Title: PRECEDE: The Pancreatic Cancer Early Detection Consortium

Introduction and Background:

Pancreatic cancer is classified as a terminal illness and one of the most aggressive and deadly forms of cancer [1,2]. At the time of diagnosis, pancreatic cancer frequently manifests in an advanced stage and has typically metastasized to other regions of the body. Pancreatic cancer, clinically known as adenocarcinoma [3], refers to a malignant tumor that develops in the glandular structures of the pancreatic ductal cells. This type of cancer, namely pancreatic ductal adenocarcinoma (PDAC), makes up over 90% of all pancreatic malignancies [4]. PDAC, or pancreatic ductal adenocarcinoma, is responsible for the highest number of cancer-related deaths worldwide because to its low survival rates [5].

Pancreatic cancer is classified as the 14th most prevalent kind of cancer and the 7th leading cause of cancer-related deaths globally. The projections from Globocan indicate that there will be a total of 458,918 cases of pancreatic cancer diagnosed worldwide in 2018, resulting in 432,242 fatalities [6].  

Significant geographical disparities in the age-adjusted incidence rates of pancreatic cancer are seen worldwide.   In Asia, certain areas have recorded incidence rates as low as 0.6 per 100,000 individuals per year, but in the West, incidence rates as high as 12.6 per 100,000 have been documented. [7] The average age standardized incidence rates for pancreatic cancer are 8.2 and 2.7 per 100,000 among men in developed and developing nations, respectively. Among females, the rates are 5.4 and 2.1 per 100,000 in developed and developing countries, respectively. [8] In India, this phenomena is also present, although there are differences reported in various locations, with the northeast having greater frequencies [9,10]. India has a comparatively lower prevalence of pancreatic cancer when compared to Western countries. In India, the incidence rates of this condition range from 0.5 to 2.4 per 100,000 individuals per year for women, and from 0.2 to 1.8 per 100,000 individuals per year for males [11].  According to the National Cancer Registry Programme (ICMR, Bengaluru), it is projected that by 2020, there would be 8440 new cases of pancreatic cancer in Indian males and 6090 new cases in Indian women [12].  The enhancement of patient outcomes depends on a comprehensive understanding of epidemiology, effective preventive measures, and rigorous scientific oversight of early detection.

The PRECEDE Consortium is a collaborative research effort by 49 academic medical centers around the world.  New York University is the coordinating center, led by Dr. Diane Simeone. It is the largest effort of its kind, using a novel model of data sharing across some of the most well-known medical centers around the world.  By combining data from all these sites, researchers will be able to more effectively and quickly identify methods of early detection that will result in treatment before the disease has spread. 

Objectives

The main objective of the PRECEDE Consortium is to build a shared resource to drive research in critical areas necessary for early detection and prevention of PDAC.

Data and samples collected for PRECEDE will allow the consortium to address a variety of topic areas including but not limited to:

1. Developing and/or validating early detection biomarker tests

2. Improving risk modeling and risk prediction for PDAC

3. Identifying and studying novel high penetrance germline pathogenic variants causing PDAC risk

4. Designing and implementing enhanced communication tools about PDAC risk, genetic testing, and early detection for patients and healthcare providers

5. Studying modifying factors for PDAC risk including common genetic variants and modifiable/lifestyle factors

6. Developing and/or validating PDAC prevention strategies for high-risk individuals

Detailed research plan

Ø  Study Design

The PRECEDE Consortium is an observational prospective cohort study, with single or serial biosample collection (every 6-12 months) in defined high-risk groups.

Ø  Characteristics of the Research Population

Number of Subjects

The study will accrue subjects who present for clinical evaluation and risk assessment at Max Super Speciality Hospital based on the history of:

- one or more family members with PDAC

- a pathogenic or likely pathogenic germline variant in a gene linked to PDAC risk

- personal history of PDAC with PGV in genes of research interest and/or part of a Familial Pancreatic Cancer kindred

- personal history of a pancreatic cystic neoplasm

We anticipate that up to 10000 subjects will be evaluated for participation in the study over a period of 120 months.

Sex of Subjects

Male and female patients are eligible.

Age of Subjects

The age range of patients will be between 18 and 90.

Ø  Inclusion Criteria

Individuals from the following groups who present for clinical evaluation and assessment of PDAC risk at Max Super speciality hospital can be offered participation in the PRECEDE database:

Cohort 1

Individuals without history of PDAC meeting any of the following criteria:

1. 2+ relatives with PDAC on same side of family where 2 affected are first degree related to each other and at least 1 affected is first degree related to subject; age 50+ or ≤10 years younger than earliest PDAC in family at time of diagnosis.

