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Despite improved clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitor treatment has limited the success of this treatment in HR+ HER2- metastatic breast cancer patients. Biomarkers are urgently needed, and longitudinal biomarker measurements may harbor more dynamic predictive and prognostic information compared to single time point measurements. The aim of this study was to explore the longitudinal evolution of circulating tumor fractions within cell-free DNA assessed by an untargeted sequencing approach during CDK4/6 therapy and to quantify the potential association between longitudinal z-score measurements and clinical outcome by using joint models. Forty-nine HR+ HER2- metastatic breast cancer patients were enrolled, and z-score levels were measured at baseline and during 132 follow-up visits (median number of measurements per patient = 3, 25th -75th percentile: 3-5, range: 1-8). We observed higher baseline z-score levels (estimated difference 0.57, 95% CI: 0.147-0.983, P-value = 0.008) and a constant increase of z-score levels over follow-up time (overall P-value for difference in log z-score over time = 0.024) in patients who developed progressive disease. Importantly, the joint model revealed that elevated z-score trajectories were significantly associated with higher progression risk (HR of log z-score at any time of follow-up = 3.3, 95% CI, 1.44-7.55, P = 0.005). In contrast, single z-score measurement at CDK4/6 inhibitor treatment start did not predict risk of progression. In this prospective study, we demonstrate proof-of-concept that longitudinal z-score trajectories rather than single time point measurements may harbor important dynamic information on the development of disease progression in HR+ HER2- breast cancer patients undergoing CDK4/6 inhibitor treatment.

The aim of this study was to detect risk factors for febrile neutropenia (FN) in patients with testicular germ cell tumors (TGCT). In this retrospective cohort study at the Medical University of Graz, we included 413 consecutive TGCT patients who received adjuvant or curative treatment with cisplatin‐based chemotherapy. FN occurred in 70 (16.9%) of 413 patients. In univariable logistic regression, higher age (odds ratio (OR) per 5 years = 1.17, 95% CI: 1.02–1.35, P = 0.022), reduced performance status (PS) (OR = 2.73, 1.47–5.06, P = 0.001), seminomatous histology (OR = 2.19, 1.26–3.78, P = 0.005), poor IGCCCG risk class (OR = 4.20, 1.71–10.33, P = 0.002), and prior radiotherapy (pRTX) (OR = 8.98, 2.09–38.61, P = 0.003) were associated with a higher risk of FN. In multivariable analysis adjusting for age and risk classification, only poor PS (OR = 2.06, 1.05–4.03, P = 0.035), seminomatous histology (OR = 2.08, 1.01–4.26, P = 0.047), and pRTX (OR = 7.31, 1.61–33.17, P = 0.010) prevailed. In the subgroup of seminoma patients (n = 104), only pRTX predicted for FN risk (OR = 5.60, 1.24–25.34, P = 0.025). Five of eight seminoma patients with pRTX developed FN (63%), as compared to 22 FN cases (23%) in the 96 seminoma patients without pRTX (P = 0.027). The eight seminoma patients who received pRTX had significantly lower pre‐chemo white blood counts (4.7 vs. 6.5 G/L), neutrophil counts (3.2 vs. 4.3 G/L), and platelet counts (185 vs. 272 G/L) than patients without pRTX (all P