000171770 001__ 171770 000171770 005__ 20260603114407.0 000171770 0247_ $$2doi$$a10.1016/j.ejca.2026.116817 000171770 0248_ $$2sideral$$a149506 000171770 037__ $$aART-2026-149506 000171770 041__ $$aeng 000171770 100__ $$aGuerrero-Zotano, Ángel 000171770 245__ $$aDynamic 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 000171770 260__ $$c2026 000171770 5060_ $$aAccess copy available to the general public$$fUnrestricted 000171770 5203_ $$aBackground 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. 000171770 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es 000171770 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000171770 700__ $$aGil-Gil, Miguel 000171770 700__ $$aWilliams, Amy 000171770 700__ $$aRuiz-Borrego, Manuel 000171770 700__ $$aRitzén, Hanna 000171770 700__ $$aCiruelos, Eva María 000171770 700__ $$aMuñoz, Montserrat 000171770 700__ $$aBermejo, Begoña 000171770 700__ $$aMargelí, Mireia 000171770 700__ $$0(orcid)0000-0002-9159-4988$$aAntón, Antonio$$uUniversidad de Zaragoza 000171770 700__ $$aKahan, Zsuzsanna 000171770 700__ $$aCsöszi, Tibor 000171770 700__ $$aAlonso Murillo, Laura 000171770 700__ $$aMurillo, Serafín Morales 000171770 700__ $$aLang, Istvan 000171770 700__ $$aRendo, Cristina Reboredo 000171770 700__ $$aAlba, Emilio 000171770 700__ $$aÁlvarez, Pablo 000171770 700__ $$ade la Haba-Rodriguez, Juan 000171770 700__ $$aÁlvarez, Isabel 000171770 700__ $$aGarcía, Andrés 000171770 700__ $$aHerranz, Jesús 000171770 700__ $$aCaballero, Rosalía 000171770 700__ $$aFisker, Helle 000171770 700__ $$aPortela, Marta 000171770 700__ $$aRojo, Federico 000171770 700__ $$aMartín, Miguel 000171770 7102_ $$11007$$2610$$aUniversidad de Zaragoza$$bDpto. Medicina, Psiqu. y Derm.$$cArea Medicina 000171770 773__ $$g242 (2026), 116817 [9 pp.]$$pEur. j. cancer$$tEuropean Journal of Cancer$$x0959-8049 000171770 8564_ $$s1548008$$uhttps://zaguan.unizar.es/record/171770/files/texto_completo.pdf$$yVersión publicada 000171770 8564_ $$s2094699$$uhttps://zaguan.unizar.es/record/171770/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000171770 909CO $$ooai:zaguan.unizar.es:171770$$particulos$$pdriver 000171770 951__ $$a2026-06-03-11:04:59 000171770 980__ $$aARTICLE