Comprehensive genomic profiling on tissue and liquid biopsy for actionable mutations in advanced solid tumors

Background: Precision oncology has transformed the treatment landscape for advanced solid tumors through comprehensive genomic profiling (CGP). While the ROME trial demonstrated clinical superiority of CGP-guided targeted therapy over standard of care (SoC), the impact of concordance between tissue and liquid biopsy on clinical outcomes remains poorly defined. This study aims to evaluate how concordance between these two biopsy modalities influences the efficacy of targeted therapy (TT) in patients with pretreated advanced solid tumors. Methods: Genomic data from 400 patients enrolled in the ROME trial who received both tissue biopsy (FoundationOne CDx) and liquid biopsy (FoundationOne Liquid CDx) were retrospectively analyzed. Patients were stratified into 3 groups: concordant (T+L, alterations detected in both modalities, n=197), tissue-only (T, n=139), and liquid-only (L, n=64). Primary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Subgroup analyses evaluated the impact of tumor fraction, number of metastatic sites, and primary tumor type on concordance. Results: Concordance between tissue and liquid biopsy was observed in 49.2% of patients. In the concordant group, targeted therapy demonstrated significant superiority over SoC with an ORR of 22.1% versus 11.8% (p=0.042), median PFS of 4.90 versus 2.80 months (HR 0.56, 95% CI 0.41-0.77), and median OS of 10.89 versus 7.42 months (HR 0.67, 95% CI 0.48-0.95). Among patients receiving targeted therapy, outcomes revealed that the T+L group achieved the longest median PFS (4.90 months), followed by the T group (3.06 months) and the L group (2.07 months). Similar patterns were observed for OS, with medians of 10.89, 9.93, and 4.05 months, respectively. Discordance was primarily attributed to differences in molecular alterations (43%), TMB divergences (35%), and technical failures (21%). High tumor fraction (>10%) emerged as a significant predictor of concordance (p<0.001). The PTEN/PI3K/AKT/mTOR pathway exhibited the highest discordance rate (50.5%), followed by FGF/FGFR (15.4%) and ERBB2 (13.2%). Conclusions: Concordance between tissue and liquid biopsy identifies patients with higher likelihood of benefiting from CGP-guided targeted therapy. These findings support the integration of both biopsy modalities in clinical practice when feasible. Discordance may reflect tumor heterogeneity, clonal evolution, or technical limitations, underscoring the need for personalized and integrated biopsy strategies. Future studies should explore strategies to optimize the combined use of both modalities and identify patient subgroups that may derive the greatest benefit from dual-biopsy approaches.