Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant. (March 2022)

• Record Type: Journal Article
• Authors: Malorni, Luca; Tyekucheva, Svitlana; Hilbers, Florentine S.; Ignatiadis, Michail; Neven, Patrick; Colleoni, Marco; Henry, Stéphanie; Ballestrero, Alberto; Bonetti, Andrea; Jerusalem, Guy; Papadimitriou, Konstantinos; Bernardo, Antonio; Seles, Elena; Duhoux, Francois P.; MacPherson, Iain R.; Thomson, Alastair; Davies, David Mark; Bergqvist, Mattias; Migliaccio, Ilenia; Gebhart, Géraldine; Zoppoli, Gabriele; Bliss, Judith M.; Benelli, Matteo; McCartney, Amelia; Kammler, Roswitha; De Swert, Heidi; Ruepp, Barbara; Fumagalli, Debora; Maibach, Rudolf; Cameron, David; Loi, Sherene; Piccart, Martine; Regan, Meredith M.;
• Is Part Of: European journal of cancer. Volume 164(2022)
• Page Start: 39
• Page End: 51
• Publication Date: 2022-03
• Subjects: Breast cancer -- Serum markers -- Thymidine kinase -- Palbociclib -- Fulvestrant -- Prognostic factors; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.12.030
• Languages: English
• ISSNs: 0959-8049

Abstract

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. Highlights: Thymidine kinase activity (TKa) is a novel circulating biomarker for hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Serum TKa prior to initiating palbociclib + fulvestrant was prognostic. Lack of TKa response at day 15 of treatment may identify primary resistance.