Clinical trial NCT04993846: Pancreatic Cancer and Oral Microbiome
Official title: Pancreatic canceR pErioDontAl sTatus and Oral micRobiome - PREDATOR Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Oral Microbiome
Pancreatic Cancer
IPMN
Parodontopathy
Lead sponsor: Azienda Ospedaliera Universitaria Integrata Verona
Sponsor class: OTHER
First posted: 2021-08-06
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with a cyto-histological diagnosis of pancreatic cancer, respecting the inclusion and exclusion criteria

Brief summary: Pancreatic cancer (PC) is a solid malignancy with a dismal prognosis. It has a 5-year survival rate of approximately 8%. This is due to the usually late diagnosis, to chemoresistance, and to intrinsic biological aggressiveness. Risk factors for PC are smoking, alcohol, chronic pancreatitis, obesity, and diabetes. Recently, research has been dedicated to the identification of a causal connection between certain pathogenic microorganisms, especially of the oral flora, and PC. This would ultimately allow to identify new biomarkers to adopt for early diagnosis, or to create new strategies for prevention.

Oral microbiota, periodontal disease and neoplastic risk

When referring to "oral microbiota" (OM), about 700 hundreds bacterial species are mentioned, colonizing the oral cavity. A change in the normal flora of the oral cavity is commonly indicated with the term "dysbiosis".

The causal connection between oral microbiota, periodontal disease and neoplastic risk is possibly triple. First, it has been found that oral flora substantially differentiates between cancer patients and controls. In particular, the most predominant phyla in cancer patients are Firmicutes and Actinobacteria, whereas Proteobacteria, Fusobacteria, and Bacteroides are more common in healthy controls. This highlights the possibility of a direct causal connection between dysbiosis and neoplastic risk. Second, oral dysbiosis represents the main risk factor of PD that per sé is a risk factor of many cancers. Third, the conditions leading to oral dysbiosis (alcohol, smoking, obesity, diabetes, chronic drugs intake, dietary habits, etc.) are the most well known risk factors either for cancer and oral dysbiosis. The common denominator is always represented by chronic inflammation and migration of microorganisms to distant sites, ultimately promoting neoplastic progression.

This tangled net of causal connections sheds light on the potential important role of the oral cavity and PD as independent risk factors for many cancers, and as modifiable elements to reduce the neoplastic risk and to perform prevention(15).

Oral microbiota, periodontal disease and pancreatic cancer

In 2012, the pioneering study by Farrell et al. showed that bacteria of the OM can discriminate PC patients from healthy subjects. Since then, few other studies have shown that changes of the OM are independent risk factors for PC and that the OM of PC patients differs than controls. The involved bacterial species are many and their role seems to be contrasting on the basis of the study considered. Farrell et al. found that the combined adoption of Neisseria elongata and Streptococcus mitis distinguished PC patients from healthy controls (both showed low levels in PC patients, AUC of combined sensitivity 0.9), and that higher levels of Granulicatella adiacens and Streptococcus Mitis distinguished PC patients from chronic pancreatitis ones. Torres et al. found a higher ratio of Leptotrichia to Porphyromonas in PC patients. Fan et al. reported that Porphyromonas gingivalis, Prevotella intermedia, Alloprevotella and Aggregatibacter actinomycetemcomitans are associated with a higher risk of PC, whereas Fusobacteria and Leptotrichia were associated with a decreased risk. Another study evaluating the diversity of OM in three groups of individuals (PC patients, patients suffering from Intraductal papillary mucinous neoplasms \[a pancreatic preneoplastic condition\], and healthy controls), excluding current smokers and users of antibiotics, found no differences in the OM, although patients with PC had a higher proportion of Firmicutes compared with Intraductal Papillary Mucinous Neoplasms (IPMNs) and controls. Lastly, a recent study by Gaiser et al. showed that the cystic fluid of patients submitted to surgery for IPMNs contained bacterial species that are commonly found in the oral cavity, including, among the others, Granulicatella adiacens, Fusobacterium nucleatum. These two, in particular, were higher in the cohort of individuals with IPMNs with high-grade dysplasia, indicating a pivotal role in tumorigenesis(19).

As regards PD, the first studies demonstrating an association between PD and PC date back to the mid of 2000's, and they were confirmed afterward, even adjusting confounders such as diabetes, pancreatitis, hyperlipemia, smoking or alcohol-related conditions. PD is strictly connected to oral hygiene, that seems to be associated to an increased risk of PC. It is now clear that PD can concur to development of PC in several ways, promoting chronic inflammation, spreading continuously to distant organs (including pancreas) pro-tumorigenic bacteria, or promoting a chronic alteration of the immune function that make the individual more prone to develop a cancer.


