Abstract GS1-06: Circulating tumor DNA (ctDNA) in human epidermal growth factor receptor 2-positive (HER2[+]) Early Breast Cancer (EBC): Translational analysis of PHERGain neoadjuvant tailored treatment study
Introduction: HER2-directed therapies have dramatically improved the outcome of patients (pts) with HER2[+]EBC, leading to the investigation of different de-escalation approaches. ctDNA is an emerging tool for risk stratification and real-time monitoring in EBC, offering the potential to personalize treatment decisions. The PHERGain study showed the feasibility of a FDG positron emission tomography (PET)-guided, pathological complete response (pCR)-adapted strategy to safely omit chemotherapy (CT) in pts with stage I-IIIA HER2[+] EBC undergoing neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab (HP). The PET- and pCR-guided approach allowed omission of CT in 37.9% of pts, achieving a 3-year invasive-disease free survival (iDFS) rate (94.8%) in the overall adaptive group. In this sub-study, we assess a tumor-uninformed epigenomic-based ctDNA assay for minimal residual disease detection to improve the prediction of pCR and 3-year iDFS, thereby enabling more tailored (neo)adjuvant treatment strategies for HER2[+] EBC pts within the framework of the PHERGain study. Methods: Details of the trial design and study population have been previously reported. Out of 356 randomized pts, 63 in group A (standard treatment) and 267 in group B (adaptive treatment) proceeded to surgery. The primary objective of the PHERGuide sub-study was to assess the correlation between ctDNA clearance after two treatment cycles and pCR (ypT0/is ypN0) in all included pts. Secondary objectives evaluated the association between ctDNA levels and patient outcomes. Blood samples were collected at baseline, after cycle 2 of neoadjuvant treatment, and pre-surgery. A total of 932 samples from 351 pts (336 baseline, 311 cycle 2, and 285 pre-surgery) were analyzed using Guardant RevealTM, a tumor-uninformed epigenomic assay that provides a binary ctDNA detection result along with an estimated tumor fraction. ctDNA clearance was defined as detectable ctDNA at baseline but undetectable at a subsequent time point. Categorical variables were analyzed using logistic regression models, and survival outcomes were assessed with Cox proportional hazards regression. Results: Of the 932 samples, 801 were eligible for this sub-study (161 in group A and 640 in group B). ctDNA was detected in 204 of 288 (71%) baseline samples suitable for analysis. Detection rates were significantly correlated with disease stage: 33% (9/27) in stage I, 73% (154/217) in stage II, and 93% (41/44) in stage III tumors (p < 0.001). A total of 126/167 (75.4%) and 124/149 (83.2%) pts with detectable baseline ctDNA showed ctDNA clearance after two treatment cycles and prior to surgery, respectively. ctDNA clearance after two treatment cycles (p = 0.003) and at the pre-surgical time point (p < 0.001) was significantly associated with achieving a pCR. No significant correlation was observed between baseline ctDNA status and pCR (p = 0.583). No patient with detectable ctDNA prior to surgery (n = 25) achieved a pCR. ctDNA positivity at baseline was associated with worse 3-year iDFS (92.5% vs. 100%, HR 0.20; 95%CI 0.02-0.98; p = 0.046). Conclusions: These findings demonstrate a significant correlation between ctDNA clearance and pCR in HER2[+] EBC pts undergoing neoadjuvant HER2-targeted therapy. Moreover, detectable ctDNA at baseline is associated with inferior 3-year outcomes. Further prospective studies are needed to confirm these results. Citation Format: A. Llombart-Cussac, J. Pérez-García, M. Ruiz-Borrego, A. Stradella, B. Bermejo, S. Escrivá-de-Romaní, C. Reboredo, N. Ribelles, A. Cortés-Salgado, C. Albacar, M. Colleoni, G. Antonarelli, G. Notini, M. Gion, J. García-Mosquera, L. Sanz, E. Martínez-García, P. González-Alonso, A. Amaya-Garrido, J. Guerrero, J. Rodríguez-Morató, L. Mina, G. Martrat, M. Quintana, F. Riva, D. Dustin, H. Zhang, M. Mancino, J. Cortés. Circulating tumor DNA (ctDNA) in human epidermal growth factor receptor 2-positive (HER2[+]) Early Breast Cancer (EBC): Translational analysis of PHERGain neoadjuvant tailored treatment study [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 GS1-06.