乳腺恶性肿瘤手术方式探讨

乳腺癌是严重威胁女性身心健康的恶性肿瘤之一,国内主流术式根治性乳房切除术可以大大降低乳腺癌死亡率。保乳手术在肿瘤治疗基础上兼顾乳房外形和患者心理,乳房肿瘤整形术通过将整形技术应用于乳腺肿瘤手术的诸多环节从而获得更显著的美学效果,两者在国内均有很大的发展空间,术式选择应当更加理性和乐观。     

Therapeutic options for metastatic breast cancer

Metastatic breast cancer (MBC) remains an incurable disease despite ongoing therapeutic advances. Recently there has been progress extending the range of available cytotoxic chemotherapy drugs and optimizing their scheduling. In addition, a greater understanding of tumor biology has led to the development of a number of targeted therapies. Several of these newer agents, such as trastuzumab, lapatinib and bevacizumab, have demonstrated activity in combination with chemotherapy and have improved the prognosis of patients with MBC. We hope that further progress elucidating the pathophysiology and biology of MBC will continue to lead to corresponding advances in treatment.     

Triple-negative breast cancer: epidemiology and management options

The triple receptor-negative breast cancer (TNBC) subtype is characterized by the lack of expression of both hormone receptors as well as lack of over-expression and/or lack of gene amplification of human epidermal growth factor receptor 2 (HER2). Approximately 10-15% of breast carcinomas are known to be of the TNBC subtype, which constitutes approximately 80% of all 'basal-like tumours'. Risk factors for TNBC include young age at breast cancer diagnosis, young age at menarche, high parity, lack of breast feeding, high body mass index and African American ethnicity. The majority of BRCA1 tumours are TNBC. TNBC has a worse prognosis and tends to relapse early compared with other subtypes of breast cancer. Conversely, it displays increased chemosensitivity compared with other breast tumour subtypes. Several agents are currently being investigated as potential therapeutic agents for the treatment of women with TNBC including agents targeted against EGFR, anti-angiogenic agents, multityrosine kinase inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors. This review focuses on the epidemiology of TNBC, its pathological features, natural history and recurrence patterns as well as current and future management options.     

Pharmacotherapeutic options for patients with refractory breast cancer

Introduction: The development of resistance to therapy is a concern in all three subtypes of breast cancer (BC). Yet, outcomes of patients with BC have improved in the past few years thanks to a molecularly targeted approach and a greater understanding of the many mechanisms through which cancer cells adapt to evade drug therapies. Indeed, there have been a number of different and active treatment strategies for hormone receptor positive (HR+ and Her2 positive BC although triple-negative breast cancer treatment remains problematical because of the early onset of resistance to treatments and the limited availability of targeted treatment options.

Areas covered: Herein, the authors present the various pharmacotherapeutic options for refractory breast cancer including their perspectives on these options.

Expert opinion: In recent years, there has been significant progress in our understanding of the biological mechanisms that cause resistance to BC treatments. The targeted therapeutic approach particularly has improved patient outcomes for those with refractory BC, but some unresolved issues still remain. In particular, we need to identify biomarkers of resistance to better tailor treatments, toxicities, and costs. Moreover, we need to determine the best sequence of treatments in refractory BC patients.     

Early stage breast cancer: treatment options and results.

Large randomized clinical trials have redefined patterns of spread which have major implications for treatment options and outcomes in early stage breast cancer. Trials comparing mastectomy plus radiotherapy with mastectomy alone in women with T1-2 N0-1 M0 disease show clearly that the probability of developing distant metastases is unaffected by treatment of the lymphatic pathways. The inference is that, for the vast majority of women presenting with early stage disease, the cancer is either confined to the breast or else disseminated via vascular and lymphatic channels more or less simultaneously. Breast cancer is almost unique in that distant metastases may remain occult for several decades before becoming clinically apparent by mechanisms which remain unclear. The probability of haematogenous dissemination correlates closely with tumour size and this observation is the basis of population-based screening programmes discussed elsewhere in this issue. By identifying tumours earlier in their evolution, effective treatment of the primary disease is expected to be curative in a greater proportion of women. The implications for breast conserving management of women with early stage breast cancer are that initial surgery and radiotherapy must be of a high quality and promptly delivered if the expected reductions in breast cancer mortality are to materialize.     

