Granzyme B Expression in the Tumor Microenvironment as a Prognostic Biomarker for Patients with Triple-Negative Breast Cancer

Tumor-infiltrating lymphocytes in the tumor microenvironment are important in the treatment of triple-negative breast cancer (TNBC). Cytotoxic T cells produce cytokines and cytotoxic factors, such as perforin and granzyme, which induce apoptosis by damaging target cells. To identify biomarkers of these cells, we investigated granzyme B (GZMB) in the tumor microenvironment as a biomarker of treatment response and prognosis in 230 patients with primary TNBC who underwent surgery without preoperative chemotherapy between January 2004 and December 2014. Programmed cell death ligand 1 (PD-L1) positivity was defined as a composite positive score ≥10 based on the PD-L1 immunostaining of tumor cells and immune cells. GZMB-high was defined as positivity in ≥1% of tumor-infiltrating lymphocytes (TILs). Among the 230 TNBC patients, 117 (50.9%) had CD8-positive infiltrating tumors. In the PD-L1-positive group, a Kaplan–Meier analysis showed that GZMB-high TNBC patients had better recurrence-free survival (RFS) and overall survival (OS) than GZMB-low patients and that OS was significantly longer (RFS: p = 0.0220, OS: p = 0.0254). A multivariate analysis also showed significantly better OS in PD-L1- and GZMB-high patients (hazard ratio: 0.25 (95% IC: 0.07–0.88), p = 0.03). Our findings indicate that GZMB is a useful prognostic biomarker in PD-L1-positive TNBC patients

BRCAness as a Biomarker for Predicting Prognosis and Response to Anthracycline-Based Adjuvant Chemotherapy for Patients with Triple-Negative Breast Cancer

<div><p>Background</p><p>Triple-negative breast cancer (TNBC) is a heterogeneous tumor that encompasses many different subclasses of the disease. In this study, we assessed BRCAness, defined as the shared characteristics between sporadic and <i>BRCA1</i>-mutated tumors, in a large cohort of TNBC cases.</p><p>Methods</p><p>The BRCAness of 262 patients with primary TNBCs resected between January 2004 and December 2014 was determined through the isolation of DNA from tumor tissue. Classification of BRCAness was performed using multiple ligation-dependent probe amplification (MLPA). The tumor subtypes were determined immunohistochemically using resected specimens.</p><p>Results</p><p>Of the 262 TNBCs, the results of the MLPA assays showed that 174 (66.4%) tumors had BRCAness. Patients with BRCAness tumors were younger than patients with non-BRCAness tumors (<i>P</i> = 0.003). There was no significant difference between the two groups regarding their pathological stages. The BRCAness group had a significantly shorter recurrence-free survival (RFS) compared with the non-BRCAness group (<i>P</i> = 0.04) and had a shorter overall survival (OS) although this did not reach statistical significance. Adjuvant treatments with anthracycline-based regimens provided significantly greater benefits to the BRCAness group (<i>P</i> = 0.003 for RFS, and <i>P</i> = 0.03 for OS). Multivariate Cox proportional hazard model analysis showed that BRCAness was an independent negative prognostic factor, and the anthracycline-based adjuvant chemotherapy was an independent positive prognostic factor for both RFS and OS in TNBC.</p><p>Conclusions</p><p>The 66.4% patients of TNBCs showed BRCAness. BRCAness is essential as a biomarker in the subclassification of TNBCs and might be of use for predicting their prognosis. Furthermore, this biomarker might be a predictive factor for the effectiveness of anthracycline-based adjuvant chemotherapy for patients with TNBCs.</p></div

Patients and tumor characteristics (<i>n</i> = 262).

<p>Patients and tumor characteristics (<i>n</i> = 262).</p

Kaplan–Meier analysis of patients who received anthracycline-based adjuvant chemotherapy versus non-anthracycline-based adjuvant chemotherapy.

<p>(A) Recurrence-free survival (RFS) of BRCAness tumors (<i>n</i> = 126). (B) Overall survival (OS) of BRCAness tumors (<i>n</i> = 126). (C) RFS of non-BRCAness tumors (<i>n</i> = 53). (D) OS of non-BRCAness tumors (<i>n</i> = 53). Anthracycline or Anthra, anthracycline-based adjuvant chemotherapy; Non-Anthracycline or Non-Anthra, non-anthracycline-based adjuvant chemotherapy.</p

Cox proportional hazards model for recurrence-free survival and overall survival (<i>n</i> = 262).

<p>Cox proportional hazards model for recurrence-free survival and overall survival (<i>n</i> = 262).</p

Kaplan–Meier analysis of patients with TNBC (<i>n</i> = 262).

<p>(A) Recurrence-free survival of BRCAness tumors versus non-BRCAness tumors. (B) Overall survival of BRCAness tumors versus non-BRCAness tumors.</p