Abstract P5-01-12: Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy
Authors: Cabel Luc , Tanguy Marie Laure , Lerebours Florence , Brain Etienne , Loirat Delphine , Bergqvist Mattias , Cottu Paul , Donnadieu Anne , Bethune Anne , Rodrigues Manuel , Pierga Jean-Yves , Bidard François-Clément 
Published: March 2020

Background: Thymidine kinase 1 (TK1) has a crucial role in DNA synthesis and cell proliferation. Prior cohort studies reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC) treated by endocrine therapy. We report here the prognostic impact of pTKa, assessed in a prospective study on ER+ HER2- MBC patients treated by endocrine therapy and CDK4/6 inhibitor.

Patients and methods: Patients were included after written informed consent into the prospective, ethically approved ALCINA study (NCT02866149), investigating the feasibility of the analysis of circulating tumor markers in blood in various early- or advanced-stage malignancies. Eligibility criteria were patients aged &gt;18 years with ER+ HER2- MBC, treated at the Institut Curie with endocrine therapy (aromatase inhibitor or fulvestrant) and palbociclib. Plasma samples were obtained at baseline (prior to treatment start) and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden), following the manufacturer recommendations and with blinded patient characteristics and outcomes. We investigated the association between baseline and 4 weeks pTKa, patient characteristics and outcomes (progression-free survival-PFS and overall survival-OS). “Low” and “high” pTKa were defined using the median level of pTKa at each time point. Quantitative pTKa were compared using the Mann-Whitney test. Survival curves were compared by an unstratified log-rank test.

Results: From 05.2016 to 08.2018, 103 patients treated with endocrine therapy and palbociclib were included. Median age was 64 years (range 26-89). Patients had received a median of 2 prior systemic therapies for MBC (range 0-10). After a median follow-up of 13.8 months (range 6-31), 73 relapses (71%) and 25 deaths (24%) were observed, with median PFS and OS of 9.6 months (95%CI[7-11.3]) and 27.9 months (95%CI[22.5-33.2]), respectively.

Median baseline pTKa was 292 Du/L (range 0-27312 Du/L, IQR[89-853]). In univariate analysis, a low baseline pTKa was significantly associated with longer PFS and OS compared with high baseline pTKa (11.7 months (95%CI[7.4-16]) vs 9.1 months [4.4-14]; p=0.02, and NR vs 24.8 months [16-33]; p=0.05, respectively).

After 4 weeks (N=85 patients), median pTKa was 134 Du/L (range 0-3877 Du/L, IQR[43-595]). In univariate analysis, a low pTKa at 4 weeks was also associated with longer PFS and OS compared with high pTKa (10.4 months [7.9-13] vs 4.7 months [1.2-8.3]; p=0.02, and NR vs 20 months [16-23]; p&lt;0.001, respectively). Patients with a PFS below 6months had a significantly higher pTKa level at 4w (median 256 Du/L versus 100Du/L, p=0.046).

After adjusting for prognostic factors (i.e. number of previous lines of systemic treatments, endocrine resistance, presence of visceral metastases, performance status, age, de novo MBC): baseline pTKa and 4w pTKa remained significant prognostic factors for both PFS and OS (p&lt;0.001). Sensitivity analyses suggested that pTKa changes between baseline and 4w had no significant prognostic impact and that 4w pTKa had a superior prognostic impact than baseline pTKa.

Conclusion: pTKa demonstrated its clinical validity as a new dynamic circulating prognostic marker for ER+ HER2- MBC patients treated with endocrine therapy and palbociclib. The clinical utility of this promising biomarker has to be determined in a adequately designed prospective trial of combined targeted and endocrine therapies.

Citation Format: Luc Cabel, Marie Laure Tanguy, Florence Lerebours, Etienne Brain, Delphine Loirat, Mattias Bergqvist, Paul Cottu, Anne Donnadieu, Anne Bethune, Manuel Rodrigues, Jean-Yves Pierga, François-Clément Bidard. Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-12.