Serum thymidine kinase activity in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole: Results from the prospective BioItaLEE trial

• Published in: European journal of cancer (1990) Vol. 186; pp. 1 - 11
• Main Authors: Malorni, Luca, Bianchini, Giampaolo, Caputo, Roberta, Zambelli, Alberto, Puglisi, Fabio, Bianchi, Giulia V., Del Mastro, Lucia, Paris, Ida, Montemurro, Filippo, Allegrini, Giacomo, Colleoni, Marco, Tamberi, Stefano, Zamagni, Claudio, Cazzaniga, Marina E., Orditura, Michele, Guarneri, Valentina, Castelletti, Daniela, Benelli, Matteo, Di Marino, Mariacristina, Arpino, Grazia, De Laurentiis, Michelino
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2023
• Subjects: Advanced breast cancer; Aminopyridines - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Aromatase Inhibitors - therapeutic use; Biomarker; Biomarkers; Breast Neoplasms - pathology; Female; Humans; Letrozole; Letrozole - therapeutic use; Proportional Hazards Models; Prospective Studies; Receptor, ErbB-2 - metabolism; Ribociclib; Thymidine kinase; Thymidine Kinase - therapeutic use; Ribociclib; Thymidine kinase; Biomarker; Advanced breast cancer; Letrozole
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2023.03.001

Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis; serum TK1 activity (sTKa) is a novel liquid biopsy biomarker of tumour cell proliferation. The phase IIIb, BioItaLEE trial (NCT03439046) collected sera from postmenopausal patients with hormone receptor–positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC) treated with first-line ribociclib plus letrozole at baseline, day 15 of cycle 1 (C1D15), day 1 of cycle 2 (C2D1), and at first imaging. Associations between sTKa assessed at different time points or sTKa dynamic patterns, and progression-free survival (PFS) were evaluated using multivariate Cox models. Overall, 287 patients were enroled. Median follow-up was 26.9 months. High sTKa (>median) at baseline was associated with higher risk of progression (hazard ratio [HR], 2.21; 95% confidence interval [95% CI], 1.45, 3.37; P = 0.0002); similar results were observed for patients with high sTKa levels at C1D15 and C2D1. Early sTKa dynamic patterns were strongly predictive of PFS. The pattern with high sTKa levels at C2D1 following initial decrease at C1D15 was associated with higher risk of progression versus the pattern with low sTKa levels at both time points (HR, 2.89; 95% CI, 1.57, 5.31; P = 0.0006), while the pattern with high sTKa levels at C1D15 was associated with the shortest PFS (HR, 5.65; CI: 2.84, 11.2; P < 0.0001). Baseline and dynamic sTKa changes provided independent information. sTKa appears to be a new promising prognostic and pharmacodynamic biomarker in patients with HR+/HER2– ABC treated with ribociclib plus letrozole as first-line therapy. •sTKa is a biomarker of outcome in ribociclib plus letrozole-treated HR+, HER2– ABC.•sTKa levels are strongly prognostic of mPFS at different time points.•sTKa early dynamic changes predict mPFS independently of prognosis by baseline sTKa.•sTKa early dynamic changes may be associated with inherent underlying tumour biology.