Exploring circulating micro‐RNA in the neoadjuvant treatment of breast cancer

Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in vivo tumour response to chemotherapeutics. Currently, there is no effective means of identifying chemotherapeutic responders from non‐responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy. Micro‐RNAs (miRNAs) are small non‐coding RNA molecules. With their tissue‐specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood‐borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed.     

Significance of immunohistochemistry in breast cancer

The biological characteristics of the tumour are used to estimate prognosis and select appropriate systemic therapy for patients with (breast) cancer. The advent of molecular technology has incorporated new biomarkers along with immunohistochemical and serum biomarkers. Immunohistochemical markers are often used to guide treatment decisions, to classify breast cancer into subtypes that are biologically distinct and behave differently, and both as prognostic and predictive factors. Steroid hormone receptors, markers of tumour proliferation, and factors involved in angiogenesis and apoptosis are of scientific interest. In this review we will provide information on the immunohistochemical markers used in the management of breast cancer patients using available data from the literature. We consider the utility of established immunohistochemical markers, and discuss the challenges involved in integrating novel molecular markers into clinical practice.     

Interpreting and integrating risk factors for patients with primary breast cancer.

The term risk factor has different meanings in different contexts. Some factors may be patient specific (e.g., race, age, socioeconomic status, and environment), while others may be disease specific (e.g., biomarkers measured on tumor specimens, serum, and bone marrow). These factors have several potential clinical uses, including diagnosing a disease or assessing the risk of developing a disease, estimating prognosis for patients diagnosed with a specific disease who receive no therapy, predicting response to a particular therapy, monitoring response to therapy during a treatment course, and identifying targets of opportunity for new therapies. This article focuses on prognostic and predictive biomarkers and provides guidelines for interpreting published reports about these biomarkers. Application of these guidelines to the assessment of micrometastases in bone marrow of patients with breast cancer yields the conclusion that standardized techniques that are sensitive and reproducible for detecting micrometastases are needed before we can evaluate their prognostic significance.     

Cyclin E as a prognostic and predictive marker in breast cancer

Breast cancer is the most common cancer in American women and is second only to lung cancer as the leading cause of death among women with solid tumors. Although chemotherapy and hormonal therapy are widely used in the primary treatment of breast cancer, appropriate selection of patients for such treatment remains challenging. Traditional prognostic factors --such as age, lymph node status, tumor size, tumor grade, and hormone receptor status--have been useful in assessing the risk for development of metastatic disease and these have been incorporated into a program that is available online for risk assessment (www.adjuvantonline.com). Molecular markers have not been incorporated into this schema but certainly have the potential for further refining risk assessment. Once the risk of recurrence is established for each patient, this can then be used to determine the potential effectiveness of hormonal therapy, chemotherapy, or the combination of these treatments. While the use of this web-based system has certainly empowered physicians and patients in making adjuvant therapy decisions, it is inadequate for precise stratification of patient cohorts into responders versus non-responders to systemic agents. Identification of accurate prognostic indicators and predictors of response have the potential to profoundly impact treatment selection for individual patients. Further, identification of prognostic factors with underlying biology that can serve as therapeutic targets will be important for identification and treatment of high-risk patients. Here we discuss the role of cyclin E as a prognostic marker and predictive factor in breast cancer management and the potential to use this marker as a target for therapy.     

Conservative Management of Positive Axilla After Neoadjuvant Systemic Therapy—The Need for,and Review of,Techniques Used for Lymph Node Localization

Involvement of axillary lymph nodes is an important prognostic factor in relationship to the management of breast cancer. However, the use of neoadjuvant systemic therapy is widespread in the treatment of positive axilla and such treatment leads to downstaging of axillary disease. Hence, the role of targeted axillary lymph node biopsy appears to play a vital role after primary systemic therapy. Given that this is a relatively novel approach, we have discussed the evidence for this approach and the different techniques currently available for localization of biopsy-proven metastatic axillary lymph nodes. We have also highlighted the need for universal guidelines for conservative management of positive axilla after systemic therapy.     

