292P Serum thymidine kinase 1 activity in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first-line with ribociclib (R) and letrozole (L) in the BioItaLEE trial

Abstract

Thymidine kinase 1 (TK1) is an enzyme downstream of the CDK4/6 pathway, with a critical role in DNA synthesis and cell proliferation. We assessed serum TK1 activity (TKa) as a prognostic and predictive biomarker of response to R+L. 287 postmenopausal patients (pts) were enrolled in the BioItaLEE trial (NCT03439046). Sera were collected at baseline (D0; n=263), day 15 of cycle 1 (D15; n=245), day 1 of cycle 2 (C2D1; n=241), and at first imaging (FI; n=203). TKa was measured with DiviTum®, an ELISA-based assay, with a limit of detection (LOD) of 20 DiviTum units (Du)/L. The predictive role of TKa dynamics was explored by defining three patterns (P): P1, TKa <LOD at D15 and C2D1; P2, TKa <LOD at D15 and >LOD at C2D1; P3, TKa >LOD at D15 and C2D1. Multivariate Cox models assessed the association between biomarkers and progression-free survival (PFS). Median follow-up was 26.9 months. High TKa (>median) at D0 was associated with poor prognosis (HR for disease progression 2.21; 95% CI 1.45,3.37; p=0.0002), whereas only 4% of pts with low TKa at FI had concomitant disease progression. Robust and complex TKa dynamics were observed, with a decrease below LOD seen in 85%, 29% and 40% of pts at D15, C2D1 and FI, respectively; 65% of pts with TKa <LOD at D15 had TKa >LOD at C2D1 (P2). TKa dynamics were strongly predictive of PFS: P2 indicated a worse outcome vs P1 (HR 2.89; 95% CI 1.57,5.31; p=0.0006), while P3 was associated with shortest PFS (HR 5.65; CI 2.84,11.2; p<0.0001). For pts in P2, low TKa (<median) at D0 correlated with a better PFS vs high TKa (HR=3.47; 95% CI 1.64,7.36; p=0.001). TKa appears to be a new promising prognostic, predictive and monitoring biomarker in pts with HR+/HER2- aBC treated with R+L as first-line therapy. Baseline and dynamic TKa changes provided independent information. Lack of TKa suppression at D15, as seen in P3, may indicate enrichment for primary resistance and poor prognosis. TKa rebound at C2D1, as seen in P2, may indicate early adaptation to R+L, while persistent suppression as observed in P1 may identify pts with sustained inhibition and excellent prognosis.