Plasma Thymidine Kinase Activity as a Biomarker in Patients with Luminal Metastatic Breast Cancer Treated with Palbociclib within the TREnd Trial

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 in vitro 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 (n ¼ 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 (n ¼ 8) showing an increase-correlating with a worse outcome than those with decreased/stable TKa (n ¼ 33; mPFS 3.0 vs 9.0 months; P ¼ 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; P ¼ 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.

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

“…In contrast, no significant association was observed between baseline pTKa and PFS. In the present study, we did not find a predictive impact of the variation of pTKa between baseline and 4 weeks, regardless of the increase/decrease cutoff used (data not shown), unlike these other studies [13,24,25]. These contradictory results could be explained by several factors.…”

“…The EFECT trial [13] suggested that patients whose sTKa increased from baseline while on endocrine therapy had a significantly shorter time to progression (3.39 months, 95%CI 2.14-4.11) than those in whom sTKa did not increase (5.39 months, 95%CI 4.01-6.68) (p = 0.0045). More recently, the TREnd trial [25] showed a significant correlation between the 4-week variation of pTKa and PFS in ER+/HER2− MBC patients treated with palbociclib (alone or in combination with endocrine therapy following progression during a previous line of therapy). In the TREnd study, pTKa increase (n = 33 patients) was associated with shorter PFS (median PFS for the group with increasing pTKa = 3.0 months, 95%CI [2.7-NA] versus 9 months for stable or decreasing pTKa, 95%CI [5.8-12.0], p = 0.002).…”

Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

“…Specifically, we observed alterations in nucleotide metabolism in MCF7/pS vs. MCF7/pR cells. Importantly, these results are in line with previous reports indicating that increased expression of thymidine kinase-1 (TK1), an enzyme of the pyrimidine salvage pathway, correlates with poor prognosis in breast cancer patients treated with palbociclib [52][53][54][55].…”

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

“…The hypothesis that baseline TKa or early changes in TKa levels might be prognostic in patients with HR+/HER2− MBC treated with CDK4/6i was then explored in TREnd [ 29 ]. In this trial, comparing the efficacy and safety of single-agent palbociclib vs. palbociclib plus the ET previously received for MBC, baseline TKa was not a poor prognostic factor.…”

“…In this trial, comparing the efficacy and safety of single-agent palbociclib vs. palbociclib plus the ET previously received for MBC, baseline TKa was not a poor prognostic factor. However, patients showing an increase in TKa after one month of treatment had a worse PFS compared to those without increase, suggesting TKa dynamics might have a role as an early marker of resistance to palbociclib [ 29 ].…”