Triple-negative Breast Cancer: a New Perspective on Biomarkers
Condition: Triple Negative Breast Neoplasms; Triple Negative Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Study type: Observational

Summary: 
      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: 
      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.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study population: 
        Women who is biopsied and diagnosed with breast cancer in the public health system is
        referred to Brazilian National Cancer Institute (INCA) through a registry and screening
        performed by the Municipal Health Department of the city of Rio de Janeiro. Therefore, it
        becomes a great field for research of cancer patients by the large number of cases.
        Absolutely all patients enrolled in INCA for treatment have their biopsy material reviewed
        in DIPAT.

        In this cohort, will be studied women with locally advanced TNBC consecutively enrolled at
        INCA between January 2010 and December 2014 that were submitted to neoadjuvant chemotherapy
        and subsequently operated.
      
Biospecimen description: 
      Paraffin-embedded Hematoxylin & Eosin (H & E) core biopsy/early biopsy and surgical specimens
      previously analyzed in the Department of Patology of the Brazilian National Cancer Institute
      (INCA) will be doubly reviewed by two pathologists in our study for histological grade
      (Scarff-Bloom-Richardson method, modified by Elston and Ellis), histological type (according
      to World Health Organization, 2012), presence of carcinoma component "in situ",
      angiolymphatic invasion, perineural infiltration, presence of lymphocytic inflammatory
      infiltrate.
    
Keywords: Neoadjuvant Chemotherapy; Predictive Biomarkers; Prognostic Biomarkers; Complete Pathological Response; Tumor Infiltrating Lymphocytes; PD-L1; PD-L2