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Clinical Trial
. 2022 Mar:164:39-51.
doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13.

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

Luca Malorni  1 , Svitlana Tyekucheva  2 , Florentine S Hilbers  3 , Michail Ignatiadis  4 , Patrick Neven  5 , Marco Colleoni  6 , Stéphanie Henry  7 , Alberto Ballestrero  8 , Andrea Bonetti  9 , Guy Jerusalem  10 , Konstantinos Papadimitriou  11 , Antonio Bernardo  12 , Elena Seles  13 , Francois P Duhoux  14 , Iain R MacPherson  15 , Alastair Thomson  16 , David Mark Davies  17 , Mattias Bergqvist  18 , Ilenia Migliaccio  19 , Géraldine Gebhart  20 , Gabriele Zoppoli  21 , Judith M Bliss  22 , Matteo Benelli  23 , Amelia McCartney  24 , Roswitha Kammler  25 , Heidi De Swert  26 , Barbara Ruepp  27 , Debora Fumagalli  28 , Rudolf Maibach  29 , David Cameron  30 , Sherene Loi  31 , Martine Piccart  32 , Meredith M Regan  33 ; International Breast Cancer Study Group; Breast International Group and PYTHIA Collaborators
Affiliations
Free article
Clinical Trial

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

Luca Malorni et al. Eur J Cancer. 2022 Mar.
Free article

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.

Keywords: Breast cancer; Fulvestrant; Palbociclib; Prognostic factors; Serum markers; Thymidine kinase.

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Conflict of interest statement

Conflict of interest statement L. Malorni reports receiving research grants (institution) from Novartis and Pfizer and serving an advisory board (honoraria) for Novartis, Seagen, Pfizer. F. Hilbers reports receiving funding (to previous Institution affiliated with) from Pfizer for conduct of the PYTHIA trial. M. Ignatiadis reports receiving research grants (to Institution) from Roche, Natera Inc, and Pfizer and serving an advisory board role (honoraria) for Novartis and Seattle Genetics. M. Colleoni reports receiving a research grant (to Institution) from Roche. G. Jerusalem reports grants (to Institution), personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Lilly, personal fees and non-financial support from Amgen, personal fees and non-financial support from BMS, personal fees and non-financial support from Astra-Zeneca, personal fees from Daiichi Sankyo, personal fees from Abbvie, non-financial support from Medimmune, and non-financial support from Merck KGaA. K. Papadimitriou reports serving an advisory board role (honoraria) for Roche, Pfizer, Lilly, and Novartis. F.P. Duhoux reports serving an advisory role (support to Institution) for Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Mundipharma, Seagen, and Teva. I. R. MacPherson reports serving as a consultant for Roche, Novartis, Pfizer, Eli Lilly, Pierre Fabre, Daiichi Sankyo, and Astrazeneca, and reports receiving travel/conference registration support from Roche, Eli Lilly, and Daichi Sankyo. A. Thomson reports receiving speaker fees from Novartis, Roche, Exact Sciences, and Lilly, reports serving on the advisory board for Novartis and MSD, and reports receiving support for attending conferences from BMS, Astellas, MSD, Ipsen, and EUSA. M. Bergqvist reports being an employee and holding stock in Biovica. G. Zoppoli reports receiving travel grants from Novartis and Roche, and reagents from ThermoFisher Scientific and Cytiva. J.M. Bliss reports receiving research funding from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Roche, and Eli Lilly. H. De Swert reports receiving research funding (to Institution) from Pfizer, Novartis, Roche, Servier, AstraZeneca, TESARO, and GSK. D. Fumagalli reports receiving research funding for the conduct of clinical trials (to Institution) from Pfizer, Biovica, Novartis, Roche/Genentech, Sanofi, Servier, AstraZeneca, TESARO, and GSK. D. Cameron reports serving on the advisory board for AstraZeneca, Pfizer, Lilly (to Institution), and IDMC (independent data monitoring committee) work (to Institution) for Lilly and unrelated research funding from Novartis. M. Piccart reports grants (to Institution) from AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon, reports receiving honoraria from AstraZeneca, Camel-IDS, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer (funded the study conception & design component), Roche-Genentech, Seattle Genetics, Immutep, Seagen, and NBE Therapeutics, and reports serving on the Scientific Board of Oncolytics. M.M. Regan reports research funding (to Institution) from Novartis, Pfizer, Ipsen, TerSera, Pierre Fabre, Roche, AstraZeneca, Bristol-Myers Squibb, and Bayer, and reports serving a consulting/advisory role for Ipsen (support to Institution), Bristol-Myers Squibb, and Tolmar Pharmaceuticals. No disclosures were reported by the other authors.

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