CNS complications of breast cancer: current and emerging treatment options

In general, the development of CNS metastases of breast cancer depends on several prognostic factors, including younger age and a negative hormone receptor status. Also, the presence of a breast cancer 1, early onset (BRCA1) germline mutation and expression of the human epidermal growth factor receptor 2 (Her2/neu) proto-oncogene seem to contribute to an increased rate of development of CNS metastases.The choice of appropriate therapy for brain metastases also depends on prognostic factors, including the age of the patient, the Karnofsky performance score, the number of brain metastases and the presence of systemic disease. Surgery followed by whole brain radiation therapy (WBRT) is generally restricted to ambulant patients with a single brain metastasis without active extracranial disease. In patients who have two to four metastases, stereotactic focal radiotherapy (i.e. radiosurgery) with or without WBRT is usually indicated. In the remainder of patients, WBRT alone provides adequate palliation. Although breast carcinoma is sensitive to chemotherapy, the role of chemotherapy in the treatment of brain metastases is still unclear. Objective responses after cyclophosphamide-based therapies were reported in studies performed in the 1980s. Subgroup analysis of data from a randomised study indicates that survival may improve if WBRT is combined with the radiosensitiser efaproxiral. Interestingly, the Her2/neu antibody trastuzumab, which does not cross the blood-brain barrier, produces systemic responses and enhanced survival, without a clear effect on brain metastases.Breast cancer constitutes the most common solid primary tumour leading to leptomeningeal disease. Clinical symptoms such as cranial nerve dysfunction or a cauda equina syndrome can be treated with local radiotherapy. A randomised study in patients with leptomeningeal disease secondary to breast cancer has revealed that intrathecal chemotherapy is associated with substantially more adverse effects than non-intrathecal treatment, without a clear benefit in terms of response or survival.Intramedullary metastasis is rare but often presents with a rapidly progressive myelopathy. Local radiotherapy may preserve neurological function.Epidural spinal cord metastasis occurs in approximately 4% of patients and can lead to paraplegia. A randomised study has shown that surgical intervention together with local radiotherapy is superior to local radiotherapy alone.     

Targeted breast cancer nanotherapeutics: options and opportunities with estrogen receptors

Breast cancer is a multifarious and heterogeneous disease. Identification of molecular alterations of surface/intracellular proteins particularly involved in proliferation and growth of breast cancer cells provides opportunities for the development of new targets for therapy. Several ligands that are routinely employed in targeted delivery to breast cancer cells have been found to be immunogenic. Therefore, endogenous bioligands may serve as a better option, which may be bio-competent and non-immunogenic, including estrogens. Membrane-associated estrogen binding sites are highly over-expressed in cancers of endocrine origin, such as breast. The selective high density of these receptor portals can be utilized for targeted breast cancer therapy. Numerous estrogen-chemotherapeutic agent conjugates have been successfully utilized for targeted drug/DNA delivery. Recently, nanocarrier(s) anchored with estrogens as site-directing ligands for the delivery of bioactive(s) have been exhaustively investigated for breast cancer therapy. This review presents a detail account of how estrogens, anti-estrogens, and their derivatives can be used for site-specific delivery of bioactive(s) to breast cancer cells. The sequential emergence of various estrogen-anticancer drug conjugates is highlighted. Additionally, carrier systems that utilize estrogens/anti-estrogens as ligands for purpose-specific site-selective novel drug delivery platforms have been reviewed and revisited in terms of their realistic clinical applications in breast cancer treatment.     

New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones

When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.     

Chemotherapy and biological treatment options in breast cancer patients with brain metastasis: an update

Introduction: Breast cancer (BC) is the second most common cause of CNS metastasis. Ten to 20% of all, and 38% of human epidermal growth factor-2(+), metastatic BC patients experience brain metastasis (BM). Prolonged survival with better control of systemic disease and limited penetration of drugs to CNS increased the probability of CNS metastasis as a sanctuary site of relapse. Treatment of CNS disease has become an important component of overall disease control and quality of life.

Areas covered: Current standard therapy for BM is whole-brain radiotherapy, surgery, stereotactic body radiation therapy for selected cases, corticosteroids and systemic chemotherapy. Little progress has been made in chemotherapy for the treatment of BM in patients with BC. Nevertheless, new treatment choices have emerged. In this review, we aimed to update current and future treatment options in systemic treatment for BM of BC.

Expert opinion: Cornerstone local treatment options for BM of BC are radiotherapy and surgery in selected cases. Efficacy of cytotoxic chemotherapeutics is limited. Among targeted therapies, lapatinib has activity in systemic treatment of BM particularly when used in combination with capecitabine. Novel agents are currently investigated.     

