Objectives: Known for their poor outcomes, triple negative breast cancers (TNBCs) have been investigated for immune checkpoint inhibitors that target Programmed death ligand 1 (PD-L1). In the recent decade, tumor-infiltrating lymphocytes (TILs) have also become potential biomarkers. The aim of the study is to determine the reproducibility of PD-L1 scoring system for TNBC (SP142 clone) and TILs interpretation in the local setting through intra- and interobserver agreement. Methodology: Forty-three primary resection specimens TNBC were evaluated on two occasions with PD-L1 (Roche VENTANA SP142 assay) and TILs by two breast pathologists and one general pathologist on physical glass slides. PD-L1 expression was determined by at least 1% positivity among immune cells within the tumoral area and contiguous peritumoral stroma while TILs was assessed based on International Immuno-Oncology Biomarker Working Group on Breast Cancer. Kappa statistic for PD-L1 and TILs categories while intraclass correlation coefficient (ICC) were assessed, with cutoffs of 0.80 and 0.70, respectively. Results: The overall interrater kappa statistic for PD-L1 on the first and second rounds were weak at 0.506 (95% CI: 0.334-0.679) and minimal at 0.314 (95% CI: 0.142-0.487), respectively. Intraobserver kappa statistic for PD-L1 were varied across the three readers while interobserver kappa values for PD-L1 showed none (0.181) to moderate (0.789) agreement. The TILs intraobserver reliability showed poor to good agreement, with the highest ICC of 0.889 (95% CI: 0.805-0.938). Conclusion This study demonstrated variable intra and interobserver agreement for both TILs and PD-L1 expression. Although it is desirable to have strong to almost perfect agreement, the kappa and ICC values suggest additional room for improvement. In light of the repercussions in management of patients who will undergo immune checkpoint inhibitor therapy, regular training sessions, concurrences of equivocal results, and possible use of digital pathology as a medium in interpreting TILs and PD-L1 stains to achieve consistent results.
Breast Neoplasms ; Triple Negative Breast Neoplasms ; Immunohistochemistry

According to the classification presented by Lehmann BD (2016), triple-negative breast cancer (TNBC) is a heterogeneous group of malignant tumors with four specific subtypes: basal-like (subtype 1 and subtype 2), mesenchymal, and luminal androgen receptor (LAR) subtypes. The basal-like subtypes of carcinomas predominate in this group, accounting for up to 80% of all cases. Despite the significantly lower proportions of mesenchymal and LAR variants in the group of breast carcinomas with a TNBC profile, such tumors are characterized by aggressive biological behavior. To this end, the LAR subtype is of particular interest, since the literature on such tumors presents different and even contradictory data concerning the disease course and prognosis. This review is devoted to the analysis of the relevant literature, reflecting the main results of studies on the molecular properties and clinical features of the disease course of LAR-type TNBC carcinomas.
Carcinoma ; Humans ; Receptors, Androgen/genetics* ; Triple Negative Breast Neoplasms/pathology*

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.
Humans ; Immunotherapy ; Molecular Targeted Therapy ; Triple Negative Breast Neoplasms/genetics*

