Abstract
BackgroundThymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774).MethodsPatients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3–5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels.ResultsDespite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The κ-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement.ConclusionsSerum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation.Trial registrationClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.
Highlights
Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation
Preclinical data indicating cyclin-dependent kinase 4/6 (CDK4/6) inhibition reduces intracellular TK1 activity in a dose-dependent manner To assess the effect of CDK4/6 inhibition on intracellular TK1 activity, the human cell line K562S was cultured in the presence of increasing concentrations of palbociclib (0.1 nM to 10 μM) for 6 h and harvested for DiviTum analysis
CDK4/6 inhibition reduced serum TK1 activity in NeoPalAna trial To determine whether serum TK1 activity could serve as a surrogate marker for CDK4/6 inhibition and tumor cell proliferation in patients receiving CDK4/6 inhibitors, we analyzed the sample set collected from patients with clinical stage II-III estrogen receptor (ER)+/HER2− breast cancer who received neoadjuvant anastrozole and palbociclib in the NeoPalAna trial [19]
Summary
Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Inhibitors against cyclin-dependent kinase 4/6 (CDK4/ 6) are an important new class of agents with substantial antitumor activity in patients with advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer [12,13,14,15,16]. These agents inhibit cell proliferation by activation of retinoblastoma protein, which binds to E2F transcription factors, leading to G0/G1 arrest [17, 18]. The preferential activity of CDK4/6 inhibitors in luminal or HR+ disease is due to the direct link between estrogen receptor (ER) signaling and CDK4/6 activation, because cyclin D is a direct transcription target of ER and other mitogenic signals associated with endocrine resistance [17, 18]
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