The changing face of breast cancer--past,present and future perspectives

Breast cancer used to be perceived as a stigmatized disease and rates of early diagnosis were poor because women were often reluctant to present to their physician. Once a diagnosis had been made, there was no adjuvant therapy and little in the way of palliative treatment for advanced disease. Fortunately, the situation today is much improved and although breast cancer remains the most common form of cancer in women, changing attitudes have helped to ensure improved awareness and earlier presentation of patients, leading to earlier diagnosis and better prognosis. Improved detection and treatment regimes have begun to impact on breast cancer mortality; important long-term treatment goals include the prevention of both disease recurrence and the development of advanced disease. This will necessitate improvements in systemic therapies based on the biological properties of the tumor rather than relying on early diagnosis and chemo-prevention. Significant progress has been made over the last 30 years, and the future of breast cancer treatment should be faced with optimism.     

The impact of age on outcome in early-stage breast cancer

Multiple studies have shown that breast-conserving therapy (BCT) and mastectomy have equivalent outcomes for large populations of women with early-stage breast cancer. For individual treatment decisions, however, it is important to appreciate the heterogeneity of disease. Recent molecular studies have suggested that "breast cancer" includes biologically distinct classes of disease; although these molecular distinctions are important, other patient-related factors also affect outcome and influence prognosis. One of the most important of these patient factors is the age of the patient at diagnosis. Numerous studies have shown very different breast cancer outcomes based on patient age; younger women typically have more aggressive tumors that are more likely to recur both locoregionally and distantly, and older women more commonly have less aggressive disease. The overall disease-specific outcomes, techniques, and doses for adjuvant radiation therapy and toxicity of treatments should be discussed within the context of age because breast cancer is a very different disease based on this factor. Arguments can be made that more aggressive locoregional therapy is warranted in populations of young women with breast cancer and perhaps less aggressive therapy in the elderly.     

Changes to Adjuvant Systemic Therapy in Breast Cancer: A Decade in Review

Breast cancer is the second most common cause of cancer death in women among the United States. Fortunately, it continues to be an active area of research. Today, it is well recognized that breast cancer can often be a systemic disease, with micrometastatic involvement at diagnosis in many patients. Over the past decade, adjuvant systemic therapy has been used to eradicate micrometastatic disease, and it has been shown to decrease the rates of recurrence and improve the survival of patients with early-stage, resected breast cancer. Some of the success of modern adjuvant systemic therapy has come from the advent of new chemotherapy and endocrine agents but also from the development of targeted therapies, which have improved the efficacy of conventional, cytotoxic therapy. There has also been increasing awareness that the dosing and schedule of administration of systemic therapies are equally important factors in achieving better outcomes in patients with early-stage breast cancer. Growing research into the biology and genomics of breast cancer has fueled the development of more accurate risk stratification tools and helped individualize the decision to recommend adjuvant systemic therapy. Herein, we present a review of salient developments over the past decade that have helped shape the adjuvant systemic therapy of today.     

乳腺癌肿瘤标志物新的研究进展

目前乳腺癌已成为危害女性健康的第一大恶性肿瘤, 且发病率呈逐年递增趋势, 其早期诊断、治疗及预后成为当下研究的热点。乳腺癌肿瘤标志物对于其早期诊断、个体化治疗及预后均具有重要的临床实践指导意义。分子生物学的不断发展, 为乳腺癌肿瘤标志物的基础与临床研究奠定了良好的基础。近年来, 乳腺癌的诊断治疗手段逐渐增多, 肿瘤标志物的应用也不断受到青睐, 经典的肿瘤标志物已不足以更好的指导临床实践, 因此不断有新的肿瘤标志物出现。为了解乳腺肿瘤标志物在乳腺癌诊治中的重要作用及其相关最新研究, 本文结合国内外最新研究报道, 对乳腺肿瘤标志物新的研究进展做一简要综述。      

