Background
Molecular subtyping of triple‐negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for ...guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs.
Materials and Methods
By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC‐based classifier, and applied it to another two cohorts (n = 183 and 214).
Results
We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC‐based luminal androgen receptor (IHC‐LAR; AR‐positive +), (b) IHC‐based immunomodulatory (IHC‐IM; AR‐negative −, CD8+), (c) IHC‐based basal‐like immune‐suppressed (IHC‐BLIS; AR−, CD8−, FOXC1+), (d) IHC‐based mesenchymal (IHC‐MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC‐based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC‐based classification and mRNA‐based classification. Multivariate survival analysis suggested that our IHC‐based classification was an independent prognostic factor for relapse‐free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC‐LAR subtype showed relative activation of HER2 pathway. The IHC‐IM subtype tended to exhibit an immune‐inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC‐BLIS subtype showed high expression of a VEGF signature. The IHC‐MES subtype displayed activation of JAK/STAT3 signaling pathway.
Conclusion
We developed an IHC‐based approach to classify TNBCs into molecular subtypes. This IHC‐based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.
Implications for Practice
An immunohistochemistry (IHC)‐based classification approach was developed for triple‐negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression‐based classification. This IHC‐based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype‐specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.
This article describes an immunohistochemistry‐based approach to classification of triple‐negative breast cancers into molecular subtypes for purposes of the translation of TNBC molecular classification into clinical practice.
γδT cells have been reported to exert immunosuppressive functions in multiple solid malignant diseases, but their immunosuppressive functional subpopulation in breast cancer (BC) is still ...undetermined. Here, we collected 40 paired BC and normal tissue samples from Chinese patients for analysis. First, we showed that γδT1 cells comprise the majority of CD3+ T cells in BC; next, we found that CD73+γδT1 cells were the predominant regulatory T-cell (Treg) population in BC, and that their prevalence in peripheral blood was also related to tumour burden. In addition, CD73+γδT1 cells exert an immunosuppressive effect via adenosine generation. We also found that BC could modulate CD73 expression on γδT cells in a non-contact manner. The microarray analysis and functional experiments indicated that breast tumour cell-derived exosomes (TDEs) could transmit lncRNA SNHG16, which upregulates CD73 expression, to Vδ1 T cells. Regarding the mechanism, SNHG16 served as a ceRNA by sponging miR-16-5p, which led to the derepression of its target gene SMAD5 and resulted in potentiation of the TGF-β1/SMAD5 pathway to upregulate CD73 expression in Vδ1 T cells. Our results showed that the BC-derived exosomal SNHG16/miR-16-5p/SMAD5-regulatory axis potentiates TGF-β1/SMAD5 pathway activation, thus inducing CD73 expression in Vδ1 T cells. Our results first identify the significance of CD73+Vδ1 Tregs in BC, and therapy targeting this subpopulation or blocking TDEs might have potential for BC treatment in the future.
Background
Triple‐negative breast cancer (TNBC) is a heterogeneous disease with subtypes having different “targetable” molecular aberrations. Metaplastic breast cancers (MpBCs) are typically TNBCs ...and commonly have alterations in the PI3K/Akt/mTOR pathway. We previously reported efficacy for an mTOR‐based chemotherapy regimen in MpBC. To determine if tumor subtype influences prognosis, we compared treatment outcomes of patients with MpBC with those of patients with nonmetaplastic TNBC receiving an mTOR‐based systemic therapy regimen.
Patients and Methods
Patients with advanced MpBC and nonmetaplastic TNBC were treated at our institution from April 16, 2009, through November 4, 2014, using mTOR inhibition (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab (DAT/DAE). Median progression‐free survival (PFS) and overall survival (OS) were estimated by the Kaplan‐Meier method. Cox regression analyses were used to evaluate associations between tumor histology and outcomes. Multivariable models were adjusted for all covariates.
Results
Fourteen patients with nonmetaplastic TNBC and 59 patients with advanced MpBC were treated with DAT/DAE. MpBC patients were older (p = .002) and less likely to have a history of bevacizumab use (p = .023). Median PFS for the nonmetaplastic TNBC and MpBC patients was 2.5 months and 4.8 months, respectively. This difference in PFS was statistically significant on univariable (p = .006) but not multivariable analysis (p = .087). Median OS for the nonmetaplastic TNBC and MpBC patients was 3.7 months and 10.0 months, respectively (p = .0003). MpBC remained significantly associated with improved OS on multivariable analysis (p < .0001).
Conclusion
In our study, DAT/DAE appeared to be more effective in MpBC compared with nonmetaplastic TNBC. These data support patient selection for targeted therapy in TNBC.
