Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant

Malorni, L. et al. (2022) Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant. European Journal of Cancer, 164, pp. 39-51. (doi: 10.1016/j.ejca.2021.12.030) (PMID:35172272)

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Background: Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant. Patients and methods: PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum samples were collected pre-treatment (pre-trt; n = 122), at day 15 of cycle 1 (D15; n = 108), during the one week-off palbociclib before initiating cycle 2 (D28; n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa. Results: Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15. Conclusions: STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. identifier: NCT02536742; EudraCT 2014-005387-15.

Item Type:Articles
Additional Information:PYTHIA received financial support for trial conduct from Pfizer and the IBCSG. Pfizer and AstraZeneca provided drug supply. BIOVICA supplied support for sample handling and assays. Pfizer and AstraZeneca did not have a role in the reporting or interpretation of the trial. Support for the coordinating group, IBCSG: Frontier Science, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland, Oncosuisse, Cancer League Switzerland, and the Foundation for Clinical Cancer Research of Eastern Switzerland. Support for the AURORA study: Breast Cancer Research Foundation (BCRF, BCRF-19-186 and ELFF-19-00) as the main funder, Foundation Cancer (Luxembourg), National Lottery (Belgium), Foundation NIF, Barrie and Dena Webb, Candriam, Fondation Futur 21, Sogerim, Think Pink Belgium (SMART Fund) and many individual donors. AURORA has also been supported by the Fund Friends of BIG, managed by the King Baudouin Foundation. Dr. Malorni is supported by a grant from the Fondazione AIRC per la Ricerca sul Cancro (22869).
Glasgow Author(s) Enlighten ID:MacPherson, Professor Iain
Authors: Malorni, L., Tyekucheva, S., Hilbers, F. S., Ignatiadis, M., Neven, P., Colleoni, M., Henry, S., Ballestrero, A., Bonetti, A., Jerusalem, G., Papadimitriou, K., Bernardo, A., Seles, E., Duhoux, F. P., MacPherson, I. R., Thomson, A., Davies, D. M., Bergqvist, M., Migliaccio, I., Gebhart, G., Zoppoli, G., Bliss, J. M., Benelli, M., McCartney, A., Kammler, R., De Swert, H., Ruepp, B., Fumagalli, D., Maibach, R., Cameron, D., Loi, S., Piccart, M., and Regan, M. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:European Journal of Cancer
ISSN (Online):1873-2364
Published Online:13 December 2021
Copyright Holders:Copyright © 2022 Elsevier Ltd.
First Published:First published in European Journal of Cancer 164:39-51
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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