413P - Clinical utility of advanced features provided by circulating tumor DNA-based comprehensive genomic profiling

Background

The use of circulating tumor DNA (ctDNA)-based comprehensive genomic profiling (CGP) has rapidly grown and it is now considered an important supplement or alternative to tissue-based CGP. In addition to the improved sensitivity in detecting somatic variants, incorporation of advanced features such fusion detection, tumor mutation burden (TMB) and microsatellite instability (MSI) are expected to increase the utility of ctDNA-based CGP tests. However, the validation of these features are often insufficient.

Methods

The results of hybrid-capture based ctDNA CGP tests performed in a single institute, from Dec. 2022 to Jul. 2023 using TruSight Oncology 500 ctDNA assay (Illumina, CA, USA) were retrospectively reviewed. For the cases with targetable fusions reported, medical records were reviewed to identify whether targeted therapy was delivered and whether there was a response. For the cases with existing tissue-derived TMB/MSI and/or deficient mismatch repair status, the results were compared to those from ctDNA CGP. To identify the effect of tumor fraction on TMB, correlation of tissue TMB (tTMB) and blood TMB (bTMB) was analyzed before and after the stratification by maximum somatic allele fraction (MSAF), which is a surrogate for the tumor fraction.

Results

Total number of tests performed during the study period was 634 and major cancer types included non-small cell lung cancer, colon cancer, gastric cancer, etc. Fusions involving actionable drivers such as RET, ALK, and FGFR2 were identified from 19 tests (3.0%) from 17 patients. Four patients started targeted therapy based solely on ctDNA result and as a result, three showed response and one was yet to be evaluated. For ctDNA-derived MSI, adjustment in the cutoff value provided by manufacturer, based on the results from matched tissue, deemed necessary. The correlation between bTMB and tTMB was not observed (ρ=0.063, P=0.641). Instead, bTMB was affected by tumor fraction, showing higher value in specimens with higher MSAF.

Conclusions

Fusions detected from ctDNA CGP showed promising clinical utility based on the observed response to the targeted agents. Adjustments in the cutoff and correction of the effect from tumor fraction is required for ctDNA-derived TMB/MSI.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.