Triple-negative breast cancer—current status and future directions

Triple-negative breast cancer (TNBC) is defined by a lack of expression of both estrogen and progesterone receptor as well as human epidermal growth factor receptor 2. It is characterized by distinct molecular, histological and clinical features including a particularly unfavorable prognosis despite increased sensitivity to standard cytotoxic chemotherapy regimens. TNBC is highly though not completely concordant with various definitions of basal-like breast cancer (BLBC) defined by high-throughput gene expression analyses. The lack in complete concordance may in part be explained by both BLBC and TNBC comprising entities that in themselves are heterogeneous. Numerous efforts are currently being undertaken to improve prognosis for patients with TNBC. They comprise both optimization of choice and scheduling of common cytotoxic agents (i.e. addition of platinum salts or dose intensification strategies) and introduction of novel agents (i.e. poly-ADP-ribose-polymerase-1 inhibitors, agents targeting the epidermal growth factor receptor, multityrosine kinase inhibitors or antiangiogenic agents).     

Metastatic breast cancer: understanding current management options

PURPOSE/OBJECTIVES: To review the standard treatment options for metastatic breast cancer, present recently approved chemotherapeutic and hormonal approaches, and describe novel biologic therapies, particularly the use of monoclonal antibodies. DATA SOURCES: Published articles, abstracts, and conference proceedings. DATA SYNTHESIS: Standard treatment options available to women with metastatic breast cancer include surgery, radiation therapy, hormonal therapy, chemotherapy, and palliative approaches. New chemotherapeutic approaches for the management of metastatic breast cancer include the recently approved agents paclitaxel, docetaxel, and capecitabine. New hormonal agents such as toremifene, letrozole, and exemestane also have been approved. Finally, an agent from a new class of agents--biologic response modifiers (BRMs)--now. Is available. Trastuzumab, a monoclonal antibody (one class of BRMs), is a new and promising approach available to a subpopulation of women with metastatic breast cancer. CONCLUSION: Although standard treatment options for the management of metastatic breast cancer may prolong survival for some, they have not resulted in a cure for the majority of women. Recent advances in the understanding of cancer cellular biology have led to newer approaches such as monoclonal antibodies and other BRMs that may offer hope of extended survival and improved quality of life for certain women. This field is growing quickly, and new targets for breast cancer therapy are being studied. IMPLICATIONS FOR NURSING PRACTICE: Nurses who become familiar with newer treatment options available for the management of metastatic breast cancer, including new chemotherapeutic and hormonal approaches and monoclonal antibody therapy, are better able to provide information and support for their patients. Clinicians must understand the criteria for patient selection for newer agents, particularly trastuzumab. In addition, recognizing adverse effects and knowing the management strategies for treatment-related toxicities help to ensure positive patient outcomes.     

Triple-negative breast cancer

Perou's molecular classification defines tumors that neither express hormone receptors nor overexpress HER2 as triple-negative (TN) tumors. These tumors account for approximately 15% of breast cancers. The so-called basaloid tumors are not always synonymous with TN tumors; they differ in the fact that they express different molecular markers, have a higher histologic grade, and have a worse prognosis. Clinically they occur in younger women as interval cancer, and the risk of recurrence is higher within the first 3 years. Distant recurrences in the brain and visceral metastases are more common than in hormone receptor-positive tumors. Therapeutically, despite being highly chemosensitive, their progression-free time is generally short. In terms of chemotherapeutic treatment, anthracyclines and taxanes are useful drugs, and high response rates have been described for the combination of ixabepilone-capecitabine and platinums. The combination with antiangiogenic drugs has also proven useful. A group of new drugs, poly-(ADP-ribose)-polymerase inhibitors, showed favorable results in TN tumors with BRCA mutation. There are currently several ongoing studies with new drugs including epidermal growth factor receptor inhibitors, c-kit inhibitors, Raf/Mek/Map kinase inhibitors and mTOR inhibitors.     

