227/3,908). Overall, 2,485 therapeutic recommendations were made: clinical trial enrolment for 72.6%; off-label/compassionate use of medications for 9.9%; use of approved agents in 11.3%; and entry to an early access programme for 6.2%. The PRISM-POrTAL trial demonstrated similar efficacy.

Commenting on the study and its findings, Dr Alexander Wyatt from the University of British Columbia, Vancouver, BC, Canada, says, “This study clearly endorses the use of practical ctDNA profiling for the detection of alterations in cancer-associated genes, which was typically done via invasive tumour tissue biopsy profiling. ctDNA can show actionable alterations that would indicate a therapeutic vulnerability and features associated with disease aggression that could help guide patient management.”

However, he cautions that analysis of ctDNA is not always appropriate. “Not all patients have ctDNA present, therefore liquid biopsy does have a high false-negative rate with commercial assays, compared to tissue-based profiling. One reason for false negatives and positives is clonal haematopoiesis, in which a subpopulation of blood progenitor cells contributing to cell-free DNA carries a genomic alteration that can masquerade as tumour-derived mutations.”

Wyatt thinks more scrutiny is needed. “Clinical trials are now needed to show that information obtained from ctDNA on genomic alterations has a high clinical value. We also need much clearer reporting of ctDNA analyses for clinicians when the cancer cannot be evaluated conclusively for genomic alterations due to a low ctDNA tumour fraction, a biomarker of the presence of a genuine tumour signal. In the future, it is likely that ctDNA assays will incorporate whole-genome sequencing and DNA methylation profiling to highlight the epigenomic and genomic features of a cancer, which will help with estimation of the tumour fraction,” he concludes.

At Gustave Roussy, the French Hub for Liquid Biopsy (FRESH) programme to facilitate access to liquid biopsy for precision oncology across France has been established.