AI Article Synopsis
- TK1 serves as a potential biomarker for response to palbociclib in advanced breast cancer, showing dynamic changes in activity levels related to treatment outcomes.
- The study found that TK1 levels were significantly affected by palbociclib, with notable reductions indicating sensitivity to the drug, while increases in TK1 activity correlated with poorer prognoses.
- Results suggest that monitoring TK1 activity could help identify patients who may need adjustments in their treatment strategies due to resistance to palbociclib.
Article Abstract
Purpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both and in patients with ABC.
Experimental Design: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor-positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the "To Reverse ENDocrine Resistance" (TREnd) trial ( = 46).
Results: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients ( = 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa ( = 33; mPFS 3.0 vs 9.0 months; = 0.002). At T2, mTKa was 251 Du/L; patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months; = 0.05).
Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.
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| http://dx.doi.org/10.1158/1078-0432.CCR-19-3271 | DOI Listing |
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