Eligibility criteria: Inclusion Criteria:

* 18-75 years;
* The ability of the subject to understand the character and individual consequences of the clinical trial
* Written informed consent

Exclusion Criteria:

* A recent history of antibiotics (\< 4 weeks before the enrolment)
* Current systemic or topic medication with steroids
* Active smoking or alcohol habits
* Vegan diet or dietary disorders (anorexia, bulimia)
* Immune system disorders
* Diabetes
* Obesity (defined as having a BMI \> 30)
* Other current malignancies
* History of gastrointestinal tract resections, chronic gastrointestinal diseases (es. Inflammatory bowel diseases, or gastroesophageal reflux disease)
* Pregnant or breastfeeding patients
* Impaired mental state or language problems

Primary outcomes:
measure: Qualitative analysis of the dental plaque microbiome in patients with pancreatic cancer vs. healthy controls and IPMN patients
timeFrame: Baseline (At enrollment)
measure: Correlation analysis between periodontal status and dental plaque microbiome
timeFrame: Baseline (At enrollment)
measure: Quantitative analysis of the dental plaque microbiome in patients with pancreatic cancer vs. healthy controls and IPMN patients
timeFrame: Baseline (At enrollment)
Secondary outcomes:
measure: Qualitative analysis of OM and periodontal status between the various stages of PC
timeFrame: Baseline (At enrollment)
Other outcomes:
Locations:
city: Verona
country: Italy
facility: General and Pancreatic Surgery Unit
city: Verona
country: Italy
facility: Section of Dentistry and Maxillofacial Surgery, Department of Surgical Sciences, Paediatrics and Gynaecology
Study officials:
References:
citation: Fan X, Alekseyenko AV, Wu J, Peters BA, Jacobs EJ, Gapstur SM, Purdue MP, Abnet CC, Stolzenberg-Solomon R, Miller G, Ravel J, Hayes RB, Ahn J. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case-control study. Gut. 2018 Jan;67(1):120-127. doi: 10.1136/gutjnl-2016-312580. Epub 2016 Oct 14.
citation: Farrell JJ, Zhang L, Zhou H, Chia D, Elashoff D, Akin D, Paster BJ, Joshipura K, Wong DT. Variations of oral microbiota are associated with pancreatic diseases including pancreatic cancer. Gut. 2012 Apr;61(4):582-8. doi: 10.1136/gutjnl-2011-300784. Epub 2011 Oct 12.
citation: Torres PJ, Fletcher EM, Gibbons SM, Bouvet M, Doran KS, Kelley ST. Characterization of the salivary microbiome in patients with pancreatic cancer. PeerJ. 2015 Nov 5;3:e1373. doi: 10.7717/peerj.1373. eCollection 2015.
citation: Olson SH, Satagopan J, Xu Y, Ling L, Leong S, Orlow I, Saldia A, Li P, Nunes P, Madonia V, Allen PJ, O'Reilly E, Pamer E, Kurtz RC. The oral microbiota in patients with pancreatic cancer, patients with IPMNs, and controls: a pilot study. Cancer Causes Control. 2017 Sep;28(9):959-969. doi: 10.1007/s10552-017-0933-8. Epub 2017 Jul 31.
citation: Michaud DS, Izard J, Wilhelm-Benartzi CS, You DH, Grote VA, Tjonneland A, Dahm CC, Overvad K, Jenab M, Fedirko V, Boutron-Ruault MC, Clavel-Chapelon F, Racine A, Kaaks R, Boeing H, Foerster J, Trichopoulou A, Lagiou P, Trichopoulos D, Sacerdote C, Sieri S, Palli D, Tumino R, Panico S, Siersema PD, Peeters PH, Lund E, Barricarte A, Huerta JM, Molina-Montes E, Dorronsoro M, Quiros JR, Duell EJ, Ye W, Sund M, Lindkvist B, Johansen D, Khaw KT, Wareham N, Travis RC, Vineis P, Bueno-de-Mesquita HB, Riboli E. Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study. Gut. 2013 Dec;62(12):1764-70. doi: 10.1136/gutjnl-2012-303006. Epub 2012 Sep 18.
citation: Vogtmann E, Han Y, Caporaso JG, Bokulich N, Mohamadkhani A, Moayyedkazemi A, Hua X, Kamangar F, Wan Y, Suman S, Zhu B, Hutchinson A, Dagnall C, Jones K, Hicks B, Shi J, Malekzadeh R, Abnet CC, Pourshams A. Oral microbial community composition is associated with pancreatic cancer: A case-control study in Iran. Cancer Med. 2020 Jan;9(2):797-806. doi: 10.1002/cam4.2660. Epub 2019 Nov 21.