Intratumoral bacterial abundance confers poor response to adjuvant gemcitabine in resected pancreatic cancer patients which is mitigated by postoperative antibiotics.

BACKGROUND: Adjuvant gemcitabine (aGC) is still a therapeutic mainstay after resection of pancreatic ductal adenocarcinoma (PDAC), but its efficacy is impaired by gram-negative intratumoral bacteria, suggesting a potential therapeutic implication of additive antibiotics. PDAC however, contains several other bacterial strains capable of gemcitabine degradation. METHODS: Using immunohistochemistry and fluorescence-in-situ-hybridization on the samples of a large cohort of resected PDAC patients, we examined how the intratumoral bacterial abundance affected patient outcomes with respect to aGC therapy and whether the use of pre- or postoperative antibiotics (ABT) improved the prognosis. We confirmed the findings in several independent external cohorts. RESULTS: High intratumoral bacterial abundance impaired aGC efficacy (disease free survival (DFS) 9.4 vs 19.1 months, p < 0.001; overall survival (OS) 19.4 vs 34.0 months, p < 0.001), which was mitigated by postoperative ABT application (DFS 7.9 vs 12.4 months, p < 0.001, OS 15.2 vs 29.6 months, p < 0.001). Postoperative ABT improved outcome of patients with low bacterial abundance in their tumors (DFS 15.1 vs 34.8 months, p < 0.001, OS 28.5 vs 56.00 months, p < 0.001). CONCLUSIONS: High intratumoral bacterial abundance may predict poor response to adjuvant gemcitabine treatment, whereas postoperative ABT improves it. We propose postoperative ABT as potential additive treatment before or during aGC therapy after PDAC resection.