Ovarian cancer biomarkers: current options and future promise

As more effective, less toxic cancer drugs reach patients, the need for accurate and reliable cancer diagnostics and prognostics has become widely appreciated. Nowhere is this need more dire than in ovarian cancer; here most women are diagnosed late in disease progression. The ability to sensitively and specifically predict the presence of early disease and its status, stage, and associated therapeutic efficacy has the potential to revolutionize ovarian cancer detection and treatment. This article reviews current ovarian cancer diagnostics and prognostics and potential biomarkers that are being studied and validated. Some of the most recent molecular approaches being used to identify genes and proteins are presented, which may represent the next generation of ovarian cancer diagnostics and prognostics.     

Treatment of triple negative breast cancer (TNBC): current options and future perspectives

Breast cancer is not considered anymore a unique disease. Microarray gene expression analysis led to the identification of 4 major breast cancer "intrinsic" subtypes, including hormone receptor (HR)-positive luminal A and B, human epidermal growth receptor 2 (HER2)-positive and basal-like breast cancer (BLBC). These subtypes have distinct phenotypes, molecular profiles, clinical behaviour and response to therapy, with the BLBC carrying the worst outcome. Microarray analysis is not feasible in routine practice and therefore oncologists rely on a simpler immunohistochemical (IHC) classification to identify relevant breast cancer subtypes. Triple negative breast cancer (TNBC) is defined by the absence of oestrogen receptor, progesterone receptor and HER2 expression at IHC analysis. TNBC is strictly related to BLBC and, given the lack of common therapeutic targets, represent a major challenge for breast oncologist. In this review we will summarize the updated knowledge on TNBC, with emphasis on its current treatment and on the new therapeutic options under development.     

Triple-negative breast cancer: A run-through of features,classification and current therapies

Breast cancer is the most prevalent cancer in women worldwide. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12–20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting-edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP-ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non-coding RNA in therapy are the key highlights in this review.     

Triple-negative breast cancers: an updated review on treatment options

Morphologic features of tumour cells have long been validated for the clinical classification of breast cancers and are regularly used as a "gold standard" to ascertain prognostic outcome in patients. Identification of molecular markers such as expression of the receptors for estrogen (er) and progesterone (pgr) and the human epidermal growth factor receptor 2 (her2) has played an important role in determining targets for the development of efficacious drugs for treatment and has also offered additional predictive value for the therapeutic assessment of patients with breast cancer. More recent technical advancements in identifying several cancer-related genes have provided further opportunities to identify specific subtypes of breast cancer. Among the subtypes, tumours with triple-negative cells are identified using specific staining procedures for basal markers such as cytokeratin 5 and 6 and the absence of er, pgr, and her2 expression. Patients with triple-negative breast cancers therefore have the disadvantage of not benefiting from currently available receptor-targeted systemic therapy. Optimal conditions for the therapeutic assessment of women with triple-negative breast tumours and for the management of their disease have yet to be validated in prospective investigations. The present review discusses the differences between triple-negative breast tumours and basal-like breast tumours and also the role of mutations in the BRCA genes. Attention is also paid to treatment options available to patients with triple-negative breast tumours.     

Skeletal metastasis in renal cell carcinoma: current and future management options

Metastasis to the skeleton is common in advanced renal cancer and leads to debilitating skeletal complications including severe pain, increased fracture rate and spinal cord compression. The incidence of renal cell carcinoma is increasing by around 2% per year and recent advances in targeted anti-angiogenic therapy for advanced disease are expected to lead to longer survival times. The clinical management of metastatic bone disease in renal cell carcinoma therefore merits greater focus than hitherto. Bone metastases arising from renal cancer are highly osteolytic and particularly destructive. Fortunately, the continuing development of anti-resorptive drugs is revolutionising the medical management of metastatic bone disease across many tumour types and making a major impact on quality of life. The bisphosphonate zoledronic acid is now licensed for use in advanced renal cell carcinoma and appears to yield a greater benefit in terms of reduction in skeletal related events than in bone metastases arising from other tumour types. Drugs which are directed at specific targets in the bone metastasis pathway are in development, including denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor kappa B ligand, which has recently been licensed in the United States for use in renal cell carcinoma, with European licensing expected soon. This review examines the increasing options for treatment of metastatic bone disease in renal cell carcinoma, with a focus on drug-based advances and progress in the development of existing and new biomarkers to support clinical management.     

