Evaluation of the Role of Immune Checkpoints in Response to Breast Cancer Neoadjuvant Therapy

Evaluation of the Role of Immune Checkpoints in Response to Breast Cancer Neoadjuvant

Breast cancer is the most common type of cancer in women and the second most common cause of death after lung cancer. In epidemiological studies, its prevalence is 22-26%, and the mortality risk due to breast cancer is around 18%.

It is known that the immune system has an important role in tumor development or tumor destruction. Recent studies have shown that tumor cells acquire escape mechanisms to escape host immunity in the tumor microenvironment.

Studies have reported that immune checkpoints are elevated in many types of cancer and have a poor prognosis. Up or down regulation of immune checkpoints is observed to protect breast cancer cells from the anti-tumor responses of the immune system. There are also immune checkpoints found in plasma in soluble form, and the number of studies evaluating soluble immune checkpoints in cancers is very limited in the literature. Measurement of soluble immune control points is easier than those expressed on the surface, and many markers can be evaluated at the same time. There are very few studies in the literature evaluating soluble immune checkpoints in breast cancer.

The aim of this study is to investigate the role of soluble immune checkpoints in predicting the response to neoadjuvant therapy in locally advanced breast cancers.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Diagnostic test: Immune checkpoint measurement

Detailed Description

Breast cancer is the most common type of cancer in women and the second most common cause of death after lung cancer. In epidemiological studies, its prevalence is 22-26%, and the mortality risk due to breast cancer is around 18%. While the classification of malignant breast tumors has traditionally been made according to their histological appearance, some subtypes have been defined according to their molecular features. The different behavior of tumors in the luminal group led to the need to divide this group into subtypes as luminal A and B. The luminal group A, which has the highest prevalence among breast cancers; It includes Her2-negative tumors with low proliferative activity, low mitotic rate and histological grade. The prognosis of patients with luminal A tumors is very good and metastases are mostly limited to bones. Luminal-B tumors have a more aggressive course. The most important difference of this group is that tumors have a high proliferation rate. The breakpoint between luminal A and B is generally accepted as less than 14% of tumor cells showing nuclear Ki67 expression immunohistochemically. In addition, approximately 30% of Her2-positive tumors are immunohistochemically in the luminal B phenotype.

It is known that the immune system has an important role in tumor development or tumor destruction. Recent studies have shown that tumor cells acquire escape mechanisms to escape host immunity in the tumor microenvironment.

Immune checkpoints are important molecules that are on the agenda especially after receiving the Nobel Prize in 2018 and in revealing the relationship between cancer and the immune system. Programmed Cell Death Protein-1 (PD-1) and its ligand, PD-L1, are immune checkpoints that act by inhibiting T cell receptor signal transmission and auxiliary stimuli. T cell immunoglobulin and mucin domain 3 (TIM-3) are mostly expressed on interferon-γ producing T cells, Tregs, dendritic cells, B cells, macrophages, natural killer cells (NK) and mast cells.

Studies have reported that immune checkpoints are elevated in many types of cancer and have a poor prognosis. Up or down regulation of immune checkpoints is observed to protect breast cancer cells from the anti-tumor responses of the immune system. Although many studies have been conducted on immune checkpoints in recent years, a limited number of immune checkpoints which are expressed on the cell surface have been evaluated in each study. There are also immune checkpoints found in plasma in soluble form, and the number of studies evaluating soluble immune checkpoints in cancers is very limited in the literature. Measurement of soluble immune control points is easier than those expressed on the surface, and many markers can be evaluated at the same time. There are very few studies in the literature evaluating soluble immune checkpoints in breast cancer.

The aim of this study is to investigate the role of soluble immune checkpoints in predicting the response to neoadjuvant therapy in locally advanced breast cancers.

• Study Type: Observational
• Enrollment (Actual): 56

Contacts and Locations

Study Locations

• Turkey
  • Istanbul, Turkey, 34098
    • Istanbul Training and Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 88 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Locally advanced Breast Cancer patients who will receive neoadjuvant therapy

Description

Inclusion Criteria:

• Locally advanced Breast Cancer patients who will receive neoadjuvant therapy

Exclusion Criteria:

• Known immunodeficiency
• Having a primary malignancy other than breast cancer,
• Pregnancy,
• Patients who refused to participate in the study

Study Plan

How is the study designed?

Design Details

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

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
No response; The breast cancer patients with no response to neoadjuvant therapy	Diagnostic test: Immune checkpoint measurement; Measurement of sCD25 (IL-2Ra), 4-1BB, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9
Moderate response; The breast cancer patients with moderate response to neoadjuvant therapy	Diagnostic test: Immune checkpoint measurement; Measurement of sCD25 (IL-2Ra), 4-1BB, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9
Good response; The breast cancer patients with good response to neoadjuvant therapy	Diagnostic test: Immune checkpoint measurement; Measurement of sCD25 (IL-2Ra), 4-1BB, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune checkpoints	Values in pg/ml of sCD25 (IL-2Ra), 4-1BB, CD27, B7.2 (CD86), Free Active TGF-β1, CTLA-4, PD-L1, PD-L2, PD-1, Tim-3, LAG-3, Galectin-9	1 day

Collaborators and Investigators

• Sponsor: Istanbul Training and Research Hospital
• Investigators: Principal Investigator: Ufuk Oguz Idiz, Assoc. Prof, Istanbul Training and Research Hospital

Publications and helpful links

General Publications

• Li Y, Cui X, Yang YJ, Chen QQ, Zhong L, Zhang T, Cai RL, Miao JY, Yu SC, Zhang F. Serum sPD-1 and sPD-L1 as Biomarkers for Evaluating the Efficacy of Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients. Clin Breast Cancer. 2019 Oct;19(5):326-332.e1. doi: 10.1016/j.clbc.2019.03.008. Epub 2019 Apr 11.
• Gershtein ES, Korotkova EA, Vorotnikov IK, Sokolov NY, Ermilova VD, Mochalova AS, Kushlinskii NE. Soluble forms of PD-1/PD-L immune checkpoint receptor and ligand in blood serum of breast cancer patients: association with clinical pathologic factors and molecular type of the tumor. Klin Lab Diagn. 2022 Feb 23;67(2):76-80. doi: 10.51620/0869-2084-2022-67-2-76-80.
• Gu D, Ao X, Yang Y, Chen Z, Xu X. Soluble immune checkpoints in cancer: production, function and biological significance. J Immunother Cancer. 2018 Nov 27;6(1):132. doi: 10.1186/s40425-018-0449-0.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): October 1, 2022

Study Registration Dates

• First Submitted: August 25, 2022
• First Submitted That Met QC Criteria: August 25, 2022
• First Posted (Actual): August 29, 2022

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Locally Advanced; immune checkpoints; Neoadjuvant
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: Breast cancer neoadjuvant

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No