Abstract Background: Liquid biopsy (LBx) enables non-invasive molecular profiling and monitoring of cancer but has been impeded by operational, computational and financial barriers. While centralized LBx testing is widely used in clinical trials and specialized centers, locally or regionally performed decentralized testing has the potential to broaden access to molecular profiling and reduce turnaround times. We evaluated the analytical performance and real-world utility of the decentralized MSK-ACCESS® powered with SOPHiA DDM™ LBx assay in patients with breast cancer. Methods: Analytical characteristics were assessed by comparing results from the decentralized LBx assay against a reference orthogonal method in two cohorts: breast cancer (n=17) and prostate cancer patients (n=55). Metrics included the mean molecular coverage, number of variants per sample and mean variant allele frequency (VAF) for single nucleotide variants (SNVs) and insertions/deletions (indels). Similar analytical performance across both cohorts was used to support assay validity. Subsequently, mutational profiles were characterized in the breast cancer cohort, with a focus on clinically relevant alterations in ESR1 and PIK3CA. These findings were extended to a larger real-world dataset from the SOPHiA GENETICS user base. Results: The MSK-ACCESS® powered with SOPHiA DDM™ assay demonstrated comparable performance across both breast and prostate cancer cohorts, with similar mean duplex molecular coverage (nbreast=1791, nprostate=1638), median somatic variant counts (nbreast=3, nprostate=2.5), and median somatic VAFs (VAFbreast=0.6%, VAFprostate=0.6%). In breast cancer samples, recurrent ESR1 mutations (e.g. E380Q, Y537S and D538G) and hotspot PIK3CA mutations (e.g. H1047R) mediating resistance were observed down to 0.06% VAF. These variants were recapitulated in the larger real-world breast cancer cohort (n=219; ESR1 mut VAFmin=0.11%, PIK3CA mut VAFmin=0.14%) confirming the solution’s reproducibility and robustness in routine decentralized use. Conclusions: The decentralized LBx assay showed consistent analytical performance across tumor types and reliably detected clinically relevant variants in breast cancer. These findings demonstrate the feasibility and clinical utility of the decentralized MSK-ACCESS® powered with SOPHiA DDM™ testing, supporting its broader implementation in precision oncology. Citation Format: F. Klemm, F. Mohammad, A. C. Tuck, X. Xing, G. Morales, A. Willig, E. Smith, M. Basgall, A. Francois, L. Canetti, E. Jorge, Z. Xu, F. Penault Llorca, M. Ferreira. Utility of MSK-ACCESS powered with SOPHiA DDM decentralized testing in patients with breast cancer. abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-01-28.
Klemm et al. (Tue,) studied this question.