Abstract 3238: Prognostic significance of ctDNA tumor fraction quantification in advanced HR-positive breast cancer

Abstract Introduction: Hormone receptor (HR)-positive breast cancer is the most common breast cancer subtype worldwide. While treatments with CDK4/6 inhibitors and endocrine therapies like aromatase inhibitors (AIs) have improved patient outcomes, the risk of disease progression persists. This study employs circulating tumor DNA (ctDNA) Next-Generation Sequencing (NGS) assays to profile gene variations and quantify tumor fraction in patients with advanced HR-positive breast cancer, aiming to identify relevant gene biomarkers and enhance patient management. Methods: In this retrospective study, plasma samples were collected from 136 patients with advanced HR-positive breast cancer before initiating first-line treatments, including CDK4/6 inhibitors, endocrine monotherapies, and chemotherapies. The study employed PredicineCARE™, a targeted NGS liquid biopsy assay with 20, 000X coverage, to detect somatic alterations and calculate tumor fractions in ctDNA. Additionally, plasma samples were collected from 58 patients after first-line AI therapy and before initiating second-line treatment with fulvestrant. To detect potential residual or progressive disease in these patients, the study utilized PredicineCARE™ Ultra, an ultra-sensitive NGS liquid biopsy assay with coverage exceeding 100, 000X. Results: In baseline samples collected before first-line treatments from 136 patients, the ctDNA assay identified positive tumor fractions in 92 patients, detecting a total of 247 somatic mutations and 311 gene copy number variations. Patients with positive tumor fractions had significantly poorer progression-free survival (PFS) (median PFS: 9.4 months vs. 15.7 months; p=0.006) and overall survival (OS) (median OS: 82 months vs. 108 months; p=0.030). Among patients with positive tumor fractions, the median tumor fraction was 9.4%, ranging from 0.5% to 88.2%. When applying a cutoff value of 1%, patients with higher tumor fractions experienced significantly poorer PFS compared to those with lower tumor fractions (median PFS: 9.4 months vs. 15.7 months; p=0.006). In the post-AI-treatment samples from 58 patients, the ultra-sensitive ctDNA assay identified positive tumor fractions in 43 patients, detecting 93 somatic mutations. When applying the same tumor fraction cutoff of 1%, patients with high tumor fractions exhibited significantly poorer OS compared to those with low tumor fractions (median OS: 19 months vs. 46 months; p=0.015). Conclusion: Quantification of tumor fractions using ctDNA NGS assays demonstrated significant prognostic value in advanced HR-positive breast cancer, not only at baseline but also in patients undergoing treatment with potential residual or progressive disease. These findings emphasize the critical role of tumor fraction as a prognostic indicator and underscore the potential of integrating ctDNA tumor fraction assessment into clinical practice. Citation Format: Hao Liao, Jianxin Zhong, Xiaoran Liu, Bin Shao, Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Huiping Li. Prognostic significance of ctDNA tumor fraction quantification in advanced HR-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3238.