Abstract PS4-02-11: Molecular and prognostic profiling of HR+/HER2+ Metastatic Breast Cancer (MBC): insights from circulating tumor DNA (ctDNA)-based genomic analysis

Abstract Background: Hormone receptor–positive/HER2-positive metastatic breast cancer (HER2+/HR+ MBC) represents a biologically distinct subtype, characterized by extensive crosstalk between estrogen receptor (ER) and HER2 signaling pathways. The treatment landscape for HER2+ MBC is rapidly evolving, with recent data from the DESTINY-Breast09 trial supporting consideration of T-DXd in the first line and the PATINA trial demonstrating that adding the CDK4/6 inhibitor palbociclib to maintenance therapy significantly prolonged progression-free survival in patients with HR+/HER2+ disease. The aim of this analysis was to compare genomic profiles and outcomes across HR+/HER2–, HER2+/HR+, and HER2+/HR– subtypes through ctDNA assessment. Methods: This retrospective study analyzed a multi-institutional cohort of 1318 patients (pts) with MBC and ctDNA testing with the Guardant360 NGS panel within a large academic consortium (PMAC). HR and HER2 status were defined based on the most recent tissue biopsy. Associations between single nucleotide variants (SNVs), copy number variations (CNVs) and breast cancer subtypes were tested by multinomial logistic regression (MLR) in terms of Relative Risk Ratio (RRR). The impact of prognosis was evaluated through Cox regression for overall survival (OS), defined from time of baseline ctDNA collection. Results: Among 1318 pts with MBC, 1104 (83.8%) had HR+/HER2–, 127 (9.6%) HER2+/HR+, and 87 (6.6%) HER2+/HR- disease. Multivariable MLR, designed with HR+/HER2- as the reference subtype, investigated clinical variables and genomic alterations across subtypes. Clinically, the presence of nodal (RRR 1.82, p 0.001) and soft tissue (RRR 2.60, p 0.001) metastases were more common for HER2+/HR+ but not for HER2+/HR-, while central nervous system (CNS) metastases were associated with both HER2+/HR+ (RRR 3.41, p 0.001) and HER2+/HR- (RRR 2.73, p = 0.006). Considering single genes alterations, at multivariable analysis, PIK3CA SNVs were less common (RRR 0.51, p = 0.010) and ERBB2 CNVs more common (RRR 41.17, p 0.001) for HER2+/HR+, while ERBB2 CNVs were also associated with HER2+/HR- (RRR 85.64, p 0.001). Considering pathway alterations, HER2+/HR+ had fewer PI3K SNVs (RRR 0.47, p = 0.003) and ER SNVs (RRR 0.52, p = 0.022), while in HER2+/HR- there were fewer ER SNVs (RRR 0.05, p = 0.004) and more MYC CNVs (RRR 5.10, p = 0.029). In OS analysis, both HER2+/HR+ (HR 0.55, p = 0.002) and HER2+/HR- (HR = 0.61, p = 0.027) had a significantly favorable prognostic impact compared to HR+/HER2-. Within the HR+/HER2- cohort, several pathway alterations were associated with worse prognosis, including ER SNVs (HR 1.33, p = 0.007), P53 SNVs (HR 1.46, p 0.001), PI3K CNVs (HR 1.54, p = 0.028) and MYC CNVs (HR 1.84, p = 0.001). In HER2+/HR+, a significant prognostic impact emerged for PI3K SNVs (HR 2.66, p = 0.016), P53 SNVs (HR 2.46, p = 0.036) and RTK CNVs (HR 3.82, p = 0.004), while in HER2+/HR- it was observed only for PI3K CNVs (HR 79.65, p = 0.003). Conclusions: Our ctDNA-based analysis confirms that HER2+/HR+ MBC is a clinically and molecularly distinct subtype. Compared with HR+/HER2– disease, HER2+/HR+ MBC is characterized by higher ERBB2 amplification and a lower frequency of ER SNVs, suggesting reduced dependence on estrogen signaling despite hormone receptor positivity, and the presence of distinct mechanisms of endocrine resistance. Prognostically, both HER2+/HR+ and HER2+/HR– subtypes had significantly more favorable overall survival, suggesting an intrinsic advantage linked to the success of therapeutics aimed at targeting HER2. These findings therefore highlight the potential value of comprehensive baseline and longitudinal mutational profiling to guide initial and maintenance therapy selection and support personalized treatment approaches in HR+/HER2+ disease. Citation Format: L. Foffano, A. Davis, C. Reduzzi, E. Podany, A. Medford, K. Clifton, M. Velimirovic, B. Pastò, L. Pontolillo, R. Occhiogrosso Abelman, C. Gianni, S. Tapiavala, E. Molteni, M. Lypsic-Sharf, E. Nicolò, E. Andreopoulou, W. Gradishar, F. Puglisi, C. Ma, A. Bardia, L. Gerratana, M. Cristofanilli. Molecular and prognostic profiling of HR+/HER2+ Metastatic Breast Cancer (MBC): insights from circulating tumor DNA (ctDNA)-based genomic analysis 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 PS4-02-11.