Genetic Markers in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancer cases and is characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Though TNBC is a highly heterogenic and aggressive disease, TNBC patients have better response to neoadjuvant therapy compared to other breast cancer subtypes. Nevertheless, patients with residual disease have a very poor prognosis, with higher probability of relapse and lower overall survival in the first years after diagnosis. TNBC has 6 subtypes with distinct molecular signatures with different prognoses and probably different responses to therapy. The precise stratification of TNBC is therefore crucial for the development of potent standardized and targeted therapies. In spite of intensive research into finding new molecular biomarkers and designing personalized therapeutic approaches, BRCA mutational status is the only clinically validated biomarker for personalized therapy in TNBC. Recent studies have reported several promising biomarkers that are currently being validated through clinical trials. The objective of this review was to summarize the clinically relevant genetic markers for TNBC that could serve as diagnostic, prognostic, or predictive or could improve personalized therapeutic strategies.     

三阴性乳腺癌的治疗进展

三阴性乳腺癌（TNBC）是一类临床病理相对独立的乳腺癌类型,具有侵袭性强、预后差的特点。由于内分泌治疗和针对HER-2的靶向治疗效果差,化疗仍是TNBC主要的治疗手段。然而TNBC具有较强的异质性,对其进行精细分型,探索新的精准治疗方法成为当务之急。本文将整理重要的临床试验结果,分析TNBC的治疗策略,包括手术治疗、放射治疗、化疗、靶向治疗以及免疫治疗等,为TNBC的临床治疗提供参考。     

Current status and future perspectives for the treatment of triple-negative breast cancer in Japan

Triple-negative breast cancer (TNBC) is negative for all three markers, namely the hormone sensitivity receptors: estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for approximately 15% of all primary breast cancer cases. In general, patients with this disease have a higher risk of recurrence and a poorer prognosis compared with those with other subtypes of breast cancer. Patients with TNBC are defined as those for whom endocrine or anti-HER2 therapy are not indicated due to poor response. It is a heterogeneous disease group that shows various characteristics. There is a group that achieves a complete response to chemotherapy and has an excellent prognosis, a group that does not respond to chemotherapy and has a poor prognosis, and a group that has an excellent inherent prognosis and does not need chemotherapy. The subdivision of TNBC cases based on the prognosis and response to therapy is an issue for the future. In addition to classifying TNBC into basal and non-basal types by testing cytokeratin 5/6 (CK5/6) and epidemic growth factor receptors (EGFR) by the immunohistochemical staining method, Ki-67 may predict sensitivity to anticancer agents and a change in Ki-67 before and after therapy may potentially predict prognosis. Patients with a non-pathologic complete response (non-pCR) to preoperative chemotherapy have a high risk of early recurrence, and measures to deal with it are therefore needed. At present, the most commonly used perioperative chemotherapy is sequential combination therapy of an anthracycline drug and a taxane drug; however, it is limited because the pathologic complete response(pCR)rates following preoperative chemotherapy range from 30 to 40%. There is also an urgent need to develop a regimen that will overcome this problem. In association with BRCA gene mutations, sensitivity to DNA-damaging anticancer agents may lead to promising therapies. However, unfortunately, the use of DNA-damaging agents such as cisplatin and carboplatin is not covered by health insurance in Japan. Various new molecular targeted drugs aimed at blocking cell proliferation factors are expected to be developed in the future. Here we have summarized the current status and issues based on the clinical experience with the diagnosis and treatment of TNBC.     

三阴性乳腺癌辅助化疗预后生物标志物的研究进展

三阴性乳腺癌（triple-negative breast cancer,TNBC）具有组织学分级高、临床分期晚、侵袭性强、易发生转移等特点。由于缺乏有效的治疗靶点,传统化疗仍是TNBC患者主要的治疗选择。作为高度异质性疾病,TNBC需要更为精确的预测生物标志物。组学技术的发展及临床试验的实施为辅助化疗预后生物标志物带来新的探索,涵盖基因、蛋白及微环境成分等不同维度,也包括多分子的联合分析应用。本文将对TNBC辅助化疗预后生物标志物及其潜在分子机制与未来发展方向进行综述。      

Early-stage Triple-negative Breast Cancer: Time to Optimize Personalized Strategies

