Biovica (Sweden)

Background Some patients with metastatic breast cancer (MBC) stay on endocrine therapy (ET) for years and others progress quickly. Serum thymidine kinase activity (TKa), an indicator of cell-proliferation, is a potential biomarker for monitoring ET and predicting MBC outcome. We have previously reported TKa as being prognostic in MBC in SWOG S0226. Here, new data on progression within 30/60 days post sampling, with a new, FDA approved version of DiviTum®TKa highlighting differences vs. a Research Use Only version is reported. Methods 1,546 serum samples from 454 patients were assessed, collected at baseline and at 4 subsequent timepoints during treatment. A new predefined cut-off tested the ability to predict disease progression. A new measuring unit, DuA (DiviTum® unit of Activity) is adopted. Results A DiviTum®TKa score <250 DuA provides a much lower risk of progression within 30/60 days after blood draw, the negative predictive value (NPV) was 96.7% and 93.5%, respectively. Patients <250 DuA experienced significantly longer progression-free survival and overall survival, demonstrated at baseline and for all time intervals. Conclusions DiviTum®TKa provides clinically meaningful information for patients with HR+ MBC. Low TKa levels provide such a high NPV for rapid progression that such patients might forego additional therapy added to single agent ET. Trial registration: NCT00075764

Abstract Background: Thymidine kinase 1 (TK1) is a fundamental enzyme in DNA synthesis. TK1 expression is E2F-dependent and peaks in the S-phase of the cell cycle. In preclinical studies, inhibition of cyclin-dependent kinase (CDK) 4/6 led to dose dependent reduction of TK1 activity in cultured media. We hypothesized that serum TK1 could serve as a non-invasive surrogate marker of cell proliferation in patients (pts) receiving CDK4/6 inhibitors. In this study, we examined serum TK1 activity from breast cancer (BC) pts enrolled on a neoadjuvant study of palbociclib (Palbo) plus anastrozole (A), for changes induced by Palbo, and correlated with changes in tumor Ki67. Methods: In this phase II neoadjuvant study, 50 pts with clinical stage II or III estrogen receptor positive (ER+) HER2- BC, received A (in combination with goserelin if premenopausal) alone for 28 days in cycle 0 (C0), followed by the addition of Palbo (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for 4 28-day cycles (C1 to C4) unless C1D15 tumor Ki67&amp;gt;10%, in which case pts went off study. Following completion of cycle 4, A was continued for another 3-5 weeks to allow Palbo washout prior to surgery, except in 8 pts who received an additional 10-12 days of Palbo immediately prior. Blood and tumor biopsies were collected at 4 time points: baseline, C1D1, C1D15, and surgery. Serum TK1 activity was measured using the highly sensitive Divitum™ assay according to the Divitum™ Instructions for use (Biovica, Sweden). Tumor Ki67 IHC was performed at the Washington University AMP laboratory using the CONFIRM anti-Ki67 rabbit monoclonal antibody (clone 30-9), and pathologist guided image analysis. Results: There was no statistically significant difference in TK activity between baseline and C1D1 serum samples (Table 1). However, serum TK activity decreased significantly from C1D1 to C1D15 following the addition of Palbo and increased significantly from C1D15 to surgery following Palbo washout (Table 1), indicating a significant effect of Palbo on TK activity. At C1D15, TK activity was below the detection limit of 20 Du/L in 44 of 48 pts, and was at low levels (24, 26, 26, and 58 Du/L) in the remaining 4 pts, indicating a profound effect by Palbo. Interestingly, the TK activities of the 4 pts with tumor Ki67 &amp;gt;10% at C1D15 were all below 20 Du/L, suggesting the possibility of tumor cell proliferation independent of CDK4/6 inhibition. The sensitivity and specificity of change (increase/decrease) in serum TK activity to predict tumor Ki67 (increase/decrease) induced by Palbo were 83% (19/23, 95%CI: 66-99%) and 93% (26/28, 95%CI: 83%-100%), respectively. The Kappa statistic was 0.761 (P&amp;lt;0.001), indicating substantial agreement between the two tests. Conclusions: Serum TK1 activity may serve as a pharmacodynamics marker of CDK4/6 inhibition and further investigation is warranted. Table 1. Serum TK1 and tumor Ki67 Serum TKKi67 Median (IQR) (Du/L)NMedian (IQR) (%)NBaseline46 (25-73)4824.34% (11.92%-35.43%)45Cycle 1 day 143 (27.5-98)495.37% (2.49%-13.59%)*45Cycle 1 day 1520 (20-20)*480.78% (0.23%-1.05%)*45Day of surgery136.0 (37.5-259)*378.33% (2.25%-23.03%)*34*P&amp;lt;0.001 compared to the preceding time point. Citation Format: Liu N, Thomas S, Luo R, Hoog J, Suh EM, Bergqvist M, Neumüller M, Guo Z, Vij K, Sanati S, Ellis M, Ma C. Serum thymidine kinase 1 activity as a pharmacodynamics marker of cyclin-dependent kinase 4/6 inhibition in patients with early stage breast cancer receiving neoadjuvant palbociclib [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-04-02.