Abstract PS5-02-07: Her2-overexpressing circulating tumor cells in patients treated by trastuzumab deruxtecan for metastatic her2+ breast cancer: clinical and prognostic implications

Abstract Background: Trastuzumab deruxtecan (T-DXd) has become the standard second-line treatment of HER2-overexpressing metastatic breast cancer (HER2+ MBC). However, to date, no reliable circulating biomarker has been identified to anticipate the resistance or sensitivity to this compound, and to better understand the underlying mechanisms of resistance / sensitivity. We evaluated in a prospective cohort the respective value of circulating tumor cell (CTC) levels, as well as CTC HER2 immunostaining and its heterogeneity, before and early during therapy as a tool to evaluate the prognosis of HER2+ MBC patients. Methods: We prospectively enrolled patients with HER2+ MBC receiving T-DXd across three French clinical centers (NCT04025541). Peripheral blood samples were collected at three timepoints: prior to treatment initiation (T1), before the second treatment cycle (T2), and at the time of confirmed disease progression (T3). CTCs were detected using the CellSearch® system. For each detected CTC, both enumeration and quantitative assessment of HER2 expression by immunofluorescence were performed. HER2 staining intensity and intra-patient heterogeneity were evaluated using the ACCEPT image analysis algorithm, enabling characterization of HER2-positive CTCs (HER2+ CTCs). Progression-free survival (PFS) was modeled based on longitudinal trajectories of HER2+ CTC levels using shared random effects joint models. Results: A total of 60 evaluable patients were enrolled between June 2021 and February 2025. As of the data cutoff (July 1, 2025), with a median follow-up of 17.2 months (95% CI: 11.6-21.7 months), 28 patients had experienced disease progression. CTCs were detectable at baseline (T1) in 20 patients (33.3%) and at the second timepoint (T2) in 4 patients (6.6%). No baseline clinical or pathological variables were found to be significantly associated with CTC positivity at T1. Neither the baseline presence of CTCs (with a median PFS of 13.6 months 7.5 - 25.4 vs. 17.1 8.9 - NA, p=0.4, for the CTC+ (≥1 detected cell) and CTC- populations, respectively) nor the longitudinal evolution model were associated with PFS. HER2+ CTCs were detected in 7 patients (11.6%). Among CTC-positive cases, no statistically significant correlation was observed between the number of CTCs and the presence of HER2+ CTCs. Notably, HER2+ CTCs were exclusively identified in patients whose tumor tissue exhibited HER2 3+ expression. While not significant (p=0.2), the HER2+ CTC population presented a PFS twice longer compared to the HER2+ CTC-negative population (25.3 8.1 - NA vs. 13.6 months 8.7 - 21.7, respectively, HR=0.48), even if the HER2+ CTC population was more heavily pretreated (median of 3 previous cytotoxic treatments in the MBC setting compared to 1 for the HER2+ CTC-negative group, p=0.01). The longitudinal evolution model was not associated with PFS. Conclusions: Detection of HER2+ CTCs appears to be a rare event in HER2+ MBC. However, their presence may help identify a subset of patients who derive greater benefit from T-DXd. Larger studies and evaluation of additional circulating biomarkers, such as ctDNA, are warranted. Citation Format: W. Jacot, F. Bidard, R. Colin-Chevalier, S. Guiu, S. Renault, G. Lossaint, J. Pierga, L. Cayrefourcq, F. Fiteni, C. Alix-Panabières. Her2-overexpressing circulating tumor cells in patients treated by trastuzumab deruxtecan for metastatic her2+ breast cancer: clinical and prognostic implications 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 PS5-02-07.