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Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation)., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Stock and Employment from Foundation Medicine, Inc: D.R.Z., A.F., Y.H., C.G., M.C., C.X., D.J., B.W., P.P., W.C., P.H., J.H., L.D., A.Y. Stock and Employment from Natera: E.R., J.S., A.K., W.G., G.B., C.H., R.R., L.R., D.H., D.S., V.P., M.D., S.F. Stock and Employment from F. Hoffmann-La Roche: C.C., N.D., V.D., P.G., S.M. Honararia- Astellas, Pfizer, Seagen, BMS, Roche, Astra-Zeneca, MSD, Natera, Merck Serono, Johnson and Johnson - T.P. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Zollinger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A majority of patients with metastatic colorectal cancer (mCRC) experience recurrence post curative-intent surgery. The addition of adjuvant chemotherapy has shown to provide limited survival benefits when applied to all patients. Therefore, a biomarker to assess molecular residual disease (MRD) accurately and guide treatment selection is highly desirable for high-risk patients. This feasibility study evaluated the prognostic value of a tissue comprehensive genomic profiling (CGP)-informed, personalized circulating tumor DNA (ctDNA) assay (FoundationOne®Tracker) (Foundation Medicine, Inc., Cambridge, MA, USA) by correlating MRD status with clinical outcomes. ctDNA analysis was performed retrospectively on plasma samples from 69 patients with resected mCRC obtained at the MRD and the follow-up time point. Tissue CGP identified potentially actionable alterations in 54% (37/69) of patients. MRD-positivity was significantly associated with lower disease-free survival (DFS) (HR: 4.97, 95% CI: 2.67−9.24, p < 0.0001) and overall survival (OS) (HR: 27.05, 95% CI: 3.60−203.46, p < 0.0001). Similarly, ctDNA positive status at the follow-up time point correlated with a marked reduction in DFS (HR: 8.78, 95% CI: 3.59−21.49, p < 0.0001) and OS (HR: 20.06, 95% CI: 2.51−160.25, p < 0.0001). The overall sensitivity and specificity at the follow-up time point were 69% and 100%, respectively. Our results indicate that MRD detection using the tissue CGP-informed ctDNA assay is prognostic of survival outcomes in patients with resected mCRC. The concurrent MRD detection and identification of actionable alterations has the potential to guide perioperative clinical decision-making., Competing Interests: S.L. has been involved in consulting/advisory roles in Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi, Sankyo, and Bristol Myers Squibb, received a speaker honorarium from Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, and Amgen, and received research funding from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb. C.X., D.R.Z., R.M., A.F., O.G., E.R., and P.H. are employees of Foundation Medicine, a wholly owned subsidiary of Roche, and have an equity interest in Roche. S.S., H.-T.W., C.C.P., and M.M. are employees of Natera, Inc. with stocks or options to own stocks. A.A. is an employee at Natera, Inc. with stocks or options to own stocks, received travel/accommodations and expenses from Natera, Inc, and has been involved in a consulting/advisory role in Mission Bio and Notable Labs. F. L. has been involved in consulting/advisory roles in Amgen, Sanofi, Bayer, and Amal Therapeutics, received speaker honoraria from Roche, Sanofi, Bayer, and Amgen, received research funding from Roche, Merck Serono, Amgen, and Bayer, and received travel, accommodations, and expenses from Rocher, Amgen and Merck Serono. M.F. has been involved in consulting/advisory roles in Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, and Roche, and received research funding from Astellas Pharma, QED Therapeutics, and Macrophage Pharma. H.N., C.R., and V.A. declare no conflict of interest.