"Sandro Pitigliani" Translational Research Unit and Medical Oncology Department, Hospital of Prato, Prato, Italy.
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.
Eur J Cancer. 2022 Mar;164:39-51. doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13.
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.
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.
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.
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.
NCT02536742; EudraCT 2014-005387-15.
细胞周期蛋白依赖性激酶 4/6 抑制剂（如帕博西利）的生物标志物对于激素受体阳性/HER2 阴性转移性乳腺癌患者仍然缺乏。胸苷激酶是细胞周期蛋白依赖性激酶 4/6 通路下游的增殖标志物。我们前瞻性地研究了血清胸苷激酶活性（sTKa）在接受帕博西利联合氟维司群治疗的患者中的预后作用。
PYTHIA 是一项 II 期、单臂、多中心的试验，共纳入 124 例绝经后激素受体阳性/HER2 阴性转移性乳腺癌患者。在治疗前（pre-trt；n=122）、第 1 周期第 15 天（D15；n=108）、第 2 周期开始前的 1 周停药期间（D28；n=108）和治疗结束时（n=76）采集血清样本。sTKa 采用 Divitum®进行中心检测，这是一种改良的 ELISA 检测方法，检测限为 20 个 Divitum 单位（Du）/L。主要研究终点为无进展生存期，评估其与治疗前和治疗期间 sTKa 的关系。
分析了 122 名女性的数据。治疗前 sTKa 与临床特征无关，与组织 Ki-67 中度相关。帕博西利联合氟维司群治疗在 D15 时明显抑制了 sTKa 水平，83%的患者检测不到 sTKa 水平。在 D28 时，60%的患者出现 sTKa 反弹。在每个时间点，较高的 sTKa 与较短的无进展生存期相关（每个 p<0.001），在 D15 时作用最强。
sTKa 是接受帕博西利治疗的患者的独立预后生物标志物。较高的治疗前 sTKa 和治疗期间不完全抑制可能会识别出预后较差和原发性耐药的患者。这需要在前瞻性比较试验中进行验证。临床试验。
NCT02536742；EudraCT 2014-005387-15。
