Abstract 969: Tumor-agnostic ctDNA monitoring in patients with metastatic HR+/HER2- breast cancer receiving first-line CDK4/6 inhibitor and endocrine therapy

Abstract Introduction: CDK4/6-inhibitors (-i) in combination with endocrine therapy are first-line treatment for metastatic HR+/HER2- breast cancer (mBC). Baseline circulating tumor DNA (ctDNA) burden and changes on therapy are prognostic in mBC. GuardantINFINITY is a tumor-agnostic platform which measures aggregated epigenomic methylation signals that can distinguish ctDNA from non-tumor derived signals and permits the detection of somatic alterations in a 753 NGS panel. Longitudinal measurement of ctDNA quantity and characterization of emerging mutations may permit early identification of resistance and allow for intervention prior to clinical/radiographic progression. Methods: Patients with HR+/HER2- mBC receiving CDK4/6i were enrolled in a prospective cohort study from 2018 onwards. Plasma samples were collected at baseline (prior to initiation of CDK4/6i) and regularly in clinical follow up. Samples were analyzed using the GuardantINFINITY platform. Clinical information, pathologic characteristics, and dates of clinical progression were collected. Results: 57 patients with 350 clinical timepoints (median of 5 per patient, range 2-15) were evaluated. Median follow up was 28.6m (range: 0.9-64.3m). Median age at diagnosis of mBC was 59 (range: 38-88). CDK4/6i received included 42/57 (73%) palbociclib, 14/57 (25%) ribociclib and 1/57 (2%) abemaciclib; 40/57 (70%) were in combination with an aromatase inhibitor and 17/57 (30%) with fulvestrant. 5/350 (1.4%) of samples failed analysis related to low cfDNA input. ctDNA was detected (by methylation) in 49/57 (86%) at baseline (1 fail, 7 not detected), and 208/345 (60%) of all samples. Median methylation-based tumour fraction (TF) at baseline was 0.0132 (range: 0.000875-0.433); a higher baseline methylation TF (≥1%) was associated with worse CDK4/6i-PFS (14.7m vs. 26.7m; HR: 2.27, 95%CI: 1.12-4.62, p=0.023). 19/49 patients had ctDNA clearance, which was associated with improved CDK4/6i-PFS (34.4m vs. 13.9m; p<0.0001). In longitudinal sampling, methylation TF rose prior to clinical progression and genomic alterations associated with CDK4/6i-resistance were detected, including copy-number loss in RB1. Conclusion: Baseline methylation TF and ctDNA clearance as measured by GuardantINFINITY were prognostic in this cohort. Longitudinal sampling permitted genomic characterization and detection of alterations conferring acquired-resistance prior to clinical progression. Clinical correlates of ctDNA detection, clearance, and further serial genomic analyses will be presented. Citation Format: Mitchell J. Elliott, Jesús Fuentes-Antrás, Aaron Dou, Nancy Gregorio, Elizabeth Shah, Emily Van de Laar, Geethika Yalamanchili, Leylah M. Drusbosky, Eitan Amir, Michelle B. Nadler, Celeste Yu, Hal K. Berman, Lillian L. Siu, Philippe L. Bedard, David W. Cescon. Tumor-agnostic ctDNA monitoring in patients with metastatic HR+/HER2- breast cancer receiving first-line CDK4/6 inhibitor and endocrine therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 969.