Abstract
Trastuzumab, pertuzumab, and a taxane (THP) has been the standard first-line therapy for HER2+ advanced breast cancer for over a decade. With new regimens emerging, genomic tools like HER2DX may help identify patients who benefit durably from THP versus those requiring intensification. Here, baseline tumor tissue from 122 patients with HER2+ treated with THP in Poland was tested with HER2DX. A previously published Spanish real-world cohort (n = 93) was added to generate a combined cohort (n = 215). Univariable analyses were performed in the Polish cohort, and multivariable Cox and logistic regression models were applied to the combined cohort. A HER2DX metastatic prognostic score was trained on overall survival (OS) in the Spanish cohort and validated in the Polish cohort. In the Polish cohort, high ERBB2 mRNA scores were associated with significantly longer real-world progression-free survival (rwPFS) (33.8 vs. 17.9 months; hazard ratio [HR] 0.57; p = 0.022) and real-world overall survival (rwOS) (75.1 vs. 40.2; HR 0.48; p = 0.009). In the combined cohort, ERBB2 high-score tumors showed prolonged rwPFS (33.8 vs. 12.5; HR 0.50; p < 0.001) and rwOS (not reached vs. 37.1; HR 0.36; p < 0.001), and higher rwORR (84.4% vs. 52.0%; p < 0.001). Prognostic value was independent of clinical variables, including number of metastatic sites. Subgroup analyses showed particularly favorable outcomes in patients with <3 sites (median rwPFS 51.7 vs. 20.3 months). The HER2DX metastatic prognostic score outperformed ERBB2 alone in the validation cohort. In conclusion, the HER2DX ERBB2 mRNA score provides independent prognostic information in HER2+ advanced breast cancer treated with THP. The HER2DX metastatic prognostic score further improves prognostic accuracy.
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The datasets analyzed during the current study are not publicly available as participants of this study did not agree for their data to be shared publicly. However, data can be made available from the corresponding author on reasonable request under a data transfer agreement and upon Ethics Committee approval.
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Acknowledgements
The study was funded by Reveal Genomics, and it was designed and performed by investigators from Hospital Universitario 12 de Octubre (Madrid, Spain), Clínic Barcelona Comprehensive Cancer Center (Barcelona, Spain), Maria Sklodowska-Curie National Research Institute of Oncology (Gliwice, Poland), and Reveal Genomics. All authors had full access to the data and final responsibility for submission. FBM received funding from Fundación científica AECC Ayudas Investigador AECC 2021 (INVES21943BRAS). AP received funding from the Breast Cancer Research Foundation (BCRF-22-198, BCRF-23-198 and BCRF-24-198), Beca Marta Santamaría, Fundación CRIS contra el Cancer PR_EX_2021-14, Agència de Gestó d’Ajuts Universitaris I de Recerca 2021 SGR 01156, Fundación Fero BECA ONCOXXI21, Asociación Cáncer de Mama Metastásico IV Premios M. Chiara Giorgetti, PI22/01017: funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union and Fundación Científica Asociación Española Contra el Cáncer which is the entity responsible for the financial support of the Excellence Program, EPAEC246711CLIN. MBS received funding from Fundación BBVA Joan Rodés-Josep Baselga 2024-2027.
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M.K., A.P. and F.B-M. designed the study. M.K., S.C., R.S-B., B.P, J.S., E.Ch., E.S., M.R., F.P., A.A., O.C., A.L., M.O-W., E.Ca., B.A., M.V., M.B., J.M., G.V., L.P., P.V., E.Ci., M.J., A.P. and F.B-M. contributed to data collection and assembly, wrote and reviewed the article, and approved the final version for submission.
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Potential conflicts of interest are the following: M.K. reports advisory board for Novartis; speaker’s honoraria from Novartis, Roche, MSD, Pfizer, Lilly, Teva, Amgen, Swixx Biopharma, Gilead, and AstraZeneca; clinical trials for Roche, MSD, Novartis, Seagen, and Gilead; conference fees for Pfizer, Roche, Novartis, Teva, Amgen, Gilead, MSD, Swixx Biopharma, and AstraZeneca; all outside the submitted work. M.J. reports conference fees for Gilead, Roche; clinical trials for Roche, MSD, Novartis, Seagen, and Gilead; speaker’s honoraria from Novartis, Roche, Lilly, Pfizer, Teva, Exact Sciences, Mammotome, and Gilead; advisory boards for Novartis and Pfizer; all outside the submitted work. A.P. reports advisory and consulting fees from AstraZeneca, Roche, Pfizer, Novartis, Daiichi Sankyo, Ona Therapeutics, and Peptomyc, lecture fees from AstraZeneca, Roche, Novartis, and Daiichi Sankyo, institutional financial interests from AstraZeneca, Novartis, Roche, and Daiichi Sankyo; stockholder and employee of Reveal Genomics; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, PCT/EP2024/068197 and EP23383369; editor of NPJ Breast Cancer journal. F.B-M. reports part-time employment from Reveal Genomics and has patents filed: PCT/EP2022/086493, PCT/EP2023/060810,PCT/EP2024/068197, and EP23383369B. MBS declares Advisor o consulting fees from Pfizer, Novartis, Lilly and Astra Zeneca and travel expenses from Pfizer, Lilly, Novartis, Astra Zeneca and Gilead. R.S.-B. reports advisory/consulting/speaker fees from Roche, AstraZeneca, Novartis, Lilly, Daiichi Sankyo, Pfizer, Eisai, GlaxoSmithKline, Reveal Genomics, and Gilead; travel expenses from Pfizer, AstraZeneca, Gilead, Novartis, and Roche. E.S. reports Advisory Board and speaker honoraria of Sysmex and Astra Zenica; and consultant of Reveal Genomics INC. A.L. reports conference fees: Accord, Novartis, clinical studies: Roche, MSD, Novartis; speaker’s honorarium: Novartis; all outside the submitted work.
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Kubeczko, M., Cobo, S., Sanchez-Bayona, R. et al. Validation of the HER2DX genomic test in first-line advanced HER2-positive breast cancer treated with trastuzumab, pertuzumab, and taxane. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00909-0
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DOI: https://doi.org/10.1038/s41523-026-00909-0