Triple negative breast cancer: a brief review of its characteristics and treatment options

Triple negative breast cancer (TNBC), an aggressive variant of breast cancer, is characterized by lack of expression of the estrogen (ER) and progesterone receptors (PRs) and the human epidermal growth factor receptor (HER-2) that are commonly observed in other breast cancer subtypes. The TNBC subtype primarily occurs in younger women of African American or Hispanic descent and tumors tend to be high grade and initially responsive to chemotherapy. However, TNBC is characteristically aggressive with high recurrence, metastatic, and mortality rates. Treatment options are limited since the hormonal receptor and HER-2 antagonists typically used for other breast cancers are ineffective. As such, the mainstay of treatment of TNBC is traditional systemic cytotoxic chemotherapy. Potential future therapies for TNBC include targeted molecular strategies including poly (adenosine diphosphate ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents. Further research aimed at identifying unique genetic characteristics of TNBC may allow development of other targeted molecular chemotherapy treatment options.     

Lapatinib ditosylate: expanding therapeutic options for receptor tyrosine-protein kinase erbB-2-positive breast cancer

Receptor tyrosine-protein kinase erbB-2 (HER2)-positive breast cancer is a specific entity with an aggressive behavior. Trastuzumab, a monoclonal antibody targeting erbB-2 (HER2) deeply transformed the outcome in patients. Nevertheless, resistance to trastuzumab is still a major concern. Lapatinib ditosylate is an orally available, small molecule targeting the tyrosine activity of the HER2 receptor. Lapatinib as a single agent and in combination therapy showed interesting activity in trastuzumab-resistant advanced tumors. In addition, lapatinib use seemed suitable in recurrent locally advanced inflammatory breast cancer and brain metastases. More recently, the Neo-ALTTO (NeoAdjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial showed that lapatinib in combination with trastuzumab and paclitaxel significantly improved the pathological complete response in a neoadjuvant setting. Several clinical trials are still ongoing and data that may change current clinical practice are awaited with much interest.     

Treatment options for esophageal cancer

There is considerable controversy over the level of evidence from randomized trials underpinning management decisions for patients presenting with localized cancer of the esophagus and esophago-gastric junction. There is also an optimism that new drugs and new approaches, including response prediction based on sequential ¹⁸FDG-PET scanning following induction chemotherapy, may improve treatments pathways and outcomes. In this review we assess the level of evidence from the major published trials, and discuss new trials and approaches.     

Expanding knowledge among Aboriginal service providers on treatment options for excessive alcohol use

Approaches to the prevention of alcohol problems among Aboriginal people in Australia have tended to emphasize primary and tertiary prevention, while neglecting secondary prevention or early intervention. In contrast, members of the wider Australian community can now access a variety of early interventions through general practice, in hospital settings and through drug and alcohol treatment agencies. As part of a survey of the use of brief interventions, 178 agencies throughout Australia were interviewed, and findings are presented from the 29 agencies in this sample which provided services primarily for Aboriginal people. Approximately half offered a variety of approaches including brief interventions, with goals of moderation; the other half were entirely abstinence-orientated. These findings are discussed in the context of expanding the options that might be offered by Aboriginal-run agencies.     

Temozolomide: Expanding its role in brain cancer

Management of central nervous system (CNS) malignancies continues to be a therapeutic challenge. Both primary and secondary (metastatic) CNS tumors are frequently resistant to commonly used chemotherapeutic agents. Surgery and radiotherapy provide palliation of symptoms but usually do not lead to curative outcomes. Alkylating agents have been used in the therapy of primary brain cancer for several decades. This group of medications has the ability to penetrate blood-brain barrier, achieving cytotoxic concentrations in cerebrospinal fluid and brain parenchyma. Temozolomide is a second-generation alkylating chemotherapeutic agent, introduced to therapy of primary brain tumors in the 1990s. It has since been approved for the therapy of recurrent and newly diagnosed malignant glioma. Temozolomide offers improved outcomes when used alone or in combination with irradiation. Its role in the therapy of other types of brain cancer, and specifically primary CNS lymphoma, continues to develop. This review will discuss the early stages of development of temozolomide, its introduction into the therapy of glioma, its role in the therapy of elderly patients, mechanisms of resistance and the evolution of its current and future applications.     

Treatment options in the management of ovarian cancer

The standard regimen used as primary chemotherapy of ovarian cancer is combination chemotherapy using paclitaxel and carboplatin. The main objective of first-line chemotherapy is to induce complete response. Although most cases respond to the initial chemotherapy, many cases relapse within 3 years. Such relapsed and persistent cases become resistant to first-line chemotherapy and require second-line chemotherapy. Objectives of such a second-line chemotherapy are to obtain disease palliation to cease disease progression. Meanwhile, consolidation or maintenance chemotherapy may be added to prevent or inhibit disease relapse for patients with advanced disease after induction of complete remission by a primary chemotherapy. When the unresectable tumour is presumed by primary surgery, neoadjuvant chemotherapy may be selected. Recently, conventional cytotoxic anticancer drugs containing paclitaxel have been shown to be capable of inhibiting angiogenesis. The notion of 'redefining' chemotherapeutic drugs has been recognised; thus, continuous low-dose chemotherapy -- so-called metronomic chemotherapy -- has been approved as a new concept. Many new molecular-targeted therapies became available for clinical cancer therapy. The explosion of new molecular targets and the development and application of many powerful technologies should accelerate the discovery of innovative molecular therapeutics. Understanding the molecular mechanisms will help to clarify the pathways in ovarian cancer development and help to identify new therapeutic and diagnostic targets. These are exciting times for new drug development and the treatment of cancer. Cautious optimism should prevail for all investigators involved in translating these exciting new biological findings into new pharmacological agents for treatment of cancer.     

