Abstract P2-01-29: Prognostic value of circulating tumor DNA in metastatic breast cancer

Abstract Introduction: Circulating tumor DNA (ctDNA) is widely used in the management of metastatic breast cancer (MBC) for tumor genotyping and detection of actionable alterations. Whether detectable ctDNA and its levels are associated with worse prognosis has not been well established yet in MBC. Available data are limited by small sample sizes and/or suboptimal ctDNA assays. In this study, we aim to evaluate the prognostic value of ctDNA detection in a large cohort of patients (pts) with MBC. Methods: We integrated clinical and ctDNA sequencing data from MBC pts treated at our institution (MSK) who underwent at least one ctDNA assessment using MSK-ACCESS, a 129-cancer-related gene assay. The assay demonstrated high sensitivity and specificity to detect tumor-derived variants as it utilizes matched WBC sequencing to filter out biological noise originating from clonal hematopoiesis or germline variants. We selected the first ctDNA assessment performed in the metastatic disease course. ctDNA level was defined as the highest variant allele frequency (maxVAF) of the detected tumor-derived variants. In case of no detectable ctDNA mutation, ctDNA level was considered as zero. Association between ctDNA detection and its levels with overall survival (OS) was assessed using uni- and multivariate left-truncation corrected Cox proportional hazard models. Results: Overall, 766 pts with at least one MSK-ACCESS between 8/2019 and 4/2024 were identified. Of those, 685 pts with complete clinical information were included in the analysis: 72% HR+/HER2-, 15% TNBC, and 13% HER2+. At the data lock, 42% of the pts had died. MSK-ACCESS was performed at or after the metastatic disease diagnosis with a median interval of 15 months (IQR: 1.4-46, 33% within 3 months). ctDNA was detectable in 73% of pts (at least one tumor-derived mutation), with a median maxVAF of 2.4% in ctDNA+ pts (IQR: 0.63-12.7%) and 34% of pts having >2 mutations. Median ctDNA levels were strongly associated with the number of metastatic sites (2.9% for ≥3 sites, 1.6% for 2, 0.7% for 1; p=0.00047), and presence of liver metastases (1.5% vs 0.76%; p=0.0013). ctDNA levels were lower in ctDNA+ pts with HR+/HER2- as compared to TNBC or HER2+ (median 1.9%, 4.2% and 4.6%, respectively, p=0.031). Detection of ctDNA was a strong prognostic factor for OS with a univariate HR of 3.9 (95% CI: 2.7-5.8) and multivariate HR of 3.7 (95% CI: 2.5-5.4). ctDNA levels were also strongly prognostic: ref: not detected, <1%: HR=2.2 (95% CI: 1.4-3.5), 1-10%: HR=3.9 (95% CI: 2.6-5.9), >10%: HR=7.3 (95% CI: 4.8-11.0), p for trend <2e-16. The number of mutations detected was associated with OS; HR=2.8 (95% CI: 1.9-4.2) for 1-2 mutations and HR=5.8 (95% CI: 3.9-8.6) for > 2 mutations, compared to none. In the analysis by receptor subtype, ctDNA levels were prognostic for both HR+/HER2- (p<2e-16) and TNBC (p=0.00045) but not for HER2+ (p=0.32). ctDNA level remained an independent prognostic factor for OS in a multivariable analysis adjusted for visceral metastasis, number of metastatic sites (at the time of metastatic relapse) and receptor subtype (HR=6.7, 95% CI: 4.4-10.2 for maxVAF >10% vs 0). Similar results were obtained using median, mean, and geometric mean VAF to estimate ctDNA levels. When restricting the analysis to HR+/HER2- MBC pts with a ctDNA collected within 3 months from metastatic diagnosis (n=152), ctDNA levels remained an independent prognostic factor for OS after adjusting for presence of visceral metastasis and number of metastatic sites (HR=4.5 95% CI: 1.6-13 for maxVAF >10% vs 0). Conclusion: In this large cohort of MBC pts, ctDNA detection and levels emerged as strong prognostic indicators for OS, independently from disease burden. Our data suggest that ctDNA levels can provide valuable insight into tumor biology as well as disease burden and may be utilized for early prognostication in MBC. Citation Format: Luc Cabel, Emanuela Ferraro, Enrico Moiso, Randy Yeh, Julia Ah-Reum An, Mehnaj Ahmed, Yuan Chen, David Solit, Michael Berger, Mark Robson, Steven Maron, Dara Ross, Sarat Chandarlapaty, Pedram Razavi. Prognostic value of circulating tumor DNA in metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-29.