Bacterial lipopolysaccharide as negative predictor of gemcitabine efficacy in advanced pancreatic cancer – translational results from the AIO-PK0104 phase 3 study

ABSTRACT Background Gram-negative bacteria mediated gemcitabine resistance in pre-clinical models. We determined if intratumoral lipopolysaccharide (LPS) detection by immunohistochemistry is associated with outcome in advanced pancreatic ductal adenocarcinoma (PDAC) treated with gemcitabine and non-gemcitabine containing 1 st -line chemotherapy. Methods We examined LPS on tumor tissue from 130 patients treated within the randomized phase 3 trial AIO-PK0104 and a validation cohort ( n =113) from a prospective biomarker study and analyzed the association of LPS detection to patient outcome according to treatment subgroups. Results In 24% of samples from the AIO-PK0104 study LPS was detected; in LPS-positive patients median OS was 4.4 months, compared to 7.3 months with LPS negative tumors (HR 1.732, p =0.010). A difference in OS was detected in the subgroup of patients treated with 1 st -line gemcitabine-based treatment (n=71; HR 2.377, p =0.002), whereas no difference in OS was observed in the non-gemcitabine subgroup (n=59; HR 1.275, p =0.478). Within the validation cohort, the LPS positivity rate was 23%, and LPS detection was correlated with impaired OS in the gemcitabine subgroup (n=94; HR 1.993, p =0.008) whereas no difference in OS was observed in the non-gemcitabine subgroup (n=19; HR 2.596, p =0.219). Conclusions The detection of intratumoral LPS as a surrogate marker for gram-negative bacterial colonization may serve as a negative predictor for gemcitabine efficacy in advanced PDAC. Clinical trial registry NCT00440167