The Role of Capecitabine in Early Stage Breast Cancer

Adjuvant systemic therapy is partly responsible for the decrease in breast cancer mortality we have seen over the past two decades. Hormonal therapy and combination chemotherapy based on anthracyclines and taxanes represent the best current approach for early breast cancer patients. Primary as well as secondary development of resistance represents the major challenges to improve our results. Major benefits have been achieved as we recognized populations with particular molecular abnormalities (HER2 positive) and applied specific targeted agents (trastuzumab). However, the addition of other traditional chemotherapy agents has remained a challenge. With consistent data both as a single agent and as part of combinations in the treatment of advanced disease, capecitabine is being explored in over 20,000 early breast cancer patients currently participating in clinical trials. In this review, we discuss the available evidence for the incorporation of capecitabine in the (neo)-adjuvant treatment of patients with breast cancer.     

Male breast cancer.

Breast cancer in the male is an uncommon disease, occurring less than 1% as often as in females. Because of its rarity, this disease has not been as extensively studied as its female counterpart. Male breast cancer is evaluated and managed in a fashion very similar to that for female breast cancer. Primary management in early stage disease is usually a modified radical mastectomy. First line hormonal therapy for metastatic disease, in our institution, is tamoxifen for patients with positive estrogen receptors. Second line therapy consists of progestins or antiandrogens/LHRH analogs. No firm recommendations can be made concerning adjuvant systemic therapy. However, it is likely that studies from female patients are adaptable. Unfortunately, carcinoma of the male breast is such an infrequently encountered tumor that unfamiliarity with the disease can lead to delays in diagnosis and treatment. An increased awareness of the disease may be expected to result in earlier detection and institution of therapy at a stage when cure may be possible.     

Adjuvant systemic management of early stage carcinoma of the breast

In the last three decades, there has been a gradual, though significant change in the treatment of early stage breast cancer. For almost a century, physicians advocated an "anatomical view" of the dissemination of this disease, which justified a more radical and mutilating treatment strategy. Finally in the mid-1970s, results from large randomized trials began to show that either mastectomy or lumpectomy with radiation therapy were appropriate treatment for women with early stage disease. These results suggested that breast cancer can actually be a systemic disease ("biological view") even in early stages. This hypothesis was confirmed when large randomized clinical trials demonstrated the effectiveness of adjuvant systemic therapy in controlling micrometastatic disease in women with node-positive and node negative disease. As we approach the end of this century, most patients with early stage disease will be offered some form of adjuvant systemic therapy, before or after local treatment with surgery, with or without local radiation therapy. There has been a lot of interest on the proper sequence of the therapeutic modalities, in particular with the recent publication of larger randomized trials of primary systemic therapy. This specific topic is discussed elsewhere in this issue by Singletary.     

Radiotherapy for breast cancer: today and tomorrow

Breast conservation therapy (BCT) with lumpectomy and radiation has allowed many women to preserve their breasts and avoid disfiguring surgery. Lumpectomy and breast irradiation is a standard therapy for early breast cancer patients who desire breast conservation. However, the overall rate of mastectomy exceeds that of BCT in the United States. There have been significant advances in patient awareness of the options available for local management of early breast cancer and changes in the attitudes of physicians, including surgeons, allowing a gradual rise in the rate of BCT in the last two decades. Now, investigations are designed to define subgroups of patients with early breast cancer in whom radiation can be safely omitted. In locally advanced breast cancer, neoadjuvant chemotherapy has allowed some women to have BCT after initial cytoreduction. This approach results in excellent local control when patients are carefully selected for BCT. There is renewed interest in postmastectomy radiation for early breast cancer patients with 1 to 3 positive lymph nodes. In this intermediate risk group for locoregional recurrence, the addition of chest wall and regional lymphatic irradiation to adjuvant systemic therapy has potential for significant improvement in ultimate survival. This concept is novel in breast cancer, a disease that was believed to be systemic at inception and in which only systemic control was thought to impact survival. In this era of effective adjuvant systemic therapy for breast cancer, local control measures have become more important as local control has real potential for impacting survival.     

