Until recently, docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC). The past year and a half has been marked by unprecedented progress in treatments for this disease. Three positive phase III clinical trials have emerged, each evaluating agents with wholly distinct mechanisms of action (sipuleucel-T, cabazitaxel and abiraterone). Herein, the three pivotal trials are described alongside both past and current large phase III studies conducted in this space. The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past. We note that newer trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome. The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this disease state.
At the 2010 meeting of the European Society for Medical Oncology (ESMO), a landmark development in prostate cancer therapy was unveiled. In a phase III study, the CYP17 inhibitor abiraterone yielded a survival advantage over placebo in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed despite prior docetaxel therapy. The data for abiraterone follow the publication of successful phase III studies earlier this year supporting two mechanistically distinct agents--namely, the novel taxane cabazitaxel and the autologous dendritic cell vaccine sipuleucel-T. A challenge that lies ahead for the scientific community is to discern the appropriate positioning of abiraterone in an increasingly crowded therapeutic landscape. Several ongoing trials are examining the agent in earlier settings (i.e., a phase III in mCRPC pre-docetaxel, and smaller studies in combination with radiation therapy or as neoadjuvant pre-surgery for localized disease). Herein, several potential strategies for abiraterone are presented to clarify the clinical utilization of this agent in the future.
Triple negative breast cancer (TNBC) is an aggressive clinical phenotype characterized by lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor–2 (HER2) overexpression. It shows substantial overlap with basal-type and BRCA1-related breast cancers, both of which also have aggressive clinical courses. However, this overlap is not complete, and the expression of ER, PR, and HER2 has been noted in basal-like tumors. TNBC also includes the normal-like subtype, and not all patients with TNBC harbor BRCA1 mutations. Because of its expression profile, TNBC is not amenable to treatment with hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are currently limited to cytotoxic chemotherapy. Overall survival, whether in early-stage or advanced disease, is poor compared with that in patients who have other phenotypes. A number of targeted approaches to TNBC are undergoing clinical evaluation, including the use of agents with poly(ADP-ribose) polymerase inhibitory properties such as iniparib (the United States Adopted Name for the investigational agent BSI-201), olaparib (AZD2281), and veliparib (ABT-888), antiangiogenic agents such as bevacizumab and sunitinib, and epidermal growth factor receptor blockers such as cetuximab and erlotinib. Encouraging results with some of these agents have been reported, thereby offering the promise for improved outcomes in patients with TNBC. The clinical characteristics of TNBC and clinical experience to date with novel targeted agents under development for this aggressive phenotype is reviewed.
Breast cancer; triple negative; phenotype; basal-like; BRCA1; targeted therapy
Docetaxel remains a cornerstone of therapy for the patient with metastatic castration-resistant prostate cancer (CRPC). However, the landscape of CRPC therapy is changing rapidly – recently, data from the phase III TROPIC study revealed a survival advantage with the novel taxane cabazitaxel/prednisone (compared with mitoxantrone/prednisone) in a cohort of 755 men with docetaxel-refractory metastatic CRPC. Interestingly, cabazitaxel bears substantial structural similiarity to docetaxel but appears to be mechanistically distinct. In preclinical studies, the agent has antitumor activity in a variety of docetaxel-refractory in vitro and in vivo models. Subsequent to phase I testing in advanced solid tumors (where neutropenia was identified as a dose-limiting toxicity), the agent was assessed in a phase II trial in advanced, taxane-refractory breast cancer and in the aforementioned phase III TROPIC study. This review describes in detail the preclinical and clinical development of cabazitaxel.
cabazitaxel; castration resistant prostate cancer; Jevtana; breast cancer; taxane
With 6 agents approved for metastatic renal cell carcinoma (mRCC) within the past 5 years, there has undoubtedly been progress in treating this disease. However, the goal of cure remains elusive, and the agents nearest approval (ie axitinib and tivozanib) abide by the same paradigm as existing drugs (i.e., inhibition of vascular endothelial growth factor, VEGF, or mammalian target of rapamycin, mTOR, signaling). The current review will focus on investigational agents that diverge from this paradigm. Specifically, novel immunotherapeutic strategies will be discussed, including vaccine therapy, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade, and programmed death-1 (PD-1) inhibition, as well as novel approaches to angiogenesis inhibition, such as abrogation of Ang/Tie-2 signaling. Pharmacologic strategies to block other potentially relevant signaling pathways, such as fibroblast growth factor receptor (FGFR) or MET inhibition, are also in various stages of development. Although VEGF and mTOR inhibition have dramatically improved outcomes for patients with mRCC, a surge above the current plateau with these agents will likely require exploring new avenues.
