Abstract PD9-03: Comprehensive genomic profiling and clinically targetable mutations of metastatic invasive lobular and no special type breast cancer

Abstract Background Next generation sequencing (NGS) of circulating tumor DNA (ctDNA) provides non-invasive and real-time information on tumor biology including resistance mechanisms, which is especially important given the increasing availability of targeted treatment options for patients (pts) with metastatic breast cancer (mBC). This study aims to understand the real-world use of ctDNA-based assays by reviewing testing patterns, genomic findings, and potential treatment impact among pts treated at a large US Comprehensive Cancer Center Network, with a focus on differences in histology: invasive lobular (ILC) versus no special type (NST) breast carcinomas. Methods From January 2016 - March 2025, 1,384 mBC pts had Guardant360 (Guardant Health) liquid biopsy testing obtained at the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center and its community locations. A total of 1,810 tests were sent. Guardant360 evaluated ctDNA for up to 83 genomic biomarkers, microsatellite instability (MSI) status, blood tumor mutation burden (bTMB) as well as epigenomic-based tumor fraction and other signals in the newest generation assay (Guardant360 Liquid; May 2025). Clinical data was obtained via the UPMC Hillman Cancer Center Tumor Registry. Clinical and genomic data were paired for analysis. Clinically relevant alterations were defined as those in PIK3CA, ESR1, ERBB2, BRCA1, BRCA2, and PALB2. Results A total of 915 pts were identified with histology information: 783 (85.6%) with NST and 132 (14.4%) with ILC. 838 pts had genomic alterations detected: 715 (91.3%) with NST and 123 (93.2%) with ILC. 77 pts did not have ctDNA detected. The 915 pts had a total of 1,165 Guardant360 tests sent; 226 pts had multiple serial NGS tests (1-9 per pt, median 2). A total of 5,392 unique gene mutations were detected with 586 unique genes mutated. Clinically relevant mutations were detected in 60.1% of pts (59.7% NST, 62.6% ILC). PIK3CA was the most common clinically relevant gene with mutations found in 36.8% of pts, and more common among pts with ILC (49.6%) compared to NST (34.6%) (p=0.002). ESR1 mutations were found in 27.4% of pts with similar rates in NST and ILC. BRCA1 mutations were found in 5.8% of pts (6% NST, 4.9% ILC). BRCA2 mutations were found in 9.7% of pts with similar rates between NST and ILC. In 208 pts (178 NST, 30 ILC) who had Guardant360 on Infinity platform, only one pt had an MSI-high tumor. Median bTMB was 8.54 mut/Mb among NST and 11.39 mut/Mb among ILC (p=0.25). Conclusion Among a large cohort of pts with mBC, 91.6% had detectable alterations including clinically relevant mutations on NGS-based ctDNA analysis. Most frequent actionable alterations were in PIK3CA and ESR1, and PIK3CA mutations were more common in ILC tumors. Additional clinical data collection is ongoing. Full analysis including longitudinal changes in genomic biomarkers will be reported in the presentation. Citation Format: H. Maynard, D. Liu, A. S. Moghaddam, S. Ali, S. Solomon, M. Balic, J. Foldi. Comprehensive genomic profiling and clinically targetable mutations of metastatic invasive lobular and no special type breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD9-03.