HER-2阳性乳腺癌分层治疗新策略

人表皮生长因子受体-2（human epidermal growth factor receptor-2，HER-2）阳性乳腺癌恶性程度高，预后不良，抗HER-2靶向药物的出现改变了HER-2阳性乳腺癌患者的预后。然而，靶向药物的疗效会受不同治疗阶段的影响，早期阶段治疗策略会影响晚期阶段的治疗选择。既往根据治疗线数来决定用药方案，无法体现靶向药物的分层治疗理念。目前，根据患者既往用药情况，基于循证医学证据，结合指南与临床经验，现已形成抗HER-2靶向治疗的分层治疗模式。本文将就HER-2阳性乳腺癌不同阶段靶向治疗的分层策略进行综述。      

Twenty years of systemic therapy for breast cancer

The past 2 decades of systemic therapy for breast cancer have been a period of monumental change, in terms of both theory and technology. Adjuvant therapy developed from two strands of research--one in systemic chemotherapy and one in hormonal therapy--both of which were aided by the application of higher statistical methodology to clinical trials. The agent with the single greatest public health impact in oncology has been tamoxifen, but problems with tamoxifen therapy led to the development of the aromatase inhibitors, and further research led to the use of hormonal therapy in a chemopreventive capacity. The evolution of systemic chemotherapy for breast cancer has been an interplay between theory-driven approaches and new agents. By the late 1980s, accumulating data revealed that overexpression of HER2 (erbB2) played an important role in a substantial portion of breast cancers, which prompted the development of trastuzumab (Herceptin), an agent targeting HER2-positive disease. Determining HER2 status proved essential to assessing patient eligibility for trastuzumab therapy. Decoding of the human genome and application of bioinformatics further revolutionized the possibilities in breast cancer treatment.     

Breast cancer 1985. What have we learned?

A popular misconception infers that all breast cancers are systemic from their inception, that variations of primary therapy will not affect prognosis, and that an effective systemic therapy is already available. This is not so. Moderate improvement in long-term survival of breast cancer patients has occurred during the last three decades, and particularly more recently, due to increased detection of "early" disease. More patients are being encountered with early Stage I lesions that are confined to the breast or with minimal axillary involvement. These patients have a minimal risk of occult systemic spread, and the majority can anticipate long-term disease-free survival through adequate primary therapy that achieves total local control. The great majority of our patients who are free of disease 15 years following aggressive primary therapy remain so thereafter. Although adjuvant multichemotherapy has prolonged disease-free survival, its effect on long-term patient survival has been marginal. Optimum control of breast cancer is achieved through early detection (most important) and aggressive primary therapy that aims to achieve total local control, plus the use of the best available systemic therapy for patients with high risk of occult systemic disease.     

Evolving Role of Risk Tailored Therapy in Early Stage HER2-Positive Breast Cancer: A Canadian Perspective

The advent of HER2-targeted therapies has led to an important shift in the management of HER2-positive early breast cancer. However, initial treatment approaches apply uniform treatment regimens to all patients, with significant treatment-related and financial toxicities for both the patient and the health care system. Recent data demonstrates that for many patients, the chemotherapy backbone, duration and nature (mono- versus dual-targeted therapy) of the HER2 blockade can be better targeted to an individual patient’s risk of recurrence. We will provide a review of current data supporting risk tailored therapy in early stage HER2-positive breast cancer along with key completed and ongoing Canadian and international risk tailored trials. Neoadjuvant systemic therapy should now be considered for patients with clinical stage 2 disease, with greater use of non-anthracycline based chemotherapy regimens. Patients with residual disease following neoadjuvant therapy should be considered for escalated treatment with adjuvant T-DM1. Patients with stage I disease can often be managed with upfront surgery and evidence-based de-escalated adjuvant chemotherapy regimens. The modest benefit of 12- versus 6 months of adjuvant HER2 therapy and/or dual adjuvant HER2 therapy should be carefully weighed against the toxicities. All patients with HER2-positive breast cancer should be enrolled in ongoing risk tailored treatment trials whenever possible. Increasing data supports risk tailored therapy in early stage HER2-positive breast cancer in place of the routine application of aggressive and toxic systemic therapy regimens to all patients. While much progress has been made towards treatment de-escalation in appropriate patients, more is needed, as we highlight in this review. Indeed, Canadian-led clinical trials are helping to lead these efforts.     

