Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant.
Malorni, Luca; Tyekucheva, Svitlana; Hilbers, Florentine Set al.
2022 • In European Journal of Cancer, 164, p. 39-51
Breast cancer; Fulvestrant; Palbociclib; Prognostic factors; Serum markers; Thymidine kinase; Piperazines; Pyridines; Thymidine Kinase; Cyclin-Dependent Kinase 4; palbociclib; Antineoplastic Combined Chemotherapy Protocols/therapeutic use; Female; Fulvestrant/therapeutic use; Humans; Male; Prospective Studies; Breast Neoplasms/drug therapy; Breast Neoplasms/pathology; Thymidine Kinase/therapeutic use; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Receptor, ErbB-2; Oncology; Cancer Research
Abstract :
[en] 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. CLINICALTRIALS.
GOV IDENTIFIER: NCT02536742; EudraCT 2014-005387-15.
Disciplines :
Oncology
Author, co-author :
Malorni, Luca; "Sandro Pitigliani" Translational Research Unit and Medical Oncology Department, Hospital of Prato, Prato, Italy. Electronic address: luca.malorni@uslcentro.toscana.it
Tyekucheva, Svitlana; International Breast Cancer Study Group Statistical Center, Department of Data Science, Dana-Farber Cancer Institute and Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: svitlana@jimmy.harvard.edu
Hilbers, Florentine S; Breast International Group, Brussels, Belgium, Department of Molecular Pathology, Netherlands Cancer Institute (NKI), Amsterdam, Netherlands. Electronic address: f.hilbers@nki.nl
Ignatiadis, Michail; Medical Oncology Department, Institut Jules Bordet and Université Libre de Bruxelles, Brussels, Belgium. Electronic address: Michail.Ignatiadis@bordet.be
Neven, Patrick; Department of Oncology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Department of Gynecology and Obstetrics and Multidisciplinary Breast Center, UZ-KU Leuven Cancer Institute (LKI), Katholieke Universiteit, Leuven, Belgium. Electronic address: patrick.neven@uzleuven.be
Colleoni, Marco; International Breast Cancer Study Group and Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy. Electronic address: marco.colleoni@ieo.it
Henry, Stéphanie; Department of Medical Oncology, Hematology, Radiotherapy and Nuclear Medicine, Université Catholique de Louvain, CHU UCL Namur (Site Ste Elisabeth), Namur, Belgium. Electronic address: stephanie.henry@uclouvain.be
Ballestrero, Alberto; Department of Internal Medicine and Oncology, IRCCS Ospedale Policlinico San Martino, Genova, Italy. Electronic address: aballestrero@unige.it
Bonetti, Andrea; Department of Oncology, AULSS 9 of the Veneto Region, Mater Salutis Hospital, Legnago, VR, Italy. Electronic address: andrea.bonetti@aulss9.veneto.it
JERUSALEM, Guy ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale
Papadimitriou, Konstantinos; Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Antwerp, Belgium. Electronic address: konstantinos.papadimitriou@uza.be
Bernardo, Antonio; Medical Oncology Unit, ICS Maugeri-IRCCS, Pavia, Italy. Electronic address: antonio.bernardo@icsmaugeri.it
Seles, Elena; Ospedale Degli Infermi, Ponderano, Italy. Electronic address: elena.seles@aslbi.piemonte.it
Duhoux, Francois P; Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, and Breast Clinic, King Albert II Cancer Institute, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address: francois.duhoux@uclouvain.be
MacPherson, Iain R; Wolfson Wohl Cancer Research Center, Institute of Cancer Sciences, University of Glasgow, UK. Electronic address: iain.macpherson@glasgow.ac.uk
Thomson, Alastair; Royal Cornwall Hospital, Truro UK. Electronic address: alastairthomson1@nhs.net
Davies, David Mark; Department of Oncology, South West Wales Oncology Center, Swansea, UK. Electronic address: Mark.Davies44@wales.nhs.uk
Migliaccio, Ilenia; "Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Prato, Italy. Electronic address: ilenia.migliaccio@uslcentro.toscana.it
Zoppoli, Gabriele; Department of Internal Medicine, Università Degli Studi di Genova and IRCCS Ospedale Policlinico Martino, Genoa, Italy. Electronic address: gabriele.zoppoli@unige.it
Bliss, Judith M; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK. Electronic address: Judith.bliss@icr.ac.uk
Benelli, Matteo; Bioinformatics Unit, Hospital of Prato, Prato, Italy. Electronic address: matteo.benelli@uslcentro.toscana.it
McCartney, Amelia; "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, Italy, School of Clinical Sciences, Monash University, Melbourne, Australia. Electronic address: amelia.mccartney@uslcentro.toscana.it
Kammler, Roswitha; International Breast Cancer Study Group, Bern, Switzerland. Electronic address: Rosita.Kammler@ibcsg.org
De Swert, Heidi; Breast International Group, Brussels, Belgium. Electronic address: heidi.deswert@bigagainstbc.org
Ruepp, Barbara; International Breast Cancer Study Group, Bern, Switzerland. Electronic address: Barbara.Ruepp@ibcsg.org
Fumagalli, Debora; Breast International Group, Brussels, Belgium. Electronic address: Debora.Fumagalli@bigagainstbc.org
Maibach, Rudolf; International Breast Cancer Study Group, Bern, Switzerland. Electronic address: rudolf.maibach@ibcsg.org
Cameron, David; Breast International Group, Brussels, Belgium, Cancer Research UK Edinburgh Center, University of Edinburgh Cancer Research Center, Edinburgh, UK. Electronic address: D.Cameron@ed.ac.uk
Loi, Sherene; International Breast Cancer Study Group and Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: sherene.loi@petermac.org
Piccart, Martine; Institut Jules Bordet and L'Universite Libre de Bruxelles, Brussels, Belgium. Electronic address: martine.piccart@bordet.be
Regan, Meredith M; International Breast Cancer Study Group Statistical Center, Division of Biostatistics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. Electronic address: mregan@jimmy.harvard.edu
International Breast Cancer Study Group
Breast International Group and PYTHIA Collaborators
Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant.
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