Exploring clinical actionability of expanded liquid biopsy in advanced breast and colorectal cancers

Background: Liquid biopsy via plasma circulating tumor DNA (ctDNA) analysis is used to aid in targeted therapy selection. While advanced lung cancer has a number of biomarkers with FDA-approved targeted therapies, advanced breast (mBC) and colorectal (mCRC) cancers have fewer targets. As biomarkers expand and technology evolves, it is important to balance broad ctDNA analysis with clinical actionability (CA). This study explored the potential CA of an integrated liquid biopsy leveraging genomic and epigenomic elements. Methods: Results of mBC (n=2149) and mCRC (n=1345) patients who had genomic and epigenomic ctDNA testing (Guardant360 Liquid) as part of routine clinical care from June 1 - July 16, 2025, were retrospectively queried; only one test per patient was analyzed. Result components were categorized by CA: immediate (guides current therapy selection); expanded (may inform further work-up or future line decision); other (novel biomarkers that may influence care over time). Each patient was classified into one group. Availability of pharmacogenomic (PGx) results was assessed independently. Results: >85% of mBC and mCRC patients had CA results with >50% classified as immediate (Table 1). For mBC, 99.9% of patients had PGx results, dramatically higher than published testing rates (<10%). Nearly 1 in 2 mBC patients had a blood-based molecular breast subtype (MBS) which may inform additional workup for hormone receptor and HER2 status. 270 mCRC patients had biomarker negative (BN) results with > 95% confidence in the absence of FDA-approved targets, enabling rapid therapy selection. For mCRC, 99.9% had PGx results, doubling published testing rates (30-50%). Novel features such as MBS and >95% BN increased CA by 6.3% in mBC and 43.7% in mCRC. Conclusions: A liquid biopsy with both genomic and epigenomic features broadens potential CA in tumors with few targeted therapy options. This data supports use of a multifaceted assay to guide first- and later-line decisions. Table 1. Result actionability and availability in mBC and mCRC mBC (n=2149) mCRC (n=1354) RESULT ACTIONABILTY Total Actionable Findings 1841 (85.7%) 1215 (89.7%) Immediate: On-label or resistance alteration, Germline or HRD/GIS (mBC only), > 90% Confident biomarker negative (mCRC only) 1080 (50.3%) 939 (69.4%) Expanded: Clinical trial or off-label option, Molecular breast subtyping only (mBC only) 611 (28.4%) 203 (15.0%) Other: Tumor fraction >0.05% 150 (7.0%) 73 (5.4%) RESULT AVAILABILITY Pharmacogenomics 2146 (99.9%) 1352 (99.9%) Molecular Breast Subtyping 1013 (47.1%) N/A > 90% Confident Biomarker Negative N/A 321 (23.7%)