Background: Triple-negative breast cancer (TNBC) comprises 15-20% of all breast cancers and is marked by early relapse and poor overall survival. Adjuvant chemotherapy has become the standard of care for these patients albeit to this time there is no consensus on its optimal chemotherapy regimen. This study determined the disease-free-survival (DFS) and overall survival (OS) of patients with stage I-III triple-negative breast cancer given adjuvant chemotherapy in Makati Medical Center from 2000 to 2015. Methods: A single institution (Makati Medical Center), retrospective cohort was conducted involving 157 stage I-III triple-negative breast cancer patients, diagnosed from January 2000 to June 2015, who completed an adjuvant chemotherapy regimen and had at least 3 years of follow up with their medical oncologist. Review of charts of these patients was done, and the demographic, clinical, histopathologic, chemotherapy, recurrence and mortality data were collected and analyzed. The OS and DFS rates were estimated using the Kaplan-Meier method. Results: 107 stage I-III triple-negative breast cancer patients who met eligibility criteria were included in the analysis. The most common chemotherapy regimens were sequential anthracycline-taxane (32 patients, 29.09%) and anthracycline-based regimens (32 patients, 29.09%). The 5-year median OS of TNBC patients given adjuvant chemotherapy was 78.94% (95% CI: 69% to 86%) while the 5-year median DFS of TNBC patients was 71.71% (95% CI: 61.68% – 79.5%). There was no significant association between overall survival or disease-free survival and treatment with a particular chemotherapy regimen. Conclusions Adjuvant chemotherapy with sequential anthracycline-taxane, concurrent anthracycline-taxane, CMF, anthracycline-based and taxane-based regimens among stage I-III triple-negative breast cancer patients in Makati Medical Center resulted in comparable overall survival and disease-free survival. The use of immune checkpoint inhibitors presents a viable option in TNBC as demonstrated in the Impassion 130 and KEYNOTE 119 trials, and should be further evaluated in the Philippine setting.
Triple Negative Breast Neoplasms ; Chemotherapy, Adjuvant ; Disease-Free Survival

PURPOSE: To better identify the physiology of triple-negative breast neoplasm (TNBN), we analyzed the TNBN gene regulatory network using gene expression data. METHODS: We collected TNBN gene expression data from The Cancer Genome Atlas to construct a TNBN gene regulatory network using least absolute shrinkage and selection operator regression. In addition, we constructed a triple-positive breast neoplasm (TPBN) network for comparison. Furthermore, survival analysis based on gene expression levels and differentially expressed gene (DEG) analysis were carried out to support and compare the network analysis results, respectively. RESULTS: The TNBN gene regulatory network, which followed a power-law distribution, had 10,237 vertices and 17,773 edges, with an average vertex-to-vertex distance of 8.6. The genes ZDHHC20 and RAPGEF6 were identified by centrality analysis to be important vertices. However, in the DEG analysis, we could not find meaningful fold changes in ZDHHC20 and RAPGEF6 between the TPBN and TNBN gene expression data. In the multivariate survival analysis, the hazard ratio for ZDHHC20 and RAPGEF6 was 1.677 (1.192–2.357) and 1.676 (1.222–2.299), respectively. CONCLUSION: Our TNBN gene regulatory network was a scale-free one, which means that the network would be easily destroyed if the hub vertices were attacked. Thus, it is important to identify the hub vertices in the network analysis. In the TNBN gene regulatory network, ZDHHC20 and RAPGEF6 were found to be oncogenes. Further study of these genes could help to reveal a novel method for treating TNBN in the future.
Breast Neoplasms ; Gene Expression* ; Gene Regulatory Networks* ; Genome ; Methods ; Oncogenes ; Physiology ; Triple Negative Breast Neoplasms*

PURPOSE: Despite the fact that the androgen receptor (AR) is known to be involved in the pathogenesis of breast cancer, its prognostic effect remains controversial. In this meta-analysis, we explored AR expression and its impact on survival outcomes in breast cancer. METHODS: We searched PubMed, EMBASE, Cochrane Library, ScienceDirect, SpringerLink, and Ovid databases and references of articles to identify studies reporting data until December 2013. Disease-free survival (DFS) and overall survival (OS) were analyzed by extracting the number of patients with recurrence and survival according to AR expression. RESULTS: There were 16 articles that met the criteria for inclusion in our meta-analysis. DFS and OS were significantly longer in patients with AR expression compared with patients without AR expression (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.40-0.90; OR, 0.53; 95% CI, 0.38-0.73, respectively). In addition, hormone receptor (HR) positive patients had a longer DFS when AR was also expressed (OR, 0.63; 95% CI, 0.41-0.98). For patients with triple negative breast cancer (TNBC), AR expression was also associated with longer DFS and OS (OR, 0.44, 95% CI, 0.26-0.75; OR, 0.26, 95% CI, 0.12-0.55, respectively). Furthermore, AR expression was associated with a longer DFS and OS in women (OR, 0.42, 95% CI, 0.27-0.64; OR, 0.47, 95% CI, 0.38-0.59, respectively). However, in men, AR expression was associated with a worse DFS (OR, 6.00; 95% CI, 1.46-24.73). CONCLUSION: Expression of AR in breast cancer might be associated with better survival outcomes, especially in patients with HR-positive tumors and TNBC, and women. Based on this meta-analysis, we propose that AR expression might be related to prognostic features and contribute to clinical outcomes.
Breast Neoplasms* ; Disease-Free Survival ; Female ; Humans ; Male ; Mortality ; Receptors, Androgen* ; Recurrence ; Triple Negative Breast Neoplasms