The management of neuroendocrine tumours: current and future medical therapy options

Neuroendocrine tumours (NETs) are a genetically diverse group of malignancies that sometimes produce peptides causing characteristic hormonal syndromes. NETs can be clinically symptomatic (functioning) or silent (non-functioning); both types frequently synthesise more than one peptide, although often these are not associated with specific syndromes. Based on data from various sources, the incidence and prevalence of NETs is increasing. The primary treatment goal for patients with NETs is curative, with symptom control and the limitation of tumour progression as secondary goals. Surgery is the only possible curative approach and so represents the traditional first-line therapy. However, as most patients with NETs are diagnosed once metastases have occurred, curative surgery is generally not possible. Patients therefore require chronic postoperative medical management with the aim of relieving symptoms and, in recent years, suppressing tumour growth and spread. Somatostatin analogues, such as octreotide long-acting repeatable (LAR), can improve the symptoms of carcinoid syndrome and stabilise tumour growth in many patients. Results from the PROMID study show that octreotide LAR 30mg is an effective antiproliferative treatment in patients with newly diagnosed, functionally active or inactive, well-differentiated metastatic midgut NETs. An antiproliferative effect can also be achieved with everolimus, and combination therapy with octreotide LAR has shown synergistic antiproliferative activity. In the future, pasireotide, the multi-receptor targeted somatostatin analogue, has the potential to be an effective therapy for de novo or octreotide-refractory carcinoid syndrome and for inhibiting tumour cell proliferation. Peptide receptor radiotherapy with [90]yttrium-DOTATOC or [177]lutetium-DOTATE is also a new interesting treatment option for NETs.     

Chemoprevention of breast cancer: current and future prospects

The groundwork for making the concept of breast cancer chemoprevention a clinical reality began over a century ago. Although tamoxifen's first clinical use was for the treatment of breast cancer, the earliest animal studies with the drug provided the scientific basis for chemoprevention. The extensive clinical experience, safety and laboratory data have made tamoxifen the current standard-of-care for the prevention of breast cancer in women at elevated risk. The STAR trial will address the value of raloxifene as a chemopreventative in postmenopausal women. Results will be available by 2005. Newer compounds are under development which hold the promise of expanded efficacy and narrower side-effect profile. These compounds will function as multifunctional medicines and will hold the promise of preventing breast and endometrial cancer, while providing the beneficial effects of preventing osteoporosis and coronary heart disease.     

Second-line treatment for advanced-stage non-small-cell lung cancer: current and future options

Non-small-cell lung cancer is the leading cause of cancer-related death in men and women. Because of its frequent presentation as advanced disease, most non-small-cell lung cancers are treated with palliative systemic therapy. Multiple trials have established the benefit of chemotherapy for palliation and disease control. Of the patients treated with first-line therapy, approximately 30%-40% will subsequently be candidates for second-line treatment. In the past year, pemetrexed and erlotinib have joined docetaxel as the only Food and Drug Administration-approved second-line therapies. Recent phase III trials have also evaluated the use of oral topotecan, polyglutamated paclitaxel, and gefitinib in this setting. In addition, multiple novel agents, including bortezomib, cetuximab, and bevacizumab, are being investigated as single agents or in combination with approved second-line therapies. With the increasing number of therapeutic options for this patient population, patient characteristics and side effect profiles are influencing the therapeutic choices made by physicians. The use of molecular markers to assist in therapeutic decision-making has yet to come to fruition. Research efforts continue to focus on identifying molecular markers and corresponding clinical features that will allow physicians to individualize patients' therapy.     

