Triple-negative Breast Cancer: a New Perspective on Biomarkers

Study Overview
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Brief Summary
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A single-institutional cohort to determine the prevalence of new immunohistochemical panel in advanced triple-negative submitted to neoadjuvant chemotherapy and its association with response and survival.

Detailed Description
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Background/Rationale: Triple negative breast cancer (TNBC) is known to be a heterogeneous disease, and different molecular sub-classifications are proposed based in specific biomarkers as immunohistochemical (IHC) expression of the androgen-receptor (AR), Epidermal growth Factor Receptor (EGFR), Cytokeratin 5/6 (CK5/6), Cytokeratin14 (CK14), Cytokeratin 17 (CK17), clusters of differentiation 117 (CD 117), p53, Ki67 level, Programmed cell death-ligand 1 (PD-L1) and PD-L2 in tumor cell membrane and the pattern of tumor infiltrating mono-lymphocytes (PD-1+, FOXP3+, CD 4+ or cluster designation 8 (CD8 +), CD 3+, cluster of differentiation 56 (CD56+), cluster designation 68 (CD68+) or CD 14+). Predicting response and survival to neoadjuvant treatment of locally advanced triple-negative breast cancer remains a major challenge. Many doubts still prevail over the role of new biomarkers in predicting different outcomes for tumors with the same stage and morphological characteristics. Objectives and Hypotheses: Primary objective: To evaluate the association of the intratumoral lymphocytic infiltrate (TILs) status profile in the core biopsy with complete pathological response (CPR) outcomes to neoadjuvant chemotherapy and progression-free survival (PFS). Secondary objectives: To evaluate the association of the others biomarkers expression profile and the quality of TILs with PFS and CPR. To determine the prevalence of a large immunohistochemical panel (AR, EGFR, CK5/6, CK14, CK17, CD 117, p53, Ki67 level, PD-L1 and PD-L2 in tumor cell membrane and the pattern of tumor infiltrating mono-lymphocytes PD-1+, FOXP3+, CD 4+ , CD8 +, CD 3+, CD56+, CD68+ and/or CD 14+), before and after neoadjuvant chemotherapy. To determine if the negativation of biomarkers after the systemic treatment is associated with CPR and PFS. Methods: Study design: A cohort with retrospective data collection and sectional analysis of pathological material. Data Source(s): Medical records and pathological material. Study Population: Women with locally advanced triple negative breast cancer consecutively enrolled at Brazilian National Cancer Institute (INCA) submitted to neoadjuvant treatment and subsequently operated. Exposure(s): Status of specified biomarkers. Outcome(s): Complete Pathologic Response and Progression free Survival and Sample Size Estimations: With a type I error of 5% and study power of 80%, it is estimated that 155 patients are needed. Statistical Analysis: Statistical analysis will be performed using SPSS (version 18.0 for windows, statistical package for social science (SPSS) Inc., Chicago, IL). Survival curves will be constructed using the Kaplan-Meier method.

Official Title
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Triple-negative Breast Cancer: a New Perspective on Predictive and Prognostic Biomarkers

Conditions
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Triple Negative Breast Neoplasms, Triple Negative Breast Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women older than 18 years Locally advanced TNBC (T3-4, any Node, M0; any Tumor, N1-3, M0) Patients submitted to anthracycline and taxane-based neoadjuvant chemotherapy and then operated between January 2010 and December 2014 at the Brazilian National Cancer Institute. Exclusion Criteria: Patients with metastatic Breast Cancer; Other non-epithelial histologies of breast cancer; Pure Ductal Carcinoma In Situ diagnoses are not eligible. Patients with scarce material for immunohistochemistry; Other primary synchronous or anachronistic tumors in the breast or other sites; No prior immunotherapeutic, chemotherapeutic or antiandrogenic drugs allowed Patients treated with alternative neoadjuvant chemotherapy regimens (not based on anthracycline and taxane) or with only hormone therapy; Patients who received chemotherapy or who were operated outside the INCA.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Single-arm cohort<br>Initially, patients will be analyzed in a single group. After determining the status of the biomarkers, the patient sample will be divided into specific groups for comparative purposes. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | The first event defined as local recurrence or distant relapse, or death, whichever come first. | Approximately 24 months: from diagnosis up to the first event defined as local recurrence or distant relapse, or death, whichever come first through study completion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate | To determine the clinical response rate in patients with palpable disease. | From date of first cycle of chemotherapy until completion of neoadjuvant treatment, approximately 16 weeks | 
| Objective response rate | To compare overall objective response rate in both treatment groups. | From date of first cycle of chemotherapy until completion of neoadjuvant treatment, approximately 16 weeks | 
| Determine predictive markers | To determine predictive markers for sensitivity and resistance to chemotherapy. | Approximately 24 weeks: from diagnosis up to surgery. | 
| Determine prognostic markers | To determine prognostic markers for progression free survival after neoadjuvant chemotherapy and surgery. | Approximately 24 months: from diagnosis up to the first event defined as local recurrence or distant relapse, or death, whichever come first through study completion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant Chemotherapy, Predictive Biomarkers, Prognostic Biomarkers, Complete Pathological Response, Tumor Infiltrating Lymphocytes, PD-L1, PD-L2