2. 2 affected first degree relatives with PDAC; age 50+ or 10 years younger than earliest PDAC in family

3. BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, EPCAM pathogenic or likely pathogenic variant AND 1 first or second degree relative with PDAC; age 50+ or 10 years younger than earliest PDAC in family

4. Familial Atypical Moles and Malignant Melanoma (FAMMM) with pathogenic or likely pathogenic CDKN2A variant; age 40+

5. Peutz-Jegher syndrome with STK11 pathogenic or likely pathogenic variant; age 35+

6. Hereditary pancreatitis with PRSS1 pathogenic or likely pathogenic variant and history of pancreatitis; age 40+

Cohort 2

Individuals without history of PDAC meeting any of the following criteria:

1. ATM, BRCA1, BRCA2, or PALB2 pathogenic or likely pathogenic variant regardless of family history, age 50+

2. 2+ relatives with PDAC on the same side of family, any degree of relation, not meeting other criteria above; age 50+ or 10 years younger than earliest PDAC in family

3. 1 first degree relative with PDAC ≤ age 45; age up to 10 years younger than PDAC diagnosis in family member

Cohort 3

Individual meeting criteria for Cohorts 1 or 2 EXCEPT age (i.e. too young to qualify for Cohorts 1 or 2)

Cohort 4

Individuals without history of PDAC presenting for evaluation who do not meet any criteria for 1-3, 6, or the Cyst Cohort.

Cohort 5

Individuals who are not otherwise engaged in pancreas surveillance at a participating site may be invited to participate in the PRECEDE database and to donate a biosample (e.g. blood, saliva, and/or buccal swab) for discovery studies. This may include relatives of individuals in Cohorts 1-4, 6, and the Cyst Cohort.

Cohort 6

Individuals with a personal history of PDAC meeting any of the following criteria:

1. Family history includes at least one first degree relative with PDAC, or 2 relatives with PDAC who are first degree related to each other

2. Personal or family history of a pathogenic or likely pathogenic germline variant in ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2,PMS2, PRSS1, STK11

3. Diagnosed ≤ age 45

Cyst Cohort

Individuals with a personal history of a pancreatic cystic neoplasm not meeting any criteria for Cohorts 1-3 or 6 (no known family history of PDAC, no known pathogenic germline variants linked to PDAC risk)

 Data and Specimens Collected

Data Collected

Informed consent will be obtained at Max Super speciality hospital, or by mail, email, or phone for all Cohorts. The consent form may be sent and returned electronically; secure electronic signature will be accepted. Demographic information, medical history, family history, lab results, and imaging results will be recorded in the consortium database.

Specimens Collected

A standardized procedure for collection and processing of human blood, fresh frozen tissue, formalin fixed paraffin embedded tissue, and pancreas cyst fluid for the PRECEDE Consortium will be applied to all biosamples collected as part of the study. Barcoded samples will be stored at Max Super speciality hospital using the specific labels for the PRECEDE study and corresponding data will be entered into the study database. Any protocol deviations should also be recorded.

Clinical data and outcomes will be obtained from institutional databases or clinical records to correlate patient information with laboratory results from biospecimens obtained for research. Patients will be followed by their attending physician and receive the standard follow-up care after the procedure in which biospecimen was obtained. It is the intent that biospecimens will be made available to all consortium investigators.

Protection of Human Subjects

Subjects will be enrolled in the protocol with full and written informed consent, which will include the gathering of protected health information (PHI). Max Super speciality hospital will be responsible for obtaining such human subjects research authorization and will create an informed consent document detailing the procedures described above in the language required by their respective organizations. The consent form may be sent and returned electronically, and secure electronic signatures will be accepted. All key personnel at hospital will have successfully completed IRB-required training and certification for human participant research. Additionally, sites Max Super speciality hospital will satisfy HIPAA researchers’ privacy requirements.

Transfer of Biological Material:

Biosamples including Blood samples are sent for freezing and, after obtaining HMSC clearance, are transferred at predetermined frequencies to the biorepository. A standardized procedure for the collection and processing of human blood will be applied to all blood samples collected as part of the study. Saliva samples Barcoded samples will be stored at the clinical centers, and corresponding data will be entered into the study database. Any protocol deviations should also be recorded by each center.

60mL of blood is collected at baseline, 120mL annually, and 60mL at other events.

The samples are shipped out at specified intervals along with accompanying data to NYU.

Publication of research findings

The investigator will use the data collated after due analysis for the purpose of publishing in national & international journals for which a copy of the final manuscript will be submitted for IEC records. The results of the study shall also be used for the purposes of national and international registration, publication and information for medical and pharmaceutical professionals.

Expected outcome

·       Development and establishment of evidence-based practice standards for genetic testing and surveillance in individuals with a family history of PDA and carriers of gene mutations linked to PDA risk.

·       Implementation of standardized protocols that guide healthcare professionals in identifying and managing high-risk individuals.

·       Development of comprehensive risk models that accurately estimate PDA risk, aiding clinicians in personalized risk assessment and guiding clinical decision-making.

·       Improved risk stratification that allows for targeted interventions and surveillance in high-risk populations.

·       Integration of findings into global healthcare policies, contributing to a paradigm shift in pancreatic cancer management on an international scale.