局部区域复发乳腺癌的治疗进展

和初治的乳腺癌相比,局部区域复发性患者的预后分析和挽救治疗策略选择存在更多的不确定性。本文首先分析了影响保乳手术和乳房切除术后局部-区域复发的高危因素以及相应的复发模式。以再次手术和包括完整复发灶及相应亚临床病灶的放射治疗为主要形式的局部治疗是综合治疗策略的基础,合理的局部治疗可以达到有效的局部疾病控制率并降低二次局部区域复发。虽然既往的前瞻性或回顾性资料对于全身治疗在局部-区域复发乳腺癌治疗中的价值始终没有确认,由多个国际乳腺癌研究组织联合发起的CALOR研究结果的公布第一次证实,在保留合理的内分泌治疗和靶向治疗的前提下,手术+放射治疗联合后续的全身化疗可以进一步提高无病生存率和总生存率,尤其在激素受体阴性的患者中获益更显著。所以结合原发病灶和复发灶的肿瘤标志物给予合理的全身治疗将成为局部区域复发患者综合治疗重要的组成部分。     

Role of biologic markers in patient selection and application to disease prevention

Aromatase inhibitors (AIs) are now under investigation for the treatment of early stage breast cancer and for disease prevention as alternatives to standard treatment with tamoxifen. Currently identified genetic risk factors of breast cancer include BRCA-1/BRCA-2 mutations, ATM mutations, and history of high estrogen levels, as evidenced by plasma analyses and/or dense bones. To date, estrogen receptor (ER) and progesterone receptor (PgR) status has predictive value for determining response to therapy in patients with hormone receptor-positive breast cancer (ER+ and/or PgR+ tumors). Recent studies have shown AIs to be safer and more effective than tamoxifen in postmenopausal women with advanced disease. Some data suggest that letrozole may be a more effective treatment than tamoxifen for patients with ER+ and/or PgR+ early breast cancers expressing ErbB-1 and/or ErbB-2. Changes in cell proliferation markers (e.g., S-phase fraction and Ki67 antigen), plasma lipid levels, and the bone resorption marker C-terminal peptide are biomarkers that have been evaluated for preventive and prognostic value in breast cancer patients and normal volunteers. Results from biomarker screens can be used to define inclusion criteria for clinical trials and eventually to individualize treatment. Gene expression profiling (microarray analysis), i.e., genomic and proteomic studies, will probably advance the discovery of new biomarkers for breast cancer prevention and treatment.     

What is the role of chemotherapy in estrogen receptor-positive,advanced breast cancer?

Most breast tumors depend on female sex hormones for development and growth, thus being amenable to endocrine therapies. In the management of estrogen receptor (ER)-positive, advanced breast cancer, conventional wisdom dictates the use of endocrine therapy for patients with good prognostic features, whereas chemotherapy is recommended for the treatment of visceral crisis. There is, however, considerable uncertainty regarding the best initial strategy for patients with poor prognostic features other than visceral crisis, such as small-volume visceral involvement and a short disease-free interval after adjuvant therapy. In this article, we examine the role of chemotherapy in ER-positive, advanced breast cancer. Our review of the literature suggests that, in the absence of visceral crisis, endocrine agents should always be considered a major option for the initial treatment of ER-positive, metastatic breast cancer due to their proven efficacy and favorable toxicity profile. Although certain chemotherapy agents can induce higher response rates and more rapid responses, which are desirable effects in particular situations, the up-front use of chemotherapy does not seem to influence the overall outcome of the disease. In the subset of patients with epidermal growth factor type 2-positive disease, on the other hand, current data still do not support the use of endocrine agents alone.     

EGF receptor in lung cancer: a successful story of targeted therapy

Lung cancer research has incorporated molecular medicine into the management of this disease during the last 5 years. Several novel tumorigenesis pathways associated with lung cancer development and proliferation have been discovered and further developed as targets. The idea behind this is to deliver individualized therapy for each patient based on his/her tumor phenotype, which may involve the overexpression or lack of certain proteins, receptors, mutations and other factors. To date, many of these characteristics have been shown to have a potential role as prognostic or predictive biomarkers, with most of the available data being obtained from retrospective analyses, various laboratory platforms, and data sets used for comparison. However, well-designed prospective randomized clinical trials are underway to validate the significance and future role of these novel biomarkers, allowing us to sort out the best personalized management for an individual with lung cancer diagnosis. Nevertheless, one of these features, the EGF receptor (EGFR) gene mutation, has emerged as a prognostic and strongly predictive biomarker when EGFR inhibition is used as a therapy for tumors that harbor the mutation. Our article displays the most recently developed data related to this biomarker and what have we learned based on the analyses of clinical trials that have studied different agents in the clinical arena.     

