Pancreatic Cancer and Oral Microbiome

August 5, 2021 updated by: Azienda Ospedaliera Universitaria Integrata Verona

Pancreatic canceR pErioDontAl sTatus and Oral micRobiome - PREDATOR Study

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Anticipated)

120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Verona, Italy
      • Verona, Italy
        • Recruiting
        • Section of Dentistry and Maxillofacial Surgery, Department of Surgical Sciences, Paediatrics and Gynaecology
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with a cyto-histological diagnosis of pancreatic cancer, respecting the inclusion and exclusion criteria

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Pancreatic cancer patients - Explorative phase
Pancreatic cancer patients evaluated at the Pancreatic Surgery Unit of the Pancreas Institute of the University of Verona will be enrolled. Fifteen PC patients per stage will be selected (15 Stage I/II, Stage III, Stage IV). Patients may have been scheduled for surgery or for biopsy for future systemic treatments. An oral microbiota (dental plaque) sample will be collected and a periodontal and dental assessment will be performed, before any therapeutic procedure, together with orthopantomography
Diagnostic test: Dental plaque sampling
Dental plaque sampling
Diagnostic test: qPCR
qPCR
Healthy controls - Explorative phase
Age-matched (+- 5 years) healthy controls referring to the Odontostomatology Unit for oral procedure according to clinical practice, with a recent (not longer than 12 months) cross-sectional abdominal imaging excluding gastrointestinal cancers.
Diagnostic test: Dental plaque sampling
Dental plaque sampling
Diagnostic test: qPCR
qPCR
Pancreatic cancer patients - Validation phase
Pancreatic cancer patients evaluated at the Pancreatic Surgery Unit of the Pancreas Institute of the University of Verona will be enrolled. Fifteen PC patients per stage will be selected (15 Stage I/II, Stage III, Stage IV). Patients may have been scheduled for surgery or for biopsy for future systemic treatments.
Diagnostic test: Dental plaque sampling
Dental plaque sampling
Diagnostic test: qPCR
qPCR
Healthy controls - Validation phase
Age-matched (+- 5 years) healthy controls referring to the Odontostomatology Unit for oral procedure according to clinical practice, with a recent (not longer than 12 months) cross-sectional abdominal imaging excluding gastrointestinal cancers.
Diagnostic test: Dental plaque sampling
Dental plaque sampling
Diagnostic test: qPCR
qPCR
IPMN patients controls - Validation phase
Patients suffering from IPMNs evaluated at outpatients clinics or scheduled for surgery.
Diagnostic test: Dental plaque sampling
Dental plaque sampling
Diagnostic test: qPCR
qPCR

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Qualitative analysis of the dental plaque microbiome in patients with pancreatic cancer vs. healthy controls and IPMN patients
Time Frame: Baseline (At enrollment)
Whole-Genome Sequencing analysis
Baseline (At enrollment)
Correlation analysis between periodontal status and dental plaque microbiome
Time Frame: Baseline (At enrollment)
According to the periodontal status (appropriate scores will be used), patients will be divided into distinct groups. The proportional means of abundance of selected genera and species, and bacterial load (real-time data) between these groups will be analyzed using the Mann-Whitney U-test. Correlations between mean distributions of the genera and species and the parodontal status scores values will be analysed using the Spearman Correlation Coefficient.
Baseline (At enrollment)
Quantitative analysis of the dental plaque microbiome in patients with pancreatic cancer vs. healthy controls and IPMN patients
Time Frame: Baseline (At enrollment)
Whole-Genome Sequencing analysis
Baseline (At enrollment)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Qualitative analysis of OM and periodontal status between the various stages of PC
Time Frame: Baseline (At enrollment)
Whole-Genome Sequencing analysis
Baseline (At enrollment)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda Ospedaliera Universitaria Integrata Verona

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 26, 2021

Primary Completion (Anticipated)

June 30, 2023

Study Completion (Anticipated)

December 31, 2023

Study Registration Dates

First Submitted

May 26, 2021

First Submitted That Met QC Criteria

August 5, 2021

First Posted (Actual)

August 6, 2021

Study Record Updates

Last Update Posted (Actual)

August 6, 2021

Last Update Submitted That Met QC Criteria

August 5, 2021

Last Verified

January 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 3292CESC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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