Triple-negative breast cancer: an unmet medical need

Triple-negative breast cancer, characterized by tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or HER-2 genes, represents an important clinical challenge because these cancers do not respond to endocrine therapy or other available targeted agents. The metastatic potential in triple-negative breast cancer is similar to that of other breast cancer subtypes, but these tumors are associated with a shorter median time to relapse and death. One important goal is therefore the identification of prognostic factors and markers to reliably select high and low risk subsets of patients with triple-negative disease for different treatment approaches of subtypes with differential responsiveness to specific agents. However, a reliable prognostic marker has been elusive, and markers have been inconsistently useful. For example, epidermal growth factor receptor (EGFR) has been studied, but there is still a lack of agreement on a standard assay or cutoff for EGFR expression levels with respect to prognosis. Similarly, because triple-negative status is sometimes used as a surrogate for basal-like breast cancer, specific basal markers have been explored. Indeed, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity may provide only an approximation of the triple-negative population and are sometimes reanalyzed using more specific indicators like CK 5/6, EGFR status, and others, again marred by discordances. Chemotherapy remains the mainstay of treatment of triple-negative breast cancer, but important limitations still need to be overcome in the next few years if any significant clinical strides are to be made. Current treatment strategies for triple-negative disease include anthracyclines, taxanes, ixabepilone, platinum agents, and biologic agents. More recently, EGFR inhibition has been proposed as a therapeutic mechanism in triple-negative breast cancer, again with mixed results. Agents that target poly(ADP-ribose) polymerase and androgen receptors have also been proposed in these patients or subsets of them, and ongoing trials should result in definitive guidance with respect to the value of these agents in triple-negative disease. Triple-negative breast cancer is clearly a distinct clinical subtype, from the perspective of both ER and HER-2 expression, but further subclassification is needed. At present, there is not a clear, proven effective single agent that targets a defining vulnerability in triple-negative breast cancer. This article will review the clinical problem of triple-negative disease, potential prognostic factors, demonstrated efficacy of currently available therapeutic options, and new potential therapies.     

Lapatinib: current status and future directions in breast cancer

Lapatinib is an oral receptor tyrosine kinase inhibitor, targeting both the ErbB-1 and ErbB-2 receptors. Pre-clinical in vitro and in vivo models indicate that lapatinib is active as monotherapy, synergistically in combination with trastuzumab, and in trastuzumab-resistant cell lines. Early clinical trials also provide evidence in patients that lapatinib is active against breast cancer. This paper reviews results of phase II and III clinical trials of lapatinib in metastatic breast cancer, evidence for its potential in patients with brain metastases, and current clinical trials as adjuvant treatment in early-stage disease. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes is allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.     

Exemestane in breast cancer: current status and future directions

Exemestane is a novel, potent, and specific third-generation aromatase inactivator developed for breast can-cer therapy. The drug is effective in patients with metastatic disease failing tamoxifen alone or tamoxifen followed by megestrol acetate or a nonsteroidal aromatase inhibitor. In a phase III study, exemestane was superior to megestrol acetate in overall survival, time to tumor progression, and time to treatment failure in women with metastatic disease who experienced failure of tamoxifen. Preliminary evidence suggests activity to exemestane exceeds that obtained with tamoxifen as first-line treatment. Two studies are comparing sequential treatment with tamoxifen followed by exemestane to tamoxifen monotherapy in the adjuvant setting. A third study is comparing the toxicity profile of exemestane with that of placebo in patients with early breast cancer who are at low risk of relapse. The findings from these studies will determine the role of exemestane in early breast cancer and lay the foundation for assessing its potential role in breast cancer prevention.     

Epothilones in breast cancer: current status and future directions

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.