CHIP detection in solid tumors differs between liquid biopsy testing approaches

Objective: Clonal hematopoiesis of indeterminate potential (CHIP) arises from somatic variants in hematopoietic progenitor cells and is more frequent in older individuals. CHIP can appear as incidental findings in cell-free DNA (cfDNA) from patients with solid tumors, introducing biological background noise that may confound result interpretation. MSK-ACCESS® powered with SOPHiA DDM™ incorporates matched white blood cell (WBC) DNA sequencing to allow filtering of CHIP and germline variants. This study evaluated CHIP detection in patients with solid tumors across different cfDNA testing approaches. Materials and Methods: We conducted a multicenter, retrospective observational study; results from one center are presented here. Samples from 102 individuals with colorectal, prostate, pancreatic, or breast cancer were analyzed. cfDNA and matched WBC gDNA were processed using MSK-ACCESS® powered with SOPHiA DDM™, which detects SNVs/INDELs, CNVs, and structural variants. Orthogonal results from a centralized, send-out cfDNA-only assay were also available, including annotations for putative germline and CHIP variants. Concordance (percent positive agreement, PPA) was assessed while also focusing on discordant CHIP calls attributable to the inclusion of WBC sequencing. Results: MSK-ACCESS® powered with SOPHiA DDM™ achieved 95% PPA for all variants with variant allele frequencies (VAF) ≥ 0.5% independent of classification, consistent with its limit of detection. Detected VAF showed strong correlation with the orthogonal assay (R 2 = 0.86). Discordant CHIP and tumor-specific calls were observed between the cfDNA-only approach and MSK-ACCESS® powered with SOPHiA DDM™. These were influenced by factors such as cfDNA-to-WBC VAF ratio thresholds, gene set composition (e.g., DNMT3A vs. TP53 ), and statistical filtering criteria. Overall percent agreement (OPA) for CHIP calls is under evaluation. Conclusion: Incorporating matched WBC sequencing, as implemented in MSK-ACCESS® powered with SOPHiA DDM™, yields a potential advantage in resolving CHIP-related ambiguity compared to tumor-only cfDNA approaches. Continued assessment across methodologies and further evaluation are warranted.