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Bacterial Lipopolysaccharide as a Negative Predictor of Adjuvant Gemcitabine Efficacy in Pancreatic Cancer.

ABSTRACT: Adjuvant gemcitabine (aGC) is one standard of care after pancreatic ductal adenocarcinoma (PDAC) resection. No biomarker for its efficacy is established. As bacteria mediate gemcitabine resistance, we analyzed whether lipopolysaccharide (LPS) as surrogate for bacterial colonization is prognostic in PDAC patients treated with aGC or without aGC adjuvant gemcitabine. We detected LPS in 86 tumors from 376 patients, which defined a specific microbiome as revealed by 16 s-rRNA-sequencing. In the 230 aGC patients, LPS conferred worse disease-free survival (8.3 vs 13.7 months; hazard ratio = 1.75, 95% confidence interval = 1.22 to 2.49; log-rank P = .002) and overall survival (21.7 vs 28.5 months; hazard ratio = 1.80, 95% confidence interval = 1.23 to 2.57; log-rank P = .001) but not in the 146 naGC patients, which was confirmed in an independent validation cohort (n = 178). LPS may serve as a negative predictor for aGC efficacy in PDAC, which suggests a role for microbiome modification to overcome bacteria-mediated chemotherapy resistance.

SUBMITTER: Guenther M

PROVIDER: S-EPMC9219162 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Bacterial Lipopolysaccharide as a Negative Predictor of Adjuvant Gemcitabine Efficacy in Pancreatic Cancer.

Guenther Michael M Gil Lina L Surendran Sai Agash SA Palm Melanie Alexandra MA Heinemann Volker V von Bergwelt-Baildon Michael M Mayerle Julia J Engel Jutta J Werner Jens J Boeck Stefan S Ormanns Steffen S

JNCI cancer spectrum 20220501 3

Adjuvant gemcitabine (aGC) is one standard of care after pancreatic ductal adenocarcinoma (PDAC) resection. No biomarker for its efficacy is established. As bacteria mediate gemcitabine resistance, we analyzed whether lipopolysaccharide (LPS) as surrogate for bacterial colonization is prognostic in PDAC patients treated with aGC or without aGC adjuvant gemcitabine. We detected LPS in 86 tumors from 376 patients, which defined a specific microbiome as revealed by 16 s-rRNA-sequencing. In the 230 ...[more]

PMID: 35587155

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Project description:BackgroundDespite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy.Methods/designThis is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m(2)) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist.DiscussionThe NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head.Trial registrationclinicalTrials.gov NCT01314027.

Project description:BackgroundPancreatic cancer is a highly malignant tumor with a poor prognosis. Chemotherapy such as gemcitabine is still an important treatment. Gemcitabine (Gem) may prolong survival time and delay the development of recurrent disease after complete resection of pancreatic cancer. Currently, some control studies have been performed between certain drugs and gemcitabine monotherapy after pancreatic cancer surgery, but the outcomes were uncertain. Here, we implemented meta-analysis to compare the efficacy between adjuvant treatments and gemcitabine monotherapy in patients with resected pancreatic cancer.MethodsPubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library searches were undertaken to identify randomized controlled trials (RCTs). Date of search ranged from January 1997 to December 2017. The meta-analysis included six RCTs. The major endpoints involved overall survival (OS), disease-free survival/progress free survival/relapse-free survival (DFS/PFS/RFS) and grade 3-4 toxicity.ResultsPooled meta-analytic estimates were derived using random-effects model. Subgroup analysis used fixed-effects model. The outcome showed that there was no difference in OS (hazard ratio (HR), 0.87; 95% CI, 0.70-1.07; P = 0.19) and DFS (HR, 0.85; 95% CI, 0.71-1.02; P = 0.08) between the adjuvant treatments group (fluorouracil+folinic acid, S-1, gemcitabine+capecitabine, gemcitabine+erlotinib and gemcitabine+uracil/tegafur) and Gem monotherapy group. However, the subgroup analysis showed that only S-1 chemotherapy, which is an oral fluoropyrimidine agent containing tegafur, gimeracil and oteracil, was significant in OS (HR, 0.59; 95% CI, 0.46-0.74; P < 0.0001) and DFS (HR, 0.63; 95% CI, 0.52-0.75; P < 0.00001) compared with Gem alone. Toxicity analysis showed there was an increased incidence of grade 3/4 diarrhea (risk ratio (RR), 5.11; 95%CI, 3.24-8.05; P < 0.00001) and decreased incidence of grade 3/4 leucopenia (RR, 0.55; 95%CI, 0.31-0.98; P = 0.04), thrombocytopenia (RR, 0.61; 95%CI, 0.39-0.97; P = 0.04) in adjuvant treatments group. Neutropenia (RR, 0.69; 95%CI, 0.36-1.29; P = 0.24) and fatigue (RR, 1.29; 95%CI, 0.95-1.77; P = 0.11) for patients between the two groups were not significantly different.ConclusionsIn our meta-analysis, a significant survival benefit is only observed in the S-1 regimen, but the results are yet to be determined. Optimal cytotoxicity or targeted drug regimens need further validation in clinical trials in the future.

Dataset Information

Bacterial Lipopolysaccharide as a Negative Predictor of Adjuvant Gemcitabine Efficacy in Pancreatic Cancer.

Publications

Bacterial Lipopolysaccharide as a Negative Predictor of Adjuvant Gemcitabine Efficacy in Pancreatic Cancer.

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