Evaluation of MMR Status and PD-L1 Expression Using Specimens Obtained by EUS-FNB in Patients With Pancreatic Cancer

NCT ID: NCT03820921

Last Updated: 2019-01-29

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 30 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-02-01
• Study Completion Date: 2022-01-01

Brief Summary

Pancreatic ductal adenocarcinoma (PDAC) has a suboptimal response to standard therapies that modestly impact survival due to its ability to evade host immune surveillance. Emerging evidence has shown that the co-inhibitory receptors, such as programmed death 1 (PD-1), play a critical role in cancer immune-editing. Programmed death-ligand 1 (PD-L1) is an immune checkpoint that is often activated in cancer and plays a pivotal role in the initiation and progression of cancer. The advent of immunotherapy, with checkpoint inhibitors, which block PD-L1 interaction between tumor cells and activated T cells, has significantly altered the treatment algorithm for several solid tumors.

However, the clinicopathologic significance and prognostic value of PD-L1 in PDAC remains controversial. The main technical ground may be that PDAC PD-L1 expression quantification is limited to surgical resection specimens and dependent on specific immunohistochemistry (IHC) tests. In addition, PD-L1 expression has not been extensively assessed before surgery in treatment-naive PDAC patients, due to the current IHC test requirement for a histologic rather than a cytologic evaluation. However, a recent study showed that EUS-fine needle biopsy (FNB) can successfully determine primary pancreas malignancy PD-L1 status.

One recently identified subtype within the genomic landscape of PDAC is the mismatch repair-deficient (dMMR) tumor. Evaluation of dMMR status is particularly important following the FDA approval of the PD-1 inhibitor, pembrolizumab, for the treatment of unresectable or metastatic, microsatellite instability-high (MSI-H) or dMMR PDAC that have progressed following prior treatment, and have no satisfactory alternative treatment options.

The objectives of the project will include the assessment of tumor PD-L1/dMMR expression in patients with PDAC using EUS-FNB samples and the prospective correlation of MMR status and PD-L1 expression with overall survival and progression-free survival of PDAC patients.

Conditions

Pancreatic Cancer

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

PATIENTS WITH PANCREATIC CANCER

All patients with a suspicion of pancreatic masses will undergo EUS (including EUS-FNB for confirmation of diagnosis). A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas mass. The diagnoses obtained by EUS-FNB will be further verified during a clinical follow-up of at least 6 months.

Immunochemistry will be performed on the EUS-FNB specimens to determine PD-L1 expression and MMR status

EUS-FNB

Intervention Type: DIAGNOSTIC_TEST

EUS WITH EUS-FNB will be performed for confirmation of diagnosis and analysis of MMR status and PD-L1 expression

Protocol of EUS with EUS-FNB should include linear EUS instruments with complete examinations of the pancreas. Tumor characteristics (echogenicity, echostructure, size) will be described as well as presence/absence of power Doppler signals.

EUS-FNB will be performed in all pancreatic masses with at least three passes in the absence of an onsite cytopathologist using a fanning technique with a 22-gauge needle (SharkCore FNB needle Medtronic Corp. or Acquire FNB needle Boston, MA).

Immunohistochemistry

Intervention Type: OTHER

IHC will be performed on treatment-naïve formalin-fixed paraffin-embedded EUS-FNB pancreatic specimens. Briefly, 4-μm-thick tissue sections will be stained using the Ventana BenchMark XT automated slide-staining system using the following antibodies: Anti-PD-L1 (clone SP263, VENTANA, Tucson, AZ), MLH1 (clone G168-728, Cell Marque, Rocklin, California, United States), MSH2 (clone FE11, Biocare Medical, Concord, Massachusetts, United States), MSH6 (clone BC/44, Biocare Medical, Concord, Massachusetts, United States), and PMS2 (clone A16-4, Biocare Medical, Concord, M Massachusetts, United States). Antigen-antibody reactions will be visualized using UltraView detection with diaminobenzidine as the chromogen. The specimen will be considered to have PD-L1 expression if PD-L1 is expressed in ≥ 1 % of tumor cells and a high level of expression if ≥ 50 %. Tumors will be classified as dMMR if they exhibit absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2).

Interventions

EUS-FNB

EUS WITH EUS-FNB will be performed for confirmation of diagnosis and analysis of MMR status and PD-L1 expression

Protocol of EUS with EUS-FNB should include linear EUS instruments with complete examinations of the pancreas. Tumor characteristics (echogenicity, echostructure, size) will be described as well as presence/absence of power Doppler signals.

EUS-FNB will be performed in all pancreatic masses with at least three passes in the absence of an onsite cytopathologist using a fanning technique with a 22-gauge needle (SharkCore FNB needle Medtronic Corp. or Acquire FNB needle Boston, MA).

Intervention Type: DIAGNOSTIC_TEST

Immunohistochemistry

IHC will be performed on treatment-naïve formalin-fixed paraffin-embedded EUS-FNB pancreatic specimens. Briefly, 4-μm-thick tissue sections will be stained using the Ventana BenchMark XT automated slide-staining system using the following antibodies: Anti-PD-L1 (clone SP263, VENTANA, Tucson, AZ), MLH1 (clone G168-728, Cell Marque, Rocklin, California, United States), MSH2 (clone FE11, Biocare Medical, Concord, Massachusetts, United States), MSH6 (clone BC/44, Biocare Medical, Concord, Massachusetts, United States), and PMS2 (clone A16-4, Biocare Medical, Concord, M Massachusetts, United States). Antigen-antibody reactions will be visualized using UltraView detection with diaminobenzidine as the chromogen. The specimen will be considered to have PD-L1 expression if PD-L1 is expressed in ≥ 1 % of tumor cells and a high level of expression if ≥ 50 %. Tumors will be classified as dMMR if they exhibit absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2).

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Age 18 to 90 years old
• men or women
• signed informed consent for EUS and EUS -FNB
• the diagnosis of adenocarcinoma histologically confirmed by FNB
• resectable, Unresectable, locally advanced and/or metastatic disease

Exclusion Criteria

-previous chemotherapy or radiotherapy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Medicine and Pharmacy Craiova

OTHER

Sponsor Role: collaborator

Ponderas Academic Hospital

OTHER

Sponsor Role: lead

Responsible Party

alina constantin

principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Central Contacts

Alina L Constantin, MD

Role: CONTACT

drconstantinalina@gmail.com

+40722468415

ADRIAN SAFTOIU, MD PHD

Role: CONTACT

adriansaftoiu@gmail.com

Other Identifiers

SUCCESS

Identifier Type: -

Identifier Source: org_study_id