171770 20260603114407.0 doi 10.1016/j.ejca.2026.116817 sideral 149506 ART-2026-149506 eng Guerrero-Zotano, Ángel Dynamic thymidine kinase activity independently captures treatment-specific biological response and is independently associated with outcomes in endocrine-resistant HR+ /HER2 − metastatic breast cancer: A translational analysis of the GEICAM/2013–02 PEARL trial 2026 Background Treatment selection in endocrine-resistant HR+ /HER2 − metastatic breast cancer (MBC) remains challenging, and early predictive biomarkers are lacking. Circulating thymidine kinase 1 activity (TKa) is a blood-based proliferation marker suitable for dynamic monitoring. Methods This translational study was conducted within the phase III GEICAM/2013–02 PEARL trial comparing endocrine therapy (ET) plus palbociclib versus capecitabine in HR+ /HER2 − MBC. Plasma from 555 patients was analyzed using a standardized FDA-cleared assay. TKa was assessed at baseline using a prespecified cutoff of 250 DuA to define low versus high proliferative activity, and additional thresholds were explored for treatment interaction and on-treatment monitoring. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using multivariable Cox models. Results Low baseline TKa (≤250 DuA) was independently associated with longer PFS (11.4 vs 4.0 months) and OS (38.5 vs 17.3 months), in multivariate analysis and irrespective of treatment. However, baseline TKa did not discriminate benefit between arms. Early on-treatment TKa dynamics provided treatment-specific information. At cycle 1 day 15, median TKa was higher with capecitabine than with ET plus palbociclib (448 vs 28 DuA), consistent with distinct mechanisms. In the capecitabine arm, a > 2-fold early increase in TKa was independently associated with improved PFS and OS. Conversely, persistently elevated TKa (>50 DuA) during ET plus palbociclib identified patients with poorer outcomes, regardless of baseline levels. Conclusions Baseline TKa is strongly prognostic, while early dynamic changes provide additional, treatment-specific information, reflecting differences in mechanism of action between therapies, that support response monitoring. Access copy available to the general public Unrestricted info:eu-repo/semantics/openAccess by-nc-nd https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Gil-Gil, Miguel Williams, Amy Ruiz-Borrego, Manuel Ritzén, Hanna Ciruelos, Eva María Muñoz, Montserrat Bermejo, Begoña Margelí, Mireia Antón, Antonio Universidad de Zaragoza (orcid)0000-0002-9159-4988 Kahan, Zsuzsanna Csöszi, Tibor Alonso Murillo, Laura Murillo, Serafín Morales Lang, Istvan Rendo, Cristina Reboredo Alba, Emilio Álvarez, Pablo de la Haba-Rodriguez, Juan Álvarez, Isabel García, Andrés Herranz, Jesús Caballero, Rosalía Fisker, Helle Portela, Marta Rojo, Federico Martín, Miguel 1007 610 Universidad de Zaragoza Dpto. Medicina, Psiqu. y Derm. Area Medicina 242 (2026), 116817 [9 pp.] Eur. j. cancer European Journal of Cancer 0959-8049 1548008 http://zaguan.unizar.es/record/171770/files/texto_completo.pdf Versión publicada 2094699 http://zaguan.unizar.es/record/171770/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:171770 articulos driver 2026-06-03-11:04:59 ARTICLE