Circulating free bacterial DNA as a novel biomarker for monitoring therapy response in patients with advanced pancreatic cancer.

BACKGROUND: Monitoring therapy response in pancreatic cancer (PDAC) remains challenging. The microbiome affects therapy efficacy, but its role in response prediction is unclear. We assessed whether changes in circulating free bacterial DNA (cfbDNA) levels predict outcome of advanced PDAC (aPDAC) patients treated with systemic chemotherapy. PATIENTS AND METHODS: We analyzed the prognostic impact of serum cfbDNA dynamics of 13 patients with aPDAC receiving mFOLFIRINOX (FFX) before treatment initiation and after two chemotherapy cycles. We validated the findings in the samples of 47 patients with locally advanced pancreatic cancer from the NEOLAP-AIO-PAK-0113 trial. RESULTS: Decreased cfbDNA during FFX treatment was associated with improved PFS (14.3 vs. 2.9 months; p < 0.001) and OS (23.2 vs. 8.4 months; p = 0.006) in the exploratory cohort. Equal or increased cfbDNA was associated with inferior OS in univariate analyses (HR, 7.74; 95% CI, 1.38-43.24; p = 0.020) and a model adjusted for CA-19-9 group (HR, 11.75; 95% CI, 1.87-73.85; p = 0.009). In the NEOLAP cohort, decreased cfbDNA was associated with improved PFS (12.4 vs. 8.7 months, p = 0.003) and OS (39.8 vs. 14.7 months, p = 0.001) in FFX treated patients, whereas in patients continuing on gemcitabine plus nab-paclitaxel (GnP), decreased cfbDNA was associated with shorter PFS (6.2 vs. 11.5 months, p < 0.001) and OS (12.9 vs. 18.8 months, p = 0.013). CONCLUSIONS: cfbDNA dynamics may serve as blood-based biomarker for monitoring therapy response in aPDAC. Its treatment-dependent predictive impact may inform clinical decisions. These findings suggest therapy-specific host-microbiome-tumor interactions and warrant prospective validation. CLINICAL TRIAL NUMBER: NCT02125136.