Molecular Profiling in ABC: is Complementary Testing with Tissue and Plasma Necessary and Clinically Relevant?

e12566 Background: This retrospective analysis explores the concordance between molecular analyses of tissue and plasma amongst Advanced Breast Cancer (ABC) patients and investigates the utility of simultaneous profiling for enhanced clinical insights. Methods: A total of 187 (177 Cancertrack paired and 10 Guardant 360) patient samples with availability of both tissue and ctDNA specimens, were subjected to comparative molecular profiling. Median age was 52 years (Range 23 – 82 years), 174 (93%) patients had advanced breast cancer and 177 (95%) patients had received prior treatments. We assigned tier 1 status to predictive biomarkers with FDA approved or guideline recommended therapies in breast cancer. Tier 2 status was assigned to alterations for which therapies were approved in different tumor type. Tier 3 had either clinical evidence in small studies or had clinical trial inclusion criteria. Results: Paired tissue-ctDNA profiling showed 139/187 (74%) samples had at least one concordant molecular alteration. Simultaneous tissue and ctDNA profiling led to the opportunity to offer Tier 1 recommended therapies in 113/187 (60%) patients. Amongst these, 71/113 (63%) exhibited concordance in tissue and circulating free DNA (cfDNA). ctDNA missed Tier 1 alterations in 14 patients which were detected by tissue biopsy. On the contrary tissue biopsy failed to detect Tier 1 alterations in 18 patients which were identified by ctDNA only. When Tier 2 and 3 alterations were considered, ctDNA identified additional alterations compared to tissue in 29 patients (37 variants), whereas tissue identified additional alterations in 20 patients (24 variants). Complementary tissue and ctDNA profiling showed alterations with potential to impact clinical management (Tier1/2/3) in 82% patients. When including only Tier 1 and 2 alterations, simultaneous profiling approach gives an opportunity to offer personalized therapy in 68% patients. The Tier1 ctDNA only alterations were most frequent in ESR1 gene. In fact, a total of a total of 29 ESR1 mutations were detected in these patients, of which 10 mutations were detected in both tissue and liquid. In 3 patients’ tissues were positive for ESR1 mutations but the corresponding ctDNA was negative. Similarly, ctDNA detected 16 ESR1 variants which were negative in the tissue sample. The most common ESR1 variants were D538G and Y537S. Conclusions: The simultaneous profiling of tissue and ctDNA enhanced overall clinical utility of molecular analysis in advanced breast cancer by identifying predictive biomarkers. The integration of data from both sources allowed for comprehensive understanding of the molecular heterogeneity in breast cancer. It underscores the potential of simultaneous profiling to guide treatment decisions and improve patient outcomes. By detecting acquired resistance ESR1 mutations more effectively, ctDNA serves as a valuable tool for monitoring as well.