Controversial Issues in Adjuvant Systemic Therapy of Early Breast Cancer

Although it has been shown that adequate local therapy of primary breast cancer decreases the risk of distant failure and death due to the disease, treatment results with local therapy alone are clearly inadequate with c. 30-40% of patients developing a disease recurrence within the first ten years after primary diagnosis. In the past 10-15 years there has been significant progress in the field of systemic adjuvant therapy of breast cancer. It is now reliably established that the concept is valid; that is, that early treatment with either cytotoxic chemotherapy or endocrine therapy does result in improved survival compared with treatment deferred until relapse. Despite considerable progress, several controversial issues remain. These include the optimal timing and sequencing of treatment, optimal drug doses, and the role of new drugs such as taxanes and new endocrine agents. The identification of more powerful prognostic and/or predictive tests might have substantial clinical implications but major breakthroughs in this field of research are still to come. A relatively new and important issue in clinical decision-making regarding the use of different adjuvant therapies is long-term toxicity such as leukemia with some types of chemotherapy and endometrial cancer (and possibly other malignancies) with long-term tamoxifen. Further progress in the field of adjuvant therapy of breast cancer continues to rely on well-designed, prospective, controlled clinical trials and overviews of such studies.     

Surgery for advanced breast cancer from the viewpoint of medical oncologist

The incidence of breast cancer is increasing among Japanese women. It is an important issue to prevent breast cancer and develop therapy for it. Breast cancer is recognized as a systemic disease due to early micrometastases, and multimodality treatment is needed. Development of newer and more effective chemotherapy and hormone therapy contributes to improvement in survival for breast cancer patients. But the optimal treatment for locally advanced breast cancer is still not established. Here we describe multimodality treatment to clarify the role of each modality, especially surgery for locally advanced and metastatic breast cancer.     

Proteomics approaches: New Technologies and Clinical Applications in Breast Carcinomas

Breast cancer is the most diagnosed cancer in women, accounting for approximately 40,000 deaths annually in the USA. In Tunisia, the incidence of breast cancer is approximately 19 new cases per 100,000 women per year. Significant advances have been made in the areas of detection and treatment, but a significant number of breast cancers are detected late. The advent of proteomics provides the hope of discovering novel biological markers that can be used for early detection, prognosis, diagnosis, and therapy. Several proteomics technologies have been used to uncover molecular mechanisms associated with breast. Introduction: Breast cancer is a major health problem and one of the leading causes of death among women worldwide. Its incidence is steadily rising in developing countries. In Tunisia, the incidence of breast cancer is approximately 19 new cases per 100,000 women per year(1). Invasive carcinomas represent 70-80% of all breast cancer and among these, infiltrating ductal carcinomas (IDCA) are the most aggressive forms and have a poor prognosis(2). Histopathologically identical breast cancers show a different biological behavior in terms of aggressiveness, progression, and response to therapy. Thus, there is a great need for new breast cancer biomarkers that might help detect this cancer at an earlier stage, to uncover prognostically distinct subclasses, and to provide best individual treatment(2). Currently, the search for specific cancer-related alterations are largely carcinoma at the global level to discover protein patterns that distinguish disease and disease-free states with high sensitivity and specificity. Two dimensional gel electrophoresis coupled with mass spectrometry constitute a new proteomicsbased paradigm for detecting disease in pathology specimens and monitoring disease response to therapy. This review describes these proteomics technologies and their application in the analysis of breast carcinoma Keywords: Breast cancer, Proteomics, Markers, 2-DE, MALDI-TOF.     

