Luca Malorni1, Svitlana Tyekucheva2, Florentine S Hilbers3, Michail Ignatiadis4, Patrick Neven5, Marco Colleoni6, Stéphanie Henry7, Alberto Ballestrero8, Andrea Bonetti9, Guy Jerusalem10, Konstantinos Papadimitriou11, Antonio Bernardo12, Elena Seles13, Francois P Duhoux14, Iain R MacPherson15, Alastair Thomson16, David Mark Davies17, Mattias Bergqvist18, Ilenia Migliaccio19, Géraldine Gebhart20, Gabriele Zoppoli21, Judith M Bliss22, Matteo Benelli23, Amelia McCartney24, Roswitha Kammler25, Heidi De Swert26, Barbara Ruepp27, Debora Fumagalli28, Rudolf Maibach29, David Cameron30, Sherene Loi31, Martine Piccart32, Meredith M Regan33. 1. "Sandro Pitigliani" Translational Research Unit and Medical Oncology Department, Hospital of Prato, Prato, Italy. Electronic address: luca.malorni@uslcentro.toscana.it. 2. 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. 3. Breast International Group, Brussels, Belgium; Department of Molecular Pathology, Netherlands Cancer Institute (NKI), Amsterdam, Netherlands. Electronic address: f.hilbers@nki.nl. 4. Medical Oncology Department, Institut Jules Bordet and Université Libre de Bruxelles, Brussels, Belgium. Electronic address: Michail.Ignatiadis@bordet.be. 5. 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. 6. International Breast Cancer Study Group and Division of Medical Senology, IEO, European Institute of Oncology, IRCCS, Milan, Italy. Electronic address: marco.colleoni@ieo.it. 7. 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. 8. Department of Internal Medicine and Oncology, IRCCS Ospedale Policlinico San Martino, Genova, Italy. Electronic address: aballestrero@unige.it. 9. Department of Oncology, AULSS 9 of the Veneto Region, Mater Salutis Hospital, Legnago, VR, Italy. Electronic address: andrea.bonetti@aulss9.veneto.it. 10. International Breast Cancer Study Group and CHU Liège, Liège University, Liège, Belgium. Electronic address: g.jerusalem@chuliege.be. 11. Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Antwerp, Belgium. Electronic address: konstantinos.papadimitriou@uza.be. 12. Medical Oncology Unit, ICS Maugeri-IRCCS, Pavia, Italy. Electronic address: antonio.bernardo@icsmaugeri.it. 13. Ospedale Degli Infermi, Ponderano, Italy. Electronic address: elena.seles@aslbi.piemonte.it. 14. 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. 15. Wolfson Wohl Cancer Research Center, Institute of Cancer Sciences, University of Glasgow, UK. Electronic address: iain.macpherson@glasgow.ac.uk. 16. Royal Cornwall Hospital, Truro UK. Electronic address: alastairthomson1@nhs.net. 17. Department of Oncology, South West Wales Oncology Center, Swansea, UK. Electronic address: Mark.Davies44@wales.nhs.uk. 18. Biovica, Uppsala, Sweden. Electronic address: mattias.bergqvist@biovica.com. 19. "Sandro Pitigliani" Translational Research Unit, Hospital of Prato, Prato, Italy. Electronic address: ilenia.migliaccio@uslcentro.toscana.it. 20. Institut Jules Bordet-Université Libre de Bruxelles, Brussels, Belgium. Electronic address: Geraldine.gebhart@bordet.be. 21. Department of Internal Medicine, Università Degli Studi di Genova and IRCCS Ospedale Policlinico Martino, Genoa, Italy. Electronic address: gabriele.zoppoli@unige.it. 22. Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK. Electronic address: Judith.bliss@icr.ac.uk. 23. Bioinformatics Unit, Hospital of Prato, Prato, Italy. Electronic address: matteo.benelli@uslcentro.toscana.it. 24. "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. 25. International Breast Cancer Study Group, Bern, Switzerland. Electronic address: Rosita.Kammler@ibcsg.org. 26. Breast International Group, Brussels, Belgium. Electronic address: heidi.deswert@bigagainstbc.org. 27. International Breast Cancer Study Group, Bern, Switzerland. Electronic address: Barbara.Ruepp@ibcsg.org. 28. Breast International Group, Brussels, Belgium. Electronic address: Debora.Fumagalli@bigagainstbc.org. 29. International Breast Cancer Study Group, Bern, Switzerland. Electronic address: rudolf.maibach@ibcsg.org. 30. 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. 31. International Breast Cancer Study Group and Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: sherene.loi@petermac.org. 32. Institut Jules Bordet and L'Universite Libre de Bruxelles, Brussels, Belgium. Electronic address: martine.piccart@bordet.be. 33. 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.
Abstract
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.
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.