Triple-negative breast cancer (TNBC) accounts for approximately 15%-20% of breast cancers diagnosed worldwide, which amounts to almost 200 000 cases each year. Although historically TNBC is considered difficult to treat with a poor prognosis, there is emerging evidence showing excellent response rates in a subset of TNBC patients. Attempts to de-escalate chemotherapy in hormone-receptor-positive (HR+) and HER2-neu amplified breast cancer subtypes have been successful. At present, robust strategies to personalize therapy in early-stage TNBC do not exist, and despite excellent response rates in a subset of patients, all patients are exposed to the same several cycles of cytotoxic chemotherapy. Personalizing therapy in TNBC represents a challenge due to the scarcity of treatment options outside of cytotoxic chemotherapy and limited predictive and prognostic biomarkers to tailor treatment. Recent developments in understanding TNBC biology have sparked interest in exploring treatment optimization and personalization with the goal of achieving excellent response rates and long-term clinical outcomes, while simultaneously reducing physical, psychological, and financial toxicities for select patients. Here, we provide an update on the current evidence to support future studies examining de-escalating chemotherapy in patients with low-risk TNBC and adjuvant intensification strategies to improve outcomes for patients who are at high risk for systemic failure despite current standard-of-care treatments.     

化疗联合PD-(L)1单抗治疗晚期三阴性乳腺癌的研究进展

乳腺癌是目前国内女性发病率最高的恶性肿瘤,其中15%~20%为三阴性乳腺癌（triple negative breast cancer,TNBC）。乳腺癌整体预后较好,但TNBC恶性程度高、治疗手段少,导致晚期TNBC患者临床预后较差。随着近几年免疫检查点抑制剂 (immune checkpoint inhibitors,ICIs)的问世,免疫治疗［主要是PD-(L)1单抗］成为TNBC患者可选择的一种治疗方式。然而PD-(L)1单抗单药治疗TNBC有效率不高,化疗联合PD-(L)1单抗能给TNBC患者带来更好的反应率和预后。化疗与PD-(L)1单抗的协同作用机制目前尚不明确,限制了化疗联合PD-(L)1单抗在TNBC中的应用。本文分别总结了化疗对肿瘤免疫微环境的调控和PD-(L)1单抗对肿瘤免疫微环境的调控,并特别从微生物组、肿瘤代谢等方面综述了化疗与PD-(L)1单抗交互作用在晚期TNBC治疗中的研究进展,以期为进一步提高化疗联合PD-(L)1单抗在TNBC中的疗效提供参考。     

GRB7 is required for triple-negative breast cancer cell invasion and survival

Triple-negative breast cancer (TNBC) is a heterogeneous disease that is usually associated with poor prognosis, and frequently associated with the basal-like breast cancer gene expression profile. There are no targeted therapeutic modalities for this disease, and no useful biomarkers. High GRB7 RNA expression levels are associated with an elevated risk of recurrence in patients with operable TNBC treated with standard adjuvant anthracycline and taxane therapy. To determine whether GRB7 is involved in the pathobiology of TNBC, we evaluated the biological effects of GRB7 inhibition in a panel of triple-negative cell lines-MDA-MB-468, MDA-MB-231, HCC70, and T4-2. We found GRB7 inhibition reduced cell motility and invasion of these cell lines and promoted cell death by apoptosis in 3D culture. These data suggest that GRB7 itself, or GRB7-dependent pathways, may prove to be important therapeutic targets in this disease.     

Diagnostic and prognostic significance of serum apolipoprotein C-I in triple-negative breast cancer based on mass spectrometry

Women with triple-negative breast cancer (TNBC) have poor prognosis because of the aggressive nature of the tumor, delayed diagnosis and non-specific symptoms in the early stages. Identification of novel specific TNBC serum biomarkers for screening and therapeutic purposes therefore remains an urgent clinical requirement.We obtained serum samples from a total of 380 recruited individuals split into mining and testing sets, with the aim of screening for reliable protein biomarkers from TNBC and non-TNBC (NTNBC) sera. Samples were assessed using mass spectrometry, followed by receiver operating characteristic (ROC), survival and hazard function curve as well as multivariate Cox regression analyses to ascertain the potential of the protein constituents as diagnostic and prognostic biomarkers for TNBC.We identified upregulated apolipoprotein C-I (apoC-I) with a validated positive effect on TNBC tumorigenesis, with confirmation in an independent test set and minimization of systematic bias by pre-analytical parameters. The apoC-I protein had superior diagnostic ability in distinguishing between TNBC and NTNBC cases. Moreover, the protein presented a more robust potential prognostic factor for TNBC than NTNBC. The apoC-I protein identified in this study presents an effective novel diagnostic and prognostic biomarker for TNBC, indicating that measurement of the peak intensity at 7785 Da in serum samples could facilitate improved early detection and estimation of postoperative survival prognosis for TNBC.     