Evolving perspectives in contralateral breast cancer

Despite extensive publications reviewing contralateral breast cancer (CBC), the role of screening and preventative measures for contralateral tumours is controversial and optimal clinical management remains undefined. This paper addresses the incidence, the predisposing factors, the prevention and the treatment of bilateral breast cancer based on a review of the literature. Risk factors for CBC include young age at primary breast cancer diagnosis, hereditary breast cancer (due to a germline mutation), familial breast cancer (one or more affected relatives), radiation exposure at a young age, lobular carcinoma in situ (LCIS), lobular invasive carcinoma and multicentricity. Retrospective studies suggest that contralateral mammographic surveillance results in the early detection of breast cancer, but no clear survival benefit has been demonstrated. Trials of adjuvant tamoxifen in breast cancer patients have shown a reduction in the incidence of CBC in both pre- and postmenopausal women. In addition, breast cancer patients treated with ovarian ablation and prednisone have significantly reduced CBC versus controls. In patients with primary breast cancer there is no evidence that contralateral breast biopsies or contralateral prophylactic mastectomy reduce mortality. Randomised, prospective trials to determine optimal surveillance, prevention and treatment strategies for the contralateral breast in breast cancer patients have not been conducted. Based on the published literature, contralateral breast surveillance in breast cancer patients reasonably includes breast self-examination, regular physical examinations and annual mammography. In women who have no evidence of distant metastasis at the time of CBC diagnosis, we recommend that the CBC be treated in the same manner as a first breast cancer, taking into account prior local and systemic therapy.     

Current status of adjuvant chemotherapy for breast cancer

Breast cancer is one of the most common malignancies among Japanese women. Approximately 40,000 new patients are diagnosed annually. In the USA, however,the mortality from breast cancer has recently been declining. A nationwide screening promotion using mammography, and recent advances in the treatment for early breast cancer have been the main reasons. It was widely accepted that for breast cancer as a systemic disease, appropriate systemic treatment of either chemotherapy and endocrine therapy improved the survival. We describe here the contributions of new agents to the improvement in survival for breast cancer patients and introduced the concept of dose density.     

Breast cancer metastasis: markers and models

Breast cancer starts as a local disease, but it can metastasize to the lymph nodes and distant organs. At primary diagnosis, prognostic markers are used to assess whether the transition to systemic disease is likely to have occurred. The prevailing model of metastasis reflects this view--it suggests that metastatic capacity is a late, acquired event in tumorigenesis. Others have proposed the idea that breast cancer is intrinsically a systemic disease. New molecular technologies, such as DNA microarrays, support the idea that metastatic capacity might be an inherent feature of breast tumours. These data have important implications for prognosis prediction and our understanding of metastasis.     

Narrowing the focus: Therapeutic cell surface targets for refractory triple-negative breast cancer

Triple-negative breast cancer (TNBC) is defined as a type of breast cancer with lack of expression of estrogen receptor, progesterone receptor and human epidermal growth factor 2 protein. In comparison to other types of breast cancer, TNBC characterizes for its aggressive behavior, more prone to early recurrence and a disease with poor response to molecular target therapy. Although TNBC is identified in only 25%-30% of American breast cancer cases annually, these tumors continue to be a therapeutic challenge for clinicians for several reasons: Tumor heterogeneity, limited and toxic systemic therapy options, and often resistance to current standard therapy, characterized by progressive disease on treatment, residual tumor after cytotoxic chemotherapy, and early recurrence after complete surgical excision. Cell-surface targeted therapies have been successful for breast cancer in general, however there are currently no approved cell-surface targeted therapies specifically indicated for TNBC. Recently, several cell-surface targets have been identified as candidates for treatment of TNBC and associated targeted therapies are in development. The purpose of this work is to review the current clinical challenges posed by TNBC, the therapeutic approaches currently in use, and provide an overview of developing cell surface targeting approaches to improve outcomes for treatment resistant TNBC.