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

Eur J Cancer. 2022 Mar:164:39-51. doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / pathology
  • Cyclin-Dependent Kinase 4
  • Female
  • Fulvestrant / therapeutic use
  • Humans
  • Male
  • Piperazines
  • Prospective Studies
  • Pyridines
  • Thymidine Kinase* / therapeutic use

Substances

  • Piperazines
  • Pyridines
  • Fulvestrant
  • Thymidine Kinase
  • Cyclin-Dependent Kinase 4
  • palbociclib

Associated data

  • ClinicalTrials.gov/NCT02536742
  • EudraCT/2014-005387-15