Emerging trends in the treatment of triple-negative breast cancer in Canada: a survey

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other subtypes and lacks common therapeutic targets, including HER 2 and the estrogen and progesterone receptors. The clinicopathological heterogeneity of the disease and limited treatment options make clinical management particularly challenging. Here we present the results of a survey of Canadian clinical oncologists regarding treatment of TNBC, and review recent and ongoing clinical research in this area. Our survey results show that the majority of respondents use a combination of anthracyclines-taxanes as adjuvant therapy for early TNBC. For the first-line treatment of metastatic TNBC, most clinicians recommend taxanes, while single agent capecitabine and platinum-based therapies are more common for subsequent lines of therapy. Despite the ongoing development of novel targeted therapies, chemotherapy remains the mainstay of treatment for TNBC.     

Exosomal miRNA profiles of triple-negative breast cancer in neoadjuvant treatment

Triple-negative breast cancer (TNBC) is characterized by aggressive clinicopathological features and is associated with a poor prognosis. Identifying patients that are non-responsive to chemotherapy remains a critical goal for effective personalized therapies. In the present study, the predictive value of exosomal microRNAs (miRNAs) was investigated in patients with TNBC. Exosomes were isolated from patients with TNBC undergoing neoadjuvant chemotherapy. Microarray-based miRNA profiles were compared between patients with pathological complete response (pCR; n=12) and non-pCR (n=12). Furthermore, the miRNA profiles of non-pCR patients with breast cancer recurrence were compared with those with no recurrence. A total of 16 differentially expressed exosomal miRNAs were identified between the patients with pCR and non-pCR by microarray analysis. Of these, a combined signature of four miRNAs (miR-4448, miR-2392, miR-2467-3p and miR-4800-3p) could be used to discriminate between pCR and non-pCR patients with TNBC with an area under the curve value of 0.7652. Furthermore, this study found 43 differentially expressed miRNAs between the patients with non-pCR and recurrence and non-pCR patients without recurrence. In network analysis, ‘pathway in cancer’, ‘focal adhesion’ and ‘cell cycle’ were identified as the crucial pathways in patients with non-pCR who also developed recurrence. Several exosomal miRNAs may be useful biomarkers to predict treatment efficacy for TNBC. The present study identified patients who were resistant to standard chemotherapy and therefore more likely to develop breast cancer recurrence.     

肿瘤干细胞在三阴性乳腺癌治疗耐药中的作用及机制研究进展

三阴性乳腺癌（TNBC）是雌激素受体（ER）、孕激素受体（PR）、人类表皮生长因子受体2（HER-2）蛋白均呈阴性的临床亚型,占所有乳腺癌病例的15%~20%。与其他亚型相比,TNBC更具侵袭性,其预后差、复发转移率和病死率高。一直以来,TNBC的治疗面临着巨大的挑战,由于治疗靶点的缺乏,细胞毒性化疗是唯一被批准用于TNBC的全身治疗方案。为了改善TNBC患者的疗效,研究者们开展了大量的临床试验来探索更多有效的治疗手段。乳腺癌干细胞（BCSC）的自我更新分化是乳腺癌发生发展的重要机制,能够调控乳腺癌的侵袭转移和治疗抵抗,TNBC中肿瘤干细胞（CSC）比例的升高与化疗耐药和不良预后相关。本综述阐述了TNBC的治疗现状以及CSC在TNBC的发生发展、治疗耐药中的作用机制,探讨了CSC及相关信号因子作为TNBC治疗靶点的潜在价值。     

Targeting triple-negative breast cancer: A clinical perspective

Triple-negative breast cancer (TNBC) is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer. TNBC accounts for approximately 10%–15% of all diagnosed breast cancer cases and represents a high unmet need in the field. Up to just a few years ago, chemotherapy was the only systemic treatment option for this subtype (1). To date, TNBC is considered a heterogeneous disease. One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases, in which Lehman et al. proposed six subtypes of TNBC as follows: two basal-like (BL1 and BL2) subtypes, a mesenchymal (M) subtype, a mesenchymal stem-like (MSL) subtype, an immunomodulatory (IM) subtype, and a luminal androgen receptor (LAR) subtype (2). Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes (TILs) or stromal cells. According to this finding, the classification of TNBC has been revised into the following four subtypes: basal 1, basal 2, LAR, and mesenchymal subtypes (3). Over the last years, several new strategies have been investigated for the treatment of patients with TNBC. Among them, immunotherapy, antibody drug conjugates, new chemotherapy agents, and targeted therapy have been and are currently being developed. The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.     