Implications for Practice
Metaplastic breast cancers (MpBCs) represent <1% of all breast cancers, demonstrate mesenchymal differentiation, and are typically resistant to chemotherapy. Patients with advanced MpBC treated with an mTOR‐based systemic therapy regimen had better long‐term outcomes compared with patients with nonmetaplastic triple‐negative breast cancer treated with the same regimen, suggesting that metaplastic histology may predict benefit from agents targeting the PI3K/Akt/mTOR pathway.
摘要
背景。三阴性乳腺癌 (TNBC) 是一种异质性疾病,其亚型具有不同的“可靶向”分子畸变。化生性乳腺癌 (MpBC) 通常是 TNBC,并且 PI3K/Akt/mTOR 通路通常发生改变。我们之前报告了基于 mTOR 的化疗方案对 MpBC 的效果。为了确定肿瘤亚型是否影响预后,我们比较了 MpBC 患者与接受基于 mTOR 的系统治疗方案的非化生性 TNBC 患者的治疗效果。
患者和方法。2009 年 4 月 16 日至 2014 年 11 月 4 日,我们机构采用 mTOR 抑制剂(替西罗莫司或依维莫司)搭配脂质体多柔比星和贝伐珠单抗 (DAT/DAE) 对晚期 MpBC 和非化生性 TNBC 患者进行治疗。我们通过 Kaplan‐Meier 法估算了患者的中位无进展生存期 (PFS) 和总生存期 (OS)。我们采用 Cox 回归分析评估了肿瘤组织学与预
后之间的关系 并针对所有协变量调整了多变量模型。结果。14名非化生性 TNBC 患者与 59 名晚期 MpBC 患者接受了 DAT/DAE 的治疗。MpBC 患者年龄较大 (p = 0.002)和贝伐珠单抗使用史的较少 (p = 0.023)。非化生性 TNBC 和 MpBC 患者的中位 PFS 分别为 2.5 个月和 4.8 个月。PFS 的这种差异在单变量分析中具有统计学意义 (p = 0.006),但在多变量分析则不具有统计学意义 (p = 0.087)。非化生性 TNBC 患者和 MpBC 患者的中位 OS 分别为 3.7 个月和 10.0 个月 (p = 0.000 3)。在多变量分析 (p < 0.0001) 中,MpBC 始终与 OS 的改善关系密切。
结论。我们的研究显示,DAT/DAE 对 MpBC 的效果优于对非化生性 TNBC 的效果。这些数据可帮助 TNBC 患者选择靶向治疗方案。
对临床实践的提示: 化生性乳腺癌 (MpBC) 占所有乳腺癌的比例 <1%,表现出间质分化,并且通常对化疗具有耐药性。采用基于 mTOR 系统治疗方案的晚期 MpBC 患者的长期预后效果优于采用相同治疗方案的非化生三阴性乳腺癌患者的长期预后效果,表明化生组织可能预测针对 PI3K/Akt/mTOR通路的制剂的疗效
This article reports the results of a post hoc analysis of a clinical trial, comparing outcomes of 14 patients with advanced nonmetaplastic triple‐negative breast cancer and 59 patients with advanced metaplastic triple‐negative breast cancer treated with targeted therapy using mTOR inhibition (temsirolimus or everolimus) with liposomal doxorubicin and bevacizumab.
Opinion Statement
Immunotherapy has become one of the greatest advances in medical oncology over the last century; however, the optimal application for the treatment of breast cancer remains an ...active area of investigation. Modern immunotherapy strategies augment the immune system and ideally, permit durable tumor-specific immune memory. In fact, several monoclonal antibodies that mediate the immune checkpoint receptors have provided the most clinically meaningful improvement for breast cancer patients to date, particularly for the triple negative subtype. Checkpoint blockade as monotherapy has demonstrated some encouraging results, although some combination strategies appear to augment those responses and may be particularly effective when administered earlier in the course of disease. For example, the combination of atezolizumab and nab-paclitaxel as first-line therapy for metastatic triple negative breast cancer demonstrated significant improvements in progression-free survival when compared with chemotherapy alone. Herein, we review the data for immune therapy in breast cancer and highlight promising future directions.
Disparities in Breast Cancer Grabinski, Victoria F; Brawley, Otis W
Obstetrics and gynecology clinics of North America
49, Številka:
1
Journal Article
Recenzirano
In the western world, breast cancer is the most common lethal cancer in women and the second leading cause of cancer death behind lung cancer. When assessing registry data, incidence and mortalty ...vary significantly by race or ethnicity and by socioeconomic status. There are a number of established risk factors, that effect risk of not just risk of breast cancer overall but the risk of certain molecular subtypes of breast cancer. Other factors in the disparity in outcomes include certain populations experiencing lower quality of care; prevention, screening, diagnosis and treatment.
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