A specific panel of fecal microbiota is highly sensitive at distinguishing pancreatic ductal adenocarcinoma (PDAC) from other high-risk disease types, including chronic pancreatitis and type 2 diabetes.
Moreover, the panel can identify PDAC regardless of disease stage, say reserachers reporting results from a case-control series of studies.
"Fecal microbiome-based detection of PDAC may provide a non-invasive, cost-effectiveness and robust approach to early PDAC-diagnosis," senior author Peer Bork, MD, European Molecular Biology Laboratory, Heidelberg, Germany, and colleagues observe.
"We developed metagenomic classifiers that robustly and accurately predict PDAC solely based on characteristic fecal microbial species," they add.
The study was published online March 7 in the journal Gut.
Commenting in an accompanying commentary, Rachel Newsome, MD, and Christian Jobin, MD, both from the University of Florida in Gainesville, Florida, point out that PDAC is associated with an extremely poor prognosis, so early detection is an essential component of improving survival. So far, little progress has been made toward this end with other detection methods, including imaging, biopsy, and sampling of blood and urine.
"The finding that microbiota is associated with various forms of cancer including pancreatic cancer has ignited interest among the scientific community in using microbiota for predictive, diagnostic and prognostic purposes," the editorialists write. This study represents an "important contribution" toward the development of predictive markers for PDAC, they add.
Newly Diagnosed PDAC
A total of 57 patients with newly diagnosed PDAC were selected from two hospitals in Spain. Fecal sampling was conducted before patients had undergone any treatment. Twenty-five patients with PDAC had early-stage disease, and the remaining 32 patients had advanced disease.
Twenty-nine patients with chronic pancreatitis were also recruited from the same hospitals, along with 50 healthy individuals matched for age and sex.
After taking into account known risk factors for PDAC, including drinking, smoking, obesity, and diabetes, a distinct microbial profile was observed in the stool samples of people with PDAC compared to patients with chronic pancreatitis and those without either disease.
"Faecal metagenomic classifiers performed much better than saliva-based classifies and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating curve (AUROC) based on a set of 27 microbial species," Bork and colleagues report. An AUROC of 0.5 corresponds to random chance, while an AUROC of 1.0 equals perfect accuracy.
When researchers combined their microbiota-based predictions with serum levels of carbohydrate antigen (CA)19-9, "performance further improved to up to 0.94 AUROC," the authors add.
Currently, the only noninvasive US Food and Drug Administration–approved PDAC diagnostic biomarker is CA 19-9, they explain. It is produced by tumor cells, but at present, CA 19-9 is only used to monitor progression of PDAC.
Further analysis incorporating machine learning techniques identified a characteristic enrichment of certain microbiota species and a relative scarcity of others. Methanobrevibacter smithii, Fusobacterium nucleatum, Alloscardovia omnicolens, Veillonella atypica, and Bacteroides finegoldii were abundant in the stool samples of the cancer patients, while Faecalibacterium prausnitzii, Bacteroides coprocola, Bifidobacterium bifidum, and Romboutsia timonensis were depleted.
This microbial profile consistently identified patients with the cancer irrespective of how far it had progressed, suggesting that characteristic microbiome signatures emerge early on and that the stool microbiome might pick up early-stage disease, the researchers point out.
The prediction capability of the microbial profile was then validated in separate group of 76 German patients, 44 of whom had PDAC and 32 of whom did not. When applied to this validation cohort, the accuracy of the two separate models developed by the researchers was comparable with that observed in the discovery cohort.
To test the disease specificity of both models, the investigators then applied the two models to 5792 samples with metagenomic datasets in 25 study populations and nine disease types. Model 1 — which was not constrained by enrichment of microbial species — had a 15% false positive rate in healthy patients.
However, the enrichment-constrained model 2 was highly specific for PDAC, with a 0 to 5% false positive rate in non-PDAC in all external populations.
Both models performed well in distinguishing between PDAC and type 2 diabetes, with a less than 2% false positive rate in this group as well.
"Alterations in pancreatic secretion, as a consequence of tumour growth in the pancreatic duct, can affect digestive function and may thus plausibly underlie characteristic gut microbiome signatures," Bork and colleagues suggest.
Moreover, the pancreatic duct directly communicates with the duodenum, thus providing a conduit through which bacteria can colonize the pancreas and contribute to carcinogenesis.
"Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible," the authors emphasize.
More Work Needed
Although the findings are promising, "the predictive markers [identified in this study] will need to be tested using a prospective cohort before reaching a conclusion on their clinical impact," the editorialists caution. The markers also need to be tested against other cancer types to ensure that the markers selected for PDAC are not shared.
Also, previous studies have identified a different set of pancreatic tumor-specific resident microbes for which further investigation is required to resolve.
"[But] overall, [this study] brings clarity to the connection between microbiome signature and PDAC and represents significant progress for non-invasive cancer detection," they conclude.
Bork and others have a pending patent application for early detection of pancreatic cancer based on microbial biomarkers. The editorialists have disclosed no relevant financial relationships.
Gut. Published online March 7, 2022. Full text, Commentary
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