Abstract PS5-01-23: Validation of the HER2DX Genomic Test in First-Line Advanced HER2-Positive Breast Cancer: Identifying Long-Term Responders to THP

Abstract Background: The HER2DX genomic test is a standardized, quantitative assay with demonstrated prognostic value in first-line advanced HER2+ breast cancer treated with trastuzumab, pertuzumab, and chemotherapy (THP). Here, we validated the test in an independent cohort (n=122) and explored its association with long-term outcomes in a combined real-world population (n=215). Methods: HER2DX testing was performed on baseline tumor tissue from 122 consecutive patients with advanced HER2+ breast cancer treated with first-line THP at the Breast Cancer Center, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice (Poland). In addition, we evaluated a 93-patient real-world cohort from Spain (NPJ Breast Cancer 2025) with updated survival data in order to create a combined cohort. The assay was conducted at a central laboratory in Barcelona, blinded to clinical outcomes. Outcomes were assessed using pre-established ERBB2 mRNA score cutoffs. Multivariable Cox models were adjusted for clinicopathological variables. Prognostic value was also assessed in the subgroup of patients achieving a response (partial or complete) to first-line THP. An improved version of the test, called HER2DX metastatic prognostic score (HER2DX-mets-score), which combines the HER2DX ERBB2 score with additional molecular signatures, was trained in the Spanish cohort and validated in the Polish cohort. Results: In the Polish cohort (n=122), the mean age was 59.2 years (range: 36-85.7), 72.1% of patients presented with de novo metastatic disease, and 59% had hormone receptor-positive tumors. The overall response rate was 68.9%, the median progression-free survival (PFS) was 28.4 months (95% CI 17.9-42.9), and the median overall survival (OS) was 51.1 months (95% CI 43.8-87.6). Patients in the high ERBB2 mRNA group had significantly improved outcomes compared to those in the combined medium/low groups: PFS (hazard ratio [HR] 0.57; 95% CI 0.35-0.92; p=0.02) and OS (HR 0.48; 95% CI 0.28-0.83; p=0.009). In the combined cohort (n=215), the prognostic value of the ERBB2 score was confirmed. Patients in the high ERBB2 group had significantly longer PFS (median 33.8 months, 95% CI 25.6-52.5) and OS (median not reached) compared to those in the medium/low group (median PFS 12.5 months, 95% CI 9.79-25; median OS 37.1 months, 95% CI 25.4-47.9), with HRs of 0.50 (95% CI 0.35-0.71; p<0.001) for PFS and 0.36 (95% CI 0.23-0.54; p<0.001) for OS. The objective response rate (ORR) was significantly higher in the High HER2DX ERBB2 group (84.4%) compared to the Low group (52.0%; p <0.001). In multivariable models, the ERBB2 score remained independently prognostic. Among patients with a response to THP, those with high ERBB2 scores had a median PFS of 33.9 months (95% CI 26.9-61) and median OS not reached, compared to 17.6 months (95% CI 10.3-42.9) and 37.1 months (95% CI 25.4-51.1) in the medium/low group, respectively. Notably, in the subgroup of patients with fewer than three metastatic sites, those with high ERBB2 scores experienced a median PFS of 51.7 months (95% CI 28.6-NA) and a median OS that was not reached, compared to 20.3 months (95% CI 10.4-41.5) and 42.4 months (95% CI 27.6-55.8) in the medium/low group. HER2DX-mets-score outperformed the ERBB2 score alone in both cohorts; detailed results will be presented at the conference. Conclusions: The HER2DX ERBB2 mRNA score provides robust, independent prognostic information in patients treated with first-line THP for advanced HER2+ breast cancer. The test may help identify individuals who could be managed with chemotherapy followed by maintenance HP, while others may require treatment intensification. These findings suggest a potential role for the HER2DX ERBB2 score, and its improved version, HER2DX metastatic prognostic score, in informing more personalized treatment strategies. Citation Format: M. Kubeczko, S. Cobo, R. Sanchez-Bayona, B. Pycinski, J. Soberino, E. Chmielik, E. Sanfeliu, M. Rey, F. Pardo, A. Aguirre, O. Castillo, A. Lesniak, M. Oczko-Wojciechowska, E. Carcelero, B. Adamo, M. Vidal, M. Bergamino, J. Maues, G. Villacampa, L. Pare, E. Ciruelos, A. Prat, M. Jarzab, F. Braso-Maritany. Validation of the HER2DX Genomic Test in First-Line Advanced HER2-Positive Breast Cancer: Identifying Long-Term Responders to THP [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 PS5-01-23.