Abstract PS2-04: Evaluating serum thymidine kinase 1 in hormone receptor positive metastatic breast cancer patients receiving first line endocrine therapy in the SWOG S0226 trial
Authors: Paoletti Costanza , Barlow William E. , Bergqvist Mattias , Mehta Rita S. , Gralow Julie R. , Hortobagyi Gabriel N. , Albain Kathy S. , Pusztai Lajos , Sharma Priyanka , Godwin Andrew K. , Thompson Alastair M. , Hayes Daniel F. , Rae James 
Published: February 2021

Abstract
Background: Endocrine therapies (ETs) are effective in hormone receptor positive metastatic breast cancer (MBC), but resistance is a major clinical problem. Thymidine Kinase 1 (TK1) plays a key role in DNA synthesis and is a marker of cellular proliferation. Serum (sTK1) activity is associated with poor prognosis in MBC patients treated with chemotherapy. SWOG S0226 trial demonstrated that anastrazole (A) + fulvestrant (F) is more effective than A alone in post-menopausal women with hormone receptor positive MBC, specifically those without prior adjuvant tamoxifen (Mehta et al NEJM 2019). We hypothesized that baseline (BL) and serial sTK1 levels are prognostic and demonstrate differential activity of A+F vs. A. Methods: sTK1 activity was assessed in 1,726 archived S0226 serum samples (BL, cycle 2, 3, 4, and 7) using DiviTum® assay (100% evaluation rate). Pre-specified cutoff of ≥200 DiviTum Unit per liter (Du/L) was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier, log-rank tests and Cox regression. Results: Serum samples at BL were available in 432/694 (62%) patients. Outcomes on this subset were comparable to those on the full trial. Median sTK1 at BL was 135 Du/L. sTK1 was elevated in 171 (40%) patients. Overall, patients with high vs. low BL sTK1 had significantly worse PFS [hazard ratio (HR)=1.76; 95% CI (1.43-2.16); P&lt;0.0001; median PFS 11.2 vs.17.3 months]. In patients with no prior adjuvant tamoxifen and high sTK1, PFS was significantly better for those treated with A+F vs. A alone [HR=0.64; 95% CI (0.43-0.95); P=0.027; median PFS 13.6 vs. 8.7 months], whereas PFS did not differ between A+F vs. A alone for those with low sTK1 (P=0.34). Differences in OS for high vs. low sTKI were even more pronounced [HR=2.38; 95% CI (1.91-2.98); p&lt;0.0001; median OS 30 vs. 58 months]. For high sTK1, OS was significantly better for those treated with A+F vs. A alone who did not have prior adjuvant tamoxifen [HR=0.58; 95% CI (0.38-0.87); P=0.0087; 46 vs. 21 months], whereas for low sTK1 there was no difference by therapy (p=0.44). During serial monitoring, patients with high sTK1 had significantly worse subsequent PFS and OS than those with low sTK1 (at cycle 2: PFS HR=1.70, P&lt;0.0001, OS HR=2.51, P&lt;0.0001). Conclusions: High sTK1 at BL and at subsequent time points is associated with worse prognosis in hormone receptor positive MBC patients starting 1st line ET. Patients with low sTK1 at BL may do relatively well on single agent and may not need combination ET. We speculate that patients with low sTK1 need only ET monotherapy and may not benefit from the addition of CDK4/6 or mTOR inhibitors. However, further evaluation of the predictive potential of sTK1 will need prospective clinical trials.
Funding: NIH/NCI grants U10CA180888, U10CA180819, U24CA196175; and in part by AstraZeneca. Biovica has funded the TK1 testing.
Citation Format: Costanza Paoletti, William E. Barlow, Mattias Bergqvist, Rita S. Mehta, Julie R. Gralow, Gabriel N. Hortobagyi, Kathy S. Albain, Lajos Pusztai, Priyanka Sharma, Andrew K. Godwin, Alastair M. Thompson, Daniel F. Hayes, James Rae. Evaluating serum thymidine kinase 1 in hormone receptor positive metastatic breast cancer patients receiving first line endocrine therapy in the SWOG S0226 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-04.