Real-world evaluation of the decentralized MSK-ACCESS powered with SOPHiA DDM liquid biopsy assay for comprehensive tumor profiling.

Abstract

e15084 Background: MSK-ACCESS powered with SOPHiA DDM is a decentralized next-generation sequencing (NGS) assay for circulating cell-free DNA (cfDNA) molecular profiling in patients diagnosed with solid tumors. It enables detection of biologically relevant alterations, including SNVs, INDELs, CNVs, and structural variants, with demonstrated analytical sensitivity down to 0.5% variant allele frequency (VAF). This study evaluated MSK-ACCESS powered with SOPHiA DDM performance and variant detection patterns across 2455 samples from diverse cancer types in a decentralized setting. Methods: 493 cfDNA samples from patients (n = 440) with colorectal, prostate, lung, breast, gynecological, and pancreatic cancers were analyzed in a retrospective, multicenter study (5 sites). Additional real-world data (n = 1962) submitted to the SOPHiA GENETICS DDM Platform submitted by the user base were reviewed for benchmarking. Materials were processed with the MSK-ACCESS powered with SOPHiA DDM solution including CUMIN molecular barcodes and variant detection was performed with the SOPHiA DDM Platform. The solution’s cfDNA/normal workflow incorporating matched white blood cell (WBC) genomic DNA (gDNA) sequencing was utilized to distinguish betweem somatic variants and clonal hematopoiesis (CH) calls based on the observed VAF ratio. Somatic variants were clustered within samples by their VAF to detect potential tumor subclones. Results: Per-sample QC criteria exceeded the minimum requirements in 94% of the study cohort and 93% of the real-world samples. Thus, both datasets were combined for further analyses. Somatic variants were detected in 85% of all samples, with high cancer-type specificity (e.g. AR in prostate, ESR1 and PIK3CA in breast, EGFR and ALK in lung cancer cases). SNVs and Indels were detected down to 0.1% VAF. Samples without detected alterations were not biased toward low quality metrics, suggesting that biological not technical factors are determinants of sensitivity. cfDNA/WBC gDNA VAF ratio filtering removed 40.1% of variant calls (6180/15449) as of CH origin. This highlights the advantage of this approach, since CH mutations in genes such as TP53, ATM and CHEK2 can be enriched for pathogenic variants, so a tumor-only approach can lead to an increased risk of false-positive calls. Subclonal variants included known resistance drivers (e.g. EGFR , ESR1 mutations in lung and breast cancer respectively). Follow-up analysis of subclonal variants to uncover additional resistance mechanisms and to distinguish primary resistance drivers from secondary events is ongoing. Conclusions: MSK-ACCESS powered with SOPHiA DDM demonstrated robust analytical performance and broad detection of biologically relevant alterations across multiple tumor types in a decentralized setting, supporting its role in comprehensive cfDNA-based genomic profiling.