Plasma thymidine kinase 1 activity and outcome of ER+ HER2− metastatic breast cancer patients treated with palbociclib and endocrine therapy

Abstract

Purpose Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2− MBC patients treated with endocrine therapy and CDK4/6 inhibitor. Experimental design Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2− MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden). Results From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0–14). Median follow-up was 13.8 months (range 6–31), with median PFS and OS of 9.6 months (95%CI [7.0–11.3]) and 28 months (95%CI [23–not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20–27,312 Du/L, IQR [89–853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1–1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2–1.6], p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI [1.3–2], p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction. Conclusion This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2− MBC patients treated with endocrine therapy and palbociclib.

Systematic Review of Molecular Biomarkers Predictive of Resistance to CDK4/6 Inhibition in Metastatic Breast Cancer

“… 45 Preliminary data from recent conference proceeding with larger patient cohorts suggest that plasma TK1 enzyme activity could be a prognostic biomarker for clinical response to palbociclib treatment, with TK1 activity levels potentially providing a dynamic marker for drug response at earlier time points to recognize the emergence of treatment resistance. 51 , 52…”

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer

“…In contrast, tissue-based biomarkers are characterized by the need to obtain new biopsies, analytical difficulties such as non-representative material or poor cellularity, and interobserver variability, although standardization improves yield and their performance. 38 Literature on TK1 activity suggests that it may have diverse interpretations: proliferation, monitoring during treatment, response to therapy or even resistance to cyclin-dependent kinase 4/6 inhibitors, 39 , 40 , 41 depending on the clinical setting in which it is assessed. No available data, however, answer the question whether changes in proliferation during NACT can exclusively explain the prognostic value of TK1 and its kinetics.…”

Circulating Biomarkers of CDK4/6 Inhibitors Response in Hormone Receptor Positive and HER2 Negative Breast Cancer

“…The prognostic role of TKa was further evaluated in 103 plasma samples obtained from ER+/HER2- MBC patients treated with ET and palbociclib within ALCINA study [ 66 ]. In this study, baseline TKa was an independent poor prognostic marker of PFS and OS.…”

“…In this study, baseline TKa was an independent poor prognostic marker of PFS and OS. Additionally, TKa at 4-week was associated with OS [ 66 ], while adding the changes in TKa at 4 weeks compared to baseline did not further increase prediction.…”