Chemotherapeutic options in the management of anal cancer

During the past two decades, anal cancer has served as a paradigm for the successful application of chemoradiation to solid tumours; so far, it remains one of the few carcinomas of the gastrointestinal tract which are curable without the need for definitive surgery. Since the original contribution by Nigro in 1974, surprisingly few changes have been made to the standard of care in chemotherapy, which still consists of a combination of 5-fluorouracil and mitomycin C. However, many issues have yet to be clarified, such as the potential role of cisplatin as a substitute to mitomycin, as well as treatment-induced toxicity in HIV-positive patients. In this paper, the management of patients with anal cancer is presented, and new chemotherapeutic options are critically reviewed. Finally, the authors’ opinion regarding currently unresolved issues in the treatment of these rare neoplasms is expressed.     

Chemotherapeutic options in the management of anal cancer

During the past two decades, anal cancer has served as a paradigm for the successful application of chemoradiation to solid tumours; so far, it remains one of the few carcinomas of the gastrointestinal tract which are curable without the need for definitive surgery. Since the original contribution by Nigro in 1974, surprisingly few changes have been made to the standard of care in chemotherapy, which still consists of a combination of 5-fluorouracil and mitomycin C. However, many issues have yet to be clarified, such as the potential role of cisplatin as a substitute to mitomycin, as well as treatment-induced toxicity in HIV-positive patients. In this paper, the management of patients with anal cancer is presented, and new chemotherapeutic options are critically reviewed. Finally, the authors' opinion regarding currently unresolved issues in the treatment of these rare neoplasms is expressed.     

Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases

For widening the therapeutic options for Candida management, the druggability of Candida proteome was systematically investigated using an innovative pipeline of high-throughput data mining algorithms, followed by in vitro validation of the observations. Through this exercise, HIV-1 protease was found to share structural similarity with secreted aspartyl protease-3 (SAP3), a virulence protein of Candida. Using the molecular fingerprint of HIV-1 protease inhibitor GRL-09510, we performed virtual screening of peptidomimetic library followed by high-precision docking and MD simulations for discovery of SAP inhibitors. Wet-lab validation of the four shortlisted peptidomimetics revealed that two molecules, when used in combination with fluconazole, could significantly reduce the dosage of fluconazole required for 50% inhibition of Candida albicans. The SAP inhibitory activity of these peptidomimetics was confirmed through SAP assays and found to be on par with pepstatin A, a known peptidomimetic inhibitor of aspartyl proteases.     

乳腺癌易感基因1在散发性乳腺癌组织中的表达

目的 探讨乳腺癌易感基因（BRCA1）蛋白在散发性乳腺癌组织中的表达.方法 收集86例乳腺癌及癌旁组织、48例乳腺增生症手术标本,采用免疫组化S-P法检测BRCA1蛋白的表达情况.结果 BRCA1表达在乳腺癌、乳腺癌旁组织、乳腺增生症中的阳性率分别为11.6%（10/86）、16.3%（14/86）和100%（48/48）,三组间比较差异有统计学意义（P＜0.01）.结论 BRCA1蛋白异常表达在散发性乳腺癌发生发展过程中起着一定作用.     

Biomarkers in breast cancer

Breast cancer is one of the most frequently diagnosed cancers among women in the western world. Due to the aggressive behaviour of some specific types and the possibility of an early diagnosis, breast cancer has been constantly studied. Tumour size, histological type, cellular and nuclear characteristics, mitotic index, vascular invasion, hormonal receptors and axillary lymph node status are biomarkers routinely used. However, these parameters are not enough to predict the course of this disease. Molecular biology advances have made it possible to find new markers, which have already been incorporated to the clinical practice. Their ultimate goal is to reduce mortality by identifying women at risk for the development of this disease, help diagnosis, determine prognosis, detect recurrences, monitor and guide treatment, and in particular cancers they are suited for general screening. Tumour markers in breast cancer were ranked in categories reflecting their clinical utility, according to the American College of Pathologists. This article focuses on traditional and new molecular markers stratifying them into categories and emphasizing their relevance in the routine evaluation of patients with breast cancer.