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Introduction: Although prognosis and treatment of metastatic breast cancer (MBC) have improved over the last years, there is still an unmet clinical need for more precise prognostic and treatment monitoring tools. Liquid-based markers are preferred since they reflect real-time tumor progression and are not dependent on repeated invasive tissue biopsies. Thymidine kinase 1 (TK1) is an enzyme involved in nucleotide metabolism and has a fundamental role in the DNA synthesis. It can be used as a marker of cell proliferation rate and the TK1 activity has demonstrated correlations to prognosis and usefulness for treatment monitoring in different malignancies. The aim of this study was to determine serum TK1 activity (sTK1) levels measured with the DiviTum assay (Biovica, Sweden), in women with MBC scheduled for 1st line systemic therapy and to evaluate its potential for prediction of outcome and treatment monitoring. Methods: 142 women with MBC scheduled for 1st line systemic treatment and included in a prospective monitoring trial (CTC-MBC, NCT01322893) were evaluated for sTK1 at baseline (BL) and during treatment at 1, 3 and 6 months. 132 patients had at least one follow-up sample. sTK1 activity levels were measured and correlations to important clinicopathological variables and prognosis (PFS and OS) at BL and during treatment were evaluated. Results: The median sTK1 level at BL was 391 u/L (range 10-35520 u/L). When comparing patients with high (above median) versus low (below median) sTK1 levels at BL, high sTK1 levels were found to be associated to worse performance status (p=0.001) and high number of metastatic sites (p=0.03). There was also a statistically significant association between high sTK1 levels and high Ki67 expression in biopsies from metastatic lesions (p=0.038). In univariable analyses high sTK1 levels correlated to worse PFS and OS (HRPFS-BL 2.32, p<0.001; HROS-BL 2.54, p<0.001) at BL. In multivariable analysis adjusted for clinically used prognostic factors, sTK1 was an independent prognostic factor for PFS and OS (HRPFS-BL 2.4, p<0.001; HROS-BL 2.0, p=0.01). During treatment, sTK1 was significantly associated with OS from each of the four time points and onwards (BL, 1, 3, 6 months) (HROS-1m 1.93, p=0.01; HROS-3m 2.35, p=0.02; HROS-6m 2.78, p=0.002) in univariable analysis. High sTK1 levels were also associated with impaired PFS (HRPFS-1m 1.48, p=0.06; HRPFS-3m 1.52, p=0.07; HRPFS-6m 2.03, p=0.009) and these associations were significant at BL and 6 months. Discussion: sTK1 activity level is an independent prognostic factor for PFS and OS in patients with MBC scheduled for 1st line systemic therapy. During treatment, sTK1 is prognostic for OS evaluated from all time-points up to 6 months. The sTK1 effects observed for PFS are slightly weaker, but still propose potential usefulness for treatment monitoring. Further, sTK1 levels correlate to Ki67 expression in metastatic lesions suggesting that it can be useful as a liquid-based real-time proliferation marker. In conclusion, these results are clinically relevant for prognostication and treatment monitoring in patients with MBC. Future studies of sTK1 are justified to further elucidate in what settings this marker is most useful. Citation Format: Larsson A-M, Jansson S, Bendahl P-O, Baker S, Bergqvist M, Aaltonen K, Rydén L. Serum thymidine kinase activity is an independent prognostic factor for progression-free and overall survival in women with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-13.

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Background: Plasma levels of cell-free DNA (cf-DNA) are known to be elevated in sepsis and high levels are associated with a poor prognosis. Mechanical ventilation affects systemic inflammation in which lung-protective ventilation attenuates the inflammatory response. The aim was to study the effect of a lung protective ventilator regime on arterial and organ-specific venous blood as well as on trans-organ differences in cf-DNA levels in a porcine post-operative sepsis model. Method: One group of anaesthetised, domestic-breed, 9-12 weeks old, pigs were ventilated with protective ventilation (V T 6 mL x kg − 1 , PEEP 10 cmH 2 O) n = 20. Another group, ventilated with a medium high tidal volume and lower PEEP, served as a control group (V T 10 mL x kg − 1 , PEEP 5 cm H 2 O) n = 10. Blood samples were taken from four sources: artery, hepatic vein, portal vein and, jugular bulb. A continuous endotoxin infusion at 0.25 μg x kg − 1 x h − 1 for 5 h was started following 2 h of laparotomy, which simulated a surgical procedure. Inflammatory cytokines and cf-DNA in plasma were analysed and trans-organ differences calculated. Results: The protective ventilation group had lower levels of cf-DNA in arterial (p = 0.02) and hepatic venous blood (p = 0.03) compared with the controls. Transhepatic differences in cf-DNA were lower in the protective group, compared with the controls (p = 0.03). No differences between the groups were noted as regards the transcerebral, transsplanchnic or the transpulmonary cf-DNA differences. Conclusions: Protective ventilation suppresses arterial levels of cf-DNA. The liver seems to be a net contributor to the systemic cf-DNA levels, but this effect is attenuated by protective ventilation.