EGF receptor in lung cancer: a successful story of targeted therapy

Lung cancer research has incorporated molecular medicine into the management of this disease during the last 5 years. Several novel tumorigenesis pathways associated with lung cancer development and proliferation have been discovered and further developed as targets. The idea behind this is to deliver individualized therapy for each patient based on his/her tumor phenotype, which may involve the overexpression or lack of certain proteins, receptors, mutations and other factors. To date, many of these characteristics have been shown to have a potential role as prognostic or predictive biomarkers, with most of the available data being obtained from retrospective analyses, various laboratory platforms, and data sets used for comparison. However, well-designed prospective randomized clinical trials are underway to validate the significance and future role of these novel biomarkers, allowing us to sort out the best personalized management for an individual with lung cancer diagnosis. Nevertheless, one of these features, the EGF receptor (EGFR) gene mutation, has emerged as a prognostic and strongly predictive biomarker when EGFR inhibition is used as a therapy for tumors that harbor the mutation. Our article displays the most recently developed data related to this biomarker and what have we learned based on the analyses of clinical trials that have studied different agents in the clinical arena.     

Markers for the identification of late breast cancer recurrence

Postmenopausal women with early breast cancer are at an ongoing risk of relapse, even after successful surgery and treatment of the primary tumor. The treatment of breast cancer has changed in the past few years because of the discovery of prognostic and predictive biomarkers that allow individualized breast cancer treatment. However, it is still not clear how to identify women that are at high risk of a late recurrence. Clinical parameters are good prognostic markers for early recurrence, but only nodal status and, to a lesser extent, tumor size have proven to be strong prognostic markers for late recurrence. Multi-gene signatures have become widely used for the prediction of overall recurrence risk and tailoring administration of adjuvant chemotherapy, but only a few have been shown to be prognostic for late (distant) relapse. There is a need to accurately identify women who may benefit from extended endocrine therapy but also those who may be spared any additional treatment. Recent results from large clinical trials have shown that the research is going in the right direction, and these results might help to optimize extended endocrine therapy for patients with early breast cancer. However, further research is needed to select individual biomarkers or multi-gene signatures that offer identification of late recurrence specifically and thus justify routine use of these tests in the clinical setting.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-015-0516-0) contains supplementary material, which is available to authorized users.     

Post-neoadjuvant strategies in breast cancer: From risk assessment to treatment escalation

The post-neoadjuvant setting in early breast cancer represents an attractive scenario for adjuvant clinical trials, offering the opportunity to test new drugs or combinations in high-risk patients who did not achieve pathologic complete response after primary treatment. No standard therapies are routinely proposed to patients with residual disease after neoadjuvant chemotherapy and few trials have explored this setting. To date, only one randomized phase III study showed the benefit of additional capecitabine after neoadjuvant chemotherapy, and international guidelines recommend at least to consider its use, particularly for triple negative breast cancer. Therefore, the management of these patients is still a clinical challenge, with limited data supporting the use of an additional adjuvant non-cross-resistant chemotherapy. Escalation strategies are currently under evaluation, with new agents proposed as supplementary post-neoadjuvant treatment (e.g. platinum salts, capecitabine, poly ADP-ribose polymerase inhibitors, immune checkpoint inhibitors, cyclin-dependent kinase 4/6 inhibitors). Based on these premises, selection criteria are critical to identify patients who may benefit from post-neoadjuvant therapies, through the validation of prognostic and predictive biomarkers for a reliable risk assessment and estimation of benefit.The present review summarizes the efforts in introducing new therapeutic options for patients with breast cancer and residual disease after neoadjuvant treatment, with a particular focus on the ongoing clinical trials and useful biomarkers for risk stratification.     

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.     

Biomarkers in breast cancer

Biomarkers are measured in the management of breast cancer patients for the following purposes. (1) Early detection of breast cancer: blood tumor markers such as CA 15-3 are useless for this detection because of a low sensitivity. Proteomics profiling has recently been investigated using blood or nipple aspirate fluid for the detection. Measurement of CEA and HER 2 in abnormal nipple discharge has been approved for diagnosis of breast cancer in Japan. (2) Monitoring of breast cancer patients: serum tumor markers are routinely measured for early detection of recurrent diseases, evaluation of therapeutic response and monitoring outcome of patients by a majority of breast cancer experts in Japan. Study results investigated by the Study Group of the Japanese Breast Cancer Society in 2001 are presented with regard to the questionnaire survey on the present status of tumor marker measurement and the clinical study on usefulness of tumor markers for the evaluation for therapeutic response. (3) Prognostic factors: new biomarkers have been investigated to select patients at high risk for distant metastases, which could not be selected by classic prognostic factors. Three prognostic factors (UPA/PAI-1, cyclin E, gene profiling), which were discussed at the 8th St. Gallen International Consensus Meeting last year, are mainly discussed. (4) Predictive factors for therapeutic response: hormone receptors (HR) have been used as reliable predictive factors for response to endocrine therapy. Other biomarkers have been investigated to select patients with tumors HR-positive but unresponsive to endocrine therapy. Current status, clinical significance, problems and future directions on predictive factors for response to cytotoxic chemotherapy are also discussed.     