Triple‐negative breast cancer: Present challenges and new perspectives

Triple‐negative breast cancers (TNBC), characterized by absence of estrogen receptor (ER), progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), are typically associated with poor prognosis, due to aggressive tumor phenotype(s), only partial response to chemotherapy and present lack of clinically established targeted therapies. Advances in the design of individualized strategies for treatment of TNBC patients require further elucidation, by combined ‘omics’ approaches, of the molecular mechanisms underlying TNBC phenotypic heterogeneity, and the still poorly understood association of TNBC with BRCA1 mutations. An overview is here presented on TNBC profiling in terms of expression signatures, within the functional genomic breast tumor classification, and ongoing efforts toward identification of new therapy targets and bioimaging markers. Due to the complexity of aberrant molecular patterns involved in expression, pathological progression and biological/clinical heterogeneity, the search for novel TNBC biomarkers and therapy targets requires collection of multi‐dimensional data sets, use of robust multivariate data analysis techniques and development of innovative systems biology approaches.     

三阴性乳腺癌的免疫联合治疗研究进展

三阴性乳腺癌（TNBC）为一种预后较差的分子亚型，传统治疗手段有限；该亚型的免疫原性强，且肿瘤微环境中肿瘤浸润淋巴细胞水平高，为免疫治疗的开展提供了基石。免疫治疗联合化疗的疗效优于单药免疫治疗，且在晚期一线TNBC的有效率高于既往多线治疗组。联合其他治疗包括抗肿瘤血管生成、免疫调节剂和PARP抑制剂的尝试亦取得初步疗效。本文就三阴性乳腺癌的免疫治疗单药及联合治疗的疗效、安全性及未来的挑战进行综述。     

Serum sPD-1 and sPD-L1 as Biomarkers for Evaluating the Efficacy of Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients

BackgroundNeoadjuvant chemotherapy (NAC) is widely administered in the primary treatment of triple-negative breast cancer (TNBC). However, serum biomarkers for evaluating or monitoring the curative efficacy of NAC have not been established. Accumulating data have shown that soluble programmed death 1 (sPD-1) and its ligand (sPD-L1) might be potential biomarkers for evaluating the curative efficacy of chemotherapy and patient prognosis in several cancers but not yet in breast cancer.Patients and MethodsBlood specimens were obtained from 66 TNBC patients who received NAC and 59 healthy women. The serum concentrations of sPD-1 and sPD-L1 were measured by enzyme-linked immunosorbent assay.ResultsCompared to healthy women, the serum concentration of sPD-1 was significantly elevated in TNBC patients before NAC (549.3 ± 58.76 pg/mL vs. 379.2 ± 17.30 pg/mL, P = .007), but there was only an increase tendency for sPD-L1 (227.7 ± 23.99 pg/mL vs. 195.0 ± 8.49 pg/mL, P = .22). The serum levels of sPD-1 and sPD-L1 before NAC in TNBC patients increased with tumor stage (P = .038 and .030, respectively). Patients who experienced complete or partial remission after NAC had significantly decreased serum levels of sPD-1 and sPD-L1 compared to patients with a poor response to NAC (P = .019 and .021, respectively).ConclusionSerum levels of sPD-1 and sPD-L1 could be used as noninvasive biomarkers for evaluating the malignancy of TNBC before NAC and for predicting the NAC response in TNBC patients.     

肿瘤浸润淋巴细胞在三阴性乳腺癌中作用的研究进展

三阴性乳腺癌（TNBC）是一种高度异质性的疾病。因缺乏有效的治疗靶标,故临床预后较差。尽管大量文献报道肿瘤浸润淋巴细胞与TNBC预后之间的关系,但区分不同类型的T淋巴细胞极其重要,因为他们在肿瘤微环境中发挥着不同的作用。此外,有研究发现肿瘤相关巨噬细胞与TNBC预后不良相关。本文将对不同淋巴细胞浸润在TNBC临床预后中的作用作一综述。     

Metastatic triple negative breast cancer: Optimizing treatment options,new and emerging targeted therapies

