Reviews on circulating biomarkers in breast cancer usually focus on one single biomarker or a selective group of biomarkers. An overview summarizing the discovery and evaluation of all blood-based biomarkers in metastatic breast cancer is lacking. This systematic review aims to identify the available evidence of known blood-based biomarkers in metastatic breast cancer, regarding their clinical utility and state-of-the-art position in the validation process. The initial search yielded 1078 original studies, of which 420 were assessed for eligibility. A total of 320 studies were included in the final synthesis. A Development, Evaluation and Application Chart (DEAC) of all biomarkers was developed. Most studies focus on identifying new biomarkers and search for relations between these biomarkers and traditional molecular characteristics. Biomarkers are usually investigated in only one study (68.8%). Only 9.8% of all biomarkers was investigated in more than five studies. Circulating tumor cells, gene expression within tumor cells and the concentration of secreted proteins are the most frequently investigated biomarkers in liquid biopsies. However, there is a lack of studies focusing on identifying the clinical utility of these biomarkers, by which the additional value still seems to be limited according to the investigated evidence.

Procalcitonin (PCT) testing can help in safely reducing antibiotic treatment duration in intensive care patients with sepsis. However, the cost-effectiveness of such PCT guidance is not yet known. A trial-based analysis was performed to estimate the cost-effectiveness of PCT guidance compared with standard of care (without PCT guidance). Patient-level data were used from the SAPS trial in which 1546 patients were randomised. This trial was performed in the Netherlands, which is a country with, on average, low antibiotic use and a short duration of hospital stay. As quality of life among sepsis survivors was not measured during the SAPS, this was derived from a Dutch follow-up study. Outcome measures were (1) incremental direct hospital cost and (2) incremental cost per quality-adjusted life year (QALY) gained from a healthcare perspective over a one-year time horizon. Uncertainty in outcomes was assessed with bootstrapping. Mean in-hospital costs were €46,081/patient in the PCT group compared with €46,146/patient with standard of care (i.e. − €65 (95% CI − €6314 to €6107); − 0.1%). The duration of the first course of antibiotic treatment was lower in the PCT group with 6.9 vs. 8.2 days (i.e. − 1.2 days (95% CI − 1.9 to − 0.4), − 14.8%). This was accompanied by lower in-hospital mortality of 21.8% vs. 29.8% (absolute decrease 7.9% (95% CI − 13.9% to − 1.8%), relative decrease 26.6%), resulting in an increase in mean QALYs/patient from 0.47 to 0.52 (i.e. + 0.05 (95% CI 0.00 to 0.10); + 10.1%). However, owing to high costs among sepsis survivors, healthcare costs over a one-year time horizon were €73,665/patient in the PCT group compared with €70,961/patient with standard of care (i.e. + €2704 (95% CI − €4495 to €10,005), + 3.8%), resulting in an incremental cost-effectiveness ratio of €57,402/QALY gained. Within this time frame, the probability of PCT guidance being cost-effective was 64% at a willingness-to-pay threshold of €80,000/QALY. Although the impact of PCT guidance on total healthcare-related costs during the initial hospitalisation episode is likely negligible, the lower in-hospital mortality may lead to a non-significant increase in costs over a one-year time horizon. However, since uncertainty remains, it is recommended to investigate the long-term cost-effectiveness of PCT guidance, from a societal perspective, in different countries and settings.