Impact of concurrent tissue (TBx) and liquid (LBx)–based comprehensive genomic profiling (CGP) on biomarker detection and first-line (1L) treatment in metastatic CRC (mCRC).

Abstract

e15619 Background: While biomarker testing to inform the use of anti-EGFR therapies in mCRC has long been a guideline-recommended practice, the growing number of approved targeted therapies heightens the importance of comprehensive biomarker testing to best inform 1L treatment. Methods: The US-based deidentified Flatiron Health-Foundation Medicine (FMI) CRC Clinico-Genomic Database (CGDB) was queried to assess the patterns of 1L biomarker ( KRAS , NRAS , and BRAF V600E) testing performed at FMI (FoundationOne CDx, FoundationOne Liquid CDx [F1LCDx]) and non-FMI central lab CGP providers for 1,270 patients (pts) diagnosed with mCRC between 9/2020-6/2025. TBx and LBx testing was classified as concurrent if both were ordered before either reported, reflex if a LBx was ordered before 1L and the TBx was ordered 1-60 days after the LBx report. Positive percent agreement (PPA) was assessed for LBx-based biomarker detection relative to TBx. For FMI samples, clonality was assessed with a method leveraging the variant allele frequency (VAF) and the copy number model to determine the allelic context and ctDNA tumor fraction (TF) was quantified using a combination of aneuploidy and VAF. Results: Of 1,270 mCRC pts with TBx and/or LBx-based biomarker testing prior to 1L, 146 (11%) had concurrent, 81 (6.4%) had reflex, 803 (63%) had TBx-only, and 240 (19%) had LBx-only testing. There were no significant differences in sex, age, socioeconomic status, CRC site, stage at diagnosis, ECOG, or MSI/dMMR status between cohorts, and LBx-first testing was more frequently at academic centers (21% vs. 5.7%, p < 0.001) and in pts with non-European ancestry (34% vs 26%, p = 0.049). The highest rates of 1L biomarker positivity were observed in pts with TBx and LBx (concurrent or reflex, 64%) vs pts with TBx (61%, p = 0.36) or LBx-only (54%, p = 0.03) testing. In pts with F1LCDx, the PPA was 81% and increased to 95% in the subset with TF ≥ 1% (n = 70). Discordant TBx/LBx results, were partially due to subclonal variants missed by both LBx ( KRAS K117N [TBx VAF 0.7%]) and TBx testing ( KRAS A146V [LBx VAF 0.2%]). Overall, 352 (28%) pts received 1L informed by only a LBx report, representing 32% of concurrent (n = 46), 82% of reflex (n = 66), and 100% of LBx-only (n = 240) pts. In the subset of 255 pts with F1LCDx, 44 (17%) had TF < 1%. In pts with 1L informed by both TBx and LBx results, concurrent ordering trended towards a faster time from first order to 1L compared to reflex (26 vs 31 days, p = 0.37). Conclusions: In this cohort, TBx and LBx-based testing was associated with higher rates of 1L biomarker detection, particularly compared to LBx-testing alone, including clonal drivers to inform 1L therapy selection and subclonal mutations with potential resistance implications. A concurrently ordered combined TBx and LBx profiling approach may be best suited for a timely, fully-informed 1L treatment decision.