The prognostic and predictive role of 21-gene recurrence scores in hormone receptor-positive early-stage breast cancer

Over the past two decades, gene expression profiling of breast cancer has emerged as an important tool in early-stage breast cancer management. The approach provides important information on underlying biological mechanisms, breast cancer classification, future risk potential of developing recurrent metastatic disease, and provides beneficial clues for adjuvant chemotherapy in hormone receptor (HR) positive breast cancer. Of the commercially available genomic tests for breast cancer, the prognostic and predictive value of 21-gene recurrence score tests have been validated using both retrospective data and prospective clinical trials. In this paper, we reviewed the current evidence on 21-gene expression profiles for HR-positive HER2-negative early-stage breast cancer management. We show that current evidence supports endocrine therapy alone as an appropriate adjuvant systemic therapy for approximately 70% of women with HR-positive, HER2-negative, node-negative breast cancer. Evolving evidence also suggests that 21-gene recurrence scores have predictive values for node-positive breast cancer and that chemotherapy can be avoided in more than half of women with nodes 1 to 3 positive HR-positive breast cancer. Furthermore, retrospective data also supports the predictive role of 21-gene recurrence scores for adjuvant radiation therapy. A prospective trial in this area is ongoing.     

乳腺癌预后分子生物标志物的研究进展

乳腺癌是女性较常见的恶性肿瘤,其发病率和死亡率均居恶性肿瘤前列,严重威胁女性的健康。乳腺癌预后生物标志物对预测乳腺肿瘤恶性程度、转移情况和复发情况,以及指导临床治疗方案等具有重要意义。近年来,乳腺癌预后相关分子生物标志物的研究不断取得进展,为有效预测乳腺癌预后状况提供了更多依据。本文将对乳腺癌预后分子生物标志物进行综述。     

Tumor markers in breast cancer- European Group on Tumor Markers recommendations.

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins (CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin (trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy.     

中国早期乳腺癌术后辅助治疗开展现状——一项基于110家医院的横断面调查研究

背景与目的：乳腺癌术后辅助治疗是乳腺癌综合治疗的重要组成部分之一。对中国乳腺癌诊疗现状进行基线调查,掌握早期乳腺癌术后辅助治疗的开展情况。方法：选取全国范围内110家乳腺癌年手术量超过200例的医疗机构,以问卷调查形式开展研究,调查内容包括手术医师及其所在科室和医院的基本情况、2017年乳腺癌手术开展情况,以及对乳腺癌术后辅助治疗相关热点问题的具体决策。结果：80.9%的受访医院使用常规病理学指标作为预后评价工具,多基因检测工具的使用比例不到20%。对于T 1a 期患者,48.2%的医院对人表皮生长因子受体2（human epidermal growth factor receptor 2,HER2）阳性型患者采用靶向治疗,77.3%的医院对三阴性乳腺癌（triple-negative breast cancer,TNBC）采用辅助化疗,蒽环类药物序贯紫杉类药物方案是最常用的化疗方案。对于高复发风险的患者,70.9%的受访医院主张密集化疗,但大部分医院的实际实施比例不到20%。对于激素受体阳性的患者,主张延长内分泌治疗时长至10年的医院占一半以上。绝经后患者联合应用双膦酸盐的比例在40%以内,绝经前患者使用卵巢功能抑制（ovarian function suppression,OFS）的比例总体也在40%以下,芳香化酶抑制剂（aromatase inhibitor,AI）是OFS的公认联合药物。结论：目前国内医院使用多基因预后预测工具的比例较低,对早期乳腺癌患者的辅助治疗决策较为保守,密集化疗、OFS和双膦酸盐等治疗方法和药物的应用比例较低。蒽环序贯紫杉方案和AI的临床应用已形成共识,延长内分泌治疗时长也成为新的趋势。