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Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer

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ClinicalTrials.gov Identifier: NCT03495544
Recruitment Status : Unknown
Verified April 2018 by Tatarstan Cancer Center.
Recruitment status was:  Recruiting
First Posted : April 12, 2018
Last Update Posted : April 12, 2018
Sponsor:
Information provided by (Responsible Party):
Tatarstan Cancer Center

Study Description
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Brief Summary:
This is a multicentre, non-interventional, prospective study to be carried out in representative oncology departments / institutions in order to determine the association between the presence of germline DNA-repair genes mutations and PD-L1 expression level in tumour and immune cells in breast cancer. No additional procedures besides those already used in the routine clinical practice will be applied to the patients.

Condition or disease Intervention/treatment
Hereditary Breast Cancer Diagnostic Test: PD-L1 expression

Detailed Description:

Breast cancer (BC) occupies the first place among malignancy in females (29.9% of all tumors in female patients in Russian Federation in 2015) [1].

One of the most perspective direction of the oncotherapy is anticancer immunotherapy - employment of inhibitors of immune checkpoints. Immune checkpoints inhibitors (such as anti-PD-1 and anti-PD-L1 antibodies) have shown good clinical efficiency in clinical research to cure such malignant tumor with high mutation load, as melanoma, lung cancer, and others.

One of the hypothesis of such effect states that, usually, more cancer neoantigens are synthetized in the tumors with high mutation load (driven by genome instability), causing severe lymphoid infiltration [2-3]. This situation is balanced by overexpression of such inhibitors of the immune response as PD-1 and PD-L1 [4 - 6].

Breast cancer - is relatively heterogenic tumor, with different genetic, morphological and phenotypic forms.

Despite relatively low expression of PD-L1 in BC in general, there are reasons to believe that genetic instability, driven by mutations in genes involved in DNA repair, can increase the immunogenicity and, thus, the expression of PD-L1 in BC.

To date, it is widely accepted that 5-10% of BC cases are represented by hereditary types, i.e. mediated by germline pathogenic mutations in genes of DNA reparation pathways. Hereditary breast cancer (HBC), as well as ovarian cancer (OC), сaused by mutations in genes BRCA1, BRCA2, CHEK2, TP53 и PTEN, and others. Thus, one of the promising directions here is to understand the inter-relation among germline pathogenic mutations associated with HBC, and activity of PD-L1. It would allow to optimize selection of anti-PD-L1 therapy, by forming group of patients (matching criteria of HBC) with high level of PD-L1 expression in cancer cells and tumor-infiltrating lymphocytes.

Study Design
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Study Type : Observational
Estimated Enrollment : 390 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Comparative, Multicenter Study Estimating Association Between Germline DNA-repair Genes Mutations and PD-L1 Expression Level in Breast Cancer
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : March 17, 2019
Estimated Study Completion Date : July 1, 2019

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Hereditary BC
Pathogenic germline mutations in DNA-repair genes (TP53 MLH1 MSH2 MSH6 PMS2 EPCAM APC MUTYH CDKN2A CDK4 ATM KIT PDGFRA CDH1 CTNNA1 PRSS1 SPINK1 BRCA1 BRCA2 FANCI FANCL PALB2 RAD51B RAD51C RAD54L RAD51D CHEK1 CHEK2 CDK12 BRIP1 PPP2R2A BARD1 PARP1 STK11 XRCC3)
 Diagnostic Test: PD-L1 expression
IHC testing of PD-L1 expression level in tumor tissue samples
Sporadic BC
Without germline mutations in DNA-repair genes (TP53 MLH1 MSH2 MSH6 PMS2 EPCAM APC MUTYH CDKN2A CDK4 ATM KIT PDGFRA CDH1 CTNNA1 PRSS1 SPINK1 BRCA1 BRCA2 FANCI FANCL PALB2 RAD51B RAD51C RAD54L RAD51D CHEK1 CHEK2 CDK12 BRIP1 PPP2R2A BARD1 PARP1 STK11 XRCC3)
 Diagnostic Test: PD-L1 expression
IHC testing of PD-L1 expression level in tumor tissue samples


Outcome Measures
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Primary Outcome Measures :
  1. Diagnostic performance of PD-L1 expression in breast cancer [ Time Frame: January 2018-January 2019 ]

    Number of samples of PD-L1 high expression in tumor and immune cells in FFPE breast tumor tissue and number of samples of PD-L1 low expression in tumor and immune cells in FFPE breast tumor tissue .

    The report will be represented as "PD-L1 high" or "PD-L1 low".



Secondary Outcome Measures :
  1. Diagnostic performance of inherited gene mutations in breast cancer [ Time Frame: January 2018-January 2019 ]
    Mutations will be determined by "pathogenic" and "non pathogenic". Number of samples with "pathogenic" and "non pathogenic" mutations .

  2. Association between germline DNA-repair genes mutations and PD-L1 expression level in in breast cancer [ Time Frame: January 2018-January 2019 ]
    To reveal the differences (percentages) of PD-L1 high tumor rate between patients with hereditary BC ( pathogenic mutations) who have clinically significant germline mutations in DNA-repair genes (HR- deficiency) and patients with sporadic BC without such mutations (non pathogenic mutations).


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
patients, female aged between 18-80yrs with breast cancer
Criteria

Inclusion Criteria:

  • 1. The voluntary obtained informed consent signed by both the subject and the investigator.

    2. Females 18 years age or more. 3. Histologically confirmed BC with known hormone receptors and HER2neu receptors status, Grade of tumor, diagnosed before enrolment into the study.

    4. Availability of FFPE tissue samples received prior to any type of antitumor treatment start. Tumour tissue samples must be satisfied IHC requirements for PD-L1 testing.

    5. Ability of blood samples receiving for NGS germline mutations testing. 6. Completed medical records (stage, receptors status, demographic data)

Exclusion Criteria:

  • Any evidence of uncontrolled system pathology, active infections, active bleeding diathesis, renal graft, including virus hepatitis B, C or HIV.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03495544


Contacts
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Contact: Marat Gordiev +79172399490 marat7925@gmail.com
Contact: Rafail Enikeev +79274027390 alba352007@yandex.ru

Locations
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Russian Federation
Tatarstan Cancer Cente Recruiting
Kazan, Tatarstan, Russian Federation, 420029
Contact: Marat Gordiev    +79172399490    marat7925@gmail.com   
Contact: Dina Sakaeva    +79033115085    d_sakaeva@mail.ru   
Sponsors and Collaborators
Tatarstan Cancer Center
  Study Documents (Full-Text)

Documents provided by Tatarstan Cancer Center:
Study Protocol and Statistical Analysis Plan  [PDF] January 1, 2018
Informed Consent Form  [PDF] January 1, 2018

More Information
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Responsible Party: Tatarstan Cancer Center
ClinicalTrials.gov Identifier: NCT03495544    
Other Study ID Numbers: ESR-17-12934
First Posted: April 12, 2018    Key Record Dates
Last Update Posted: April 12, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Supporting Materials: Study Protocol

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases