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

Guenther, M.; Haas, M.; Heinemann, V.; Kruger, S.; Westphalen, C. B.; von Bergwelt-Baildon, M.; Mayerle, J.; Werner, J.; Kirchner, T.; Boeck, S.; Ormanns, S.

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 1st-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 1st-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