Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0913-7) contains supplementary material, which is available to authorized users.

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

“…Abemaciclib was FDA approved in September 2017 in combination with fulvestrant as a second-line treatment after the phase II MONARCH-2 trial (Sledge et al 2017) and as monotherapy after progression on endocrine therapy and chemotherapy from the phase II MONARCH-1 trial . It was later approved in February 2018 in combination with letrozole as first-line treatment based on results from the phase III MONARCH-3 trial (Goetz et al 2017).…”

“…One possible explanation may be that p19 INK4D is transcribed downstream of E2F activity due to non-functional Rb, and further E2F targets, cyclin D3 and CDKN2D were also identified in the patients with refractory tumours. The same group subsequently identified that another E2F target, thymidine kinase 1, may be useful as a pharmacodynamic biomarker to monitor the initial patient response to CDK4/6 inhibitors (Bagegni et al 2017).…”

“…The clinical efficacy of endocrine therapy doublet combination therapy with mTOR, PI3K, and CDK4/6 inhibitors (Baselga et al 2012, Finn et al 2015, Finn et al 2016, Goetz et al 2017, Sledge et al 2017, Slamon et al 2018, and the cross talk between these pathways (Fig. 2), have led to the logical development of clinical trials of triplet therapy combinations of CDK4/6 and PI3K pathway inhibitors with an endocrine therapy backbone (Table 3).…”

Statistical and Bioinformatic Analysis of Hemimethylation Patterns in Lung Cancer

“…GNAS is observed in both tumor and normal samples, as well as in the hemimethylation study for breast cancer cell lines [8]. MEIS1 is also a hub gene that interacts with genes like KMT2A [39] and TK1 [40]. While these genes are not hemimethylated in our samples, they are known to be associated with cancer.…”

Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm

“…TK-1 overexpression is similarly observed in cancer models, 30,31 and its association with the Ki67 proliferation index has been demonstrated in various cancers. [32][33][34] Interestingly, AAA [ 18 F]FLT uptake was observed after 14 days of AngII infusion, when aneurysms expand, but this effect was weaker after 28 days, when the growth phase begins to plateau, suggesting decreased cell proliferation in late-stage AAA. This supports the idea of early-stage cellular remodeling leading to late-stage replicative senescence, which has been reported in end-stage human AAA samples.…”