Triple negative breast cancer (TNBC) is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. It also has a distinct epidemiology. TNBCs are frequently of high histologic grade, typically more aggressive and difficult to treat than hormone receptor‐positive tumors, and they are associated with a higher risk of early relapse with visceral metastasis after surgery, chemotherapy and/or radiotherapy. The lack of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression precludes the use of targeted therapies in advanced stages, and the only approved systemic treatment option is chemotherapy with or without bevacizumab. In patients with advanced TNBC, responses to chemotherapy occur, but are often of short duration and it is associated with poor prognosis. The median overall survival for patients with metastatic TNBC is about 9–12 months with conventional cytotoxic agents. Given the suboptimal outcomes with chemotherapy, new targeted therapies for TNBC are urgently needed. This review summarizes the clinical efficacy, perspectives and future challenges of using new treatment options for metastatic TNBC, such as poly‐ADP‐ribose‐polymerase inhibitors, antiandrogen therapies and immune checkpoint inhibitors (antiprogrammed death receptor‐1/PD‐L1 monoclonal antibodies).     

早期三阴性乳腺癌新辅助免疫治疗联合化疗的研究进展

三阴性乳腺癌（triple-negative breast cancer,TNBC）占乳腺癌的15%～20%,具有侵袭性强,预后差的特点,且以紫杉烷类、蒽环类及环磷酰胺为基础的新辅助化疗方案疗效与患者长期生存获益仍不尽人意。TNBC因免疫原性较强,免疫治疗可使其有较大的疗效获益。近年来,早期TNBC患者新辅助免疫治疗联合化疗的研究引起人们广泛关注,本文将就早期TNBC新辅助免疫治疗联合化疗的治疗策略、疗效与安全性,及影响其疗效因素的研究进行综述。      

Biomarkers in triple negative breast cancer: A review

Breast cancer is an intrinsically heterogeneous disease. In the world about 1 million cases of breast cancer are diagnosed annually and more than 170000 are triple-negative. Characteristic feature of triple negative breast cancer (TNBC) is that it lacks expression of oestrogen, progesterone and human epidermal growth factor receptor-2/neu receptors. They comprise 15%-20% of all breast cancers. We did a systematic review of PubMed and conference databases to identify studies published on biomarkers in TNBC. We included studies with biomarkers including: Epidermal growth factor receptor, vascular endothelial growth factor, c-Myc, C-kit and basal cytokeratins, Poly(ADP-ribose) polymerase-1, p53, tyrosinase kinases, m-TOR, heat and shock proteins and TOP-2A in TNBC. We also looked for studies published on synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. TNBC is a complex disease subtype with many subclasses. Majority TNBC have a basal-like molecular phenotype by gene expression profiling. Their clinical and pathologic features overlap with hereditary BRCA1 related breast cancers. Management of these tumours is a challenge to the clinician because of its aggressive behaviour, poor outcome, and absence of targeted therapies. As the complexity of this disease is being simplified over time new targets are also being discovered for the treatment of this disease. There are many biomarkers in TNBC being used in clinical practice. Biomarkers may be useful as prognostic or predictive indicators as well as suggest possible targets for novel therapies. Many targeted agents are being studied for treatment of TNBC.     

三阴性乳腺癌组织中TOPK的表达及其与新辅助化疗治疗反应和预后的相关性

目的:探讨T-LAK细胞起源的蛋白激酶（TOPK）在三阴性乳腺癌（TNBC）组织中的表达和作用,研究TOPK表达与新辅助化疗（NACT）治疗反应和预后的关系。方法:收集66例采用多西他赛+表柔比星+环磷酰胺（TEC）NACT方案的TNBC患者治疗前后的组织学标本,用免疫组化的方法检测TOPK和Ki-67的表达,采用Miller-Payne（MP）系统评估治疗反应,并对患者的无进展生存期（PFS）进行生存分析。结果:MP分级较低（1-3级）的患者组织中的TOPK阳性率高于MP分级较高（4-5级）的患者,在NACT治疗中TOPK阳性患者的预后不佳。同时发现MP 1-3级患者在NACT后组织中TOPK表达升高,而MP 4-5级患者NACT后组织中TOPK表达降低。NACT治疗后组织中TOPK升高的患者的PFS较TOPK降低者差。接受者操作特性曲线（ROC）结果表明,NACT前后患者组织中TOPK表达变化对预后的评估准确性更高。结论:TNBC组织中TOPK水平高的患者对NACT治疗反应不佳,并且预后较差。TOPK表达水平可能提示TNBC的NACT治疗反应和预后。