Tumor heterogeneity of triple-negative breast cancer (TNBC) has been the main barrier in conquering breast cancer. To dissect the molecular diversity of TNBC and discover therapeutic targets for TNBC, the molecular classification of TNBC is a prioritized issue in research area. Accordingly, recent studies have been successful in classifying TNBC into several distinct subtypes with specific biologic pathways. Despite the different methodologies used and varied number of final subtypes, these studies identically suggested that TNBC consists of four major subtypes: basal-like, mesenchymal, luminal androgen receptor, and immune-enriched. By reviewing these methods of classifications of TNBC, we highlight the unmet need to develop a molecular classifier suited for TNBC.
Breast Neoplasms ; Classification* ; Gene Expression ; Phenobarbital ; Population Characteristics ; Receptors, Androgen ; Triple Negative Breast Neoplasms*

Intratumor heterogeneity within a single tumor mass is one of the hallmarks of malignancy and has been reported in various tumor types. The molecular characterization of intratumor heterogeneity in breast cancer is a significant challenge for effective treatment. Using single-cell RNA sequencing (RNA-seq) data from a public resource, an ERBB pathway activated triple-negative cell population was identified. The differential expression of three subtyping marker genes (ERBB2, ESR1, and PGR) was not changed in the bulk RNA-seq data, but the single-cell transcriptomes showed intratumor heterogeneity. This result shows that ERBB signaling is activated using an indirect route and that the molecular subtype is changed on a single-cell level. Our data propose a different view on breast cancer subtypes, clarifying much confusion in this field and contributing to precision medicine.
Breast Neoplasms ; Population Characteristics ; Precision Medicine ; Sequence Analysis, RNA ; Transcriptome ; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) has a higher risk of death within 5 years of being diagnosed than the other forms of breast cancer. It is the second leading cause of death due to cancer among women. Currently, however, no diagnostic blood-based biomarker exists to identify the early stages of TNBC. To address this point, we utilized a human protein microarray system to identify serum autoantibodies that showed different expression patterns between TNBC and normal serum samples, and identified five autoantibodies showing TNBC-specific expression. Among them, we selected the thioredoxin-like 2 (TXNL2) autoantibody and evaluated its diagnostic relevance by dot blot analysis with the recombinant TXNL2 protein. We demonstrated that the TXNL2 autoantibody showed 2- to 6-fold higher expression in TNBC samples than in normal samples suggesting that serum TXNL2 autoantibodies are potential biomarkers for TNBC.
Autoantibodies ; Biomarkers ; Breast Neoplasms ; Cause of Death ; Female ; Humans ; Protein Array Analysis ; Triple Negative Breast Neoplasms*

PURPOSE: Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment. MATERIALS AND METHODS: This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups. RESULTS: A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS. CONCLUSION: Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.
Breast Neoplasms* ; Breast* ; Comorbidity ; Diagnosis ; Disease-Free Survival ; Humans ; Retrospective Studies ; Survival Rate ; Time-to-Treatment ; Triple Negative Breast Neoplasms