renal cell carcinoma; targeted therapy; XL184; CVX-060; AMG-386; BMS-936558; AV-951
With an explosion of available treatments for metastatic renal cell carcinoma (mRCC) in recent years, it is important to recognize that approved targeted therapies fall broadly into only two mechanistic categories. The first category, vascular endothelial growth factor (VEGF)-directed therapies, includes sunitinib, pazopanib, sorafenib and bevacizumab. The second category includes inhibitors of the mammalian target of rapamycin (mTOR), namely everolimus and temsirolimus. A pivotal trial of ever-olimus supports use of the agent in patients with mRCC refractory to VEGF- tyrosine kinase inhibitors (TKI) therapy, while pivotal data for temsirolimus supports use in poor-prognosis patients as first-line therapy. Multiple reviews exist to delineate the laboratory and clinical development of mTOR inhibitors. This paper will outline the future applications of these therapies. It will explore ongoing trials evaluating combinations of mTOR inhibitors with other targeted therapies, along with sequencing strategies and biomarker discovery efforts. The application of mTOR inhibitors in unique populations is also described.
mTOR; Everolimus; Temsirolimus; Deferolimus; INTORACT; TORAVA; BeST; Biomarkers; Clinical trials
Endocrine therapy in the setting of breast cancer has undoubtedly advanced clinical outcomes in this disease, but treatment with endocrine therapy is accompanied by a wide spectrum of side effects. It is of prime importance to understand and characterize these toxicities to facilitate clinical decision-making. Somewhat surprisingly, there is a relative paucity of data pertaining to cognitive changes associated with endocrine therapy. In this article we review cognitive associated with two classes of endocrine therapy: (1) selective estrogen receptor modulators (SERMs; tamoxifen and raloxifene) and (2) aromatase inhibitors (AIs; anastrozole, letrozole, and exemestane). Companion studies to the Multiple Outcome of Raloxifene Evaluation (MORE), the Study of Tamoxifen and Raloxifene (STAR) and National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trials provide relevant data to understand the effect of SERMs on cognition. In contrast, substudies of the Arimidex, Taxmoxifen Alone or in Combination (ATAC), Tamoxifen and Exemestane Adjuvant Multinational (TEAM) and Breast International Group (BIG) 1–98 trials juxtapose cognitive effects of AIs against those of tamoxifen. These and other studies are examined herein to provide a comprehensive overview of the effect of endocrine therapy on cognition.
Significant advances have been made in the diagnosis and treatment of female breast cancer, resulting in a decline in incidence and a global improvement in clinical outcome. The statistics for male breast cancer (MBC) stand in sharp contrast – over the past several decades, there has been a steady rise in the incidence of this disease, and clinical outcome has improved at a much slower pace. In the current review, the clinicopathologic features of MBC are described in detail. An emphasis is placed on molecular profiling of MBC, which may identify candidate biomarkers and putative targets for pharmacologic intervention. The current role of cytotoxic chemotherapy and endocrine therapy (including tamoxifen, aromatase inhibitors and GnRH analogues) is defined in the context of currently available studies. Furthermore, the potential role of targeted agents, including HER2-directed therapies, PARP inhibitors, and angiogenesis inhibitors, is delineated.
Signal transducer and activator of transcription 3 (Stat3) has emerged as a critical regulator for tumor-associated inflammation. Activation of Stat3 negatively regulates the Th1-type immune response and promotes expansion of myeloid-derived suppressor cells (MDSCs) and regulatory T-cell functions in the tumor microenvironment. Mounting evidence suggests that Stat3 and related pathways may serve as a target for changing the tumor immunologic microenvironment to benefit cancer immunotherapies. Many recent studies support the use of certain tyrosine kinase inhibitors, through inhibition of Stat3, in decreasing immunosuppression in the tumor microenvironment. Other potential therapeutic avenues include the use of targeted delivery of Stat3 siRNA into immune cells. Here, we describe the role of Stat3 in regulating the immunologic properties of tumors as a background for Stat3-based therapeutic interventions.
Papillary carcinoma of the breast represents approximately 0.5% of all newly diagnosed cases of breast cancer. The prevalence of both invasive and in situ papillary carcinoma seems to be greater older postmenopausal women, and -in relative terms-in males. Histologic features of the tumor include cellular proliferations surrounding fibrovascular cores, with or without invasion. In this review, characteristics of both in situ and invasive disease are outlined. Immunohistochemical analyses of papillary carcinoma suggest the utility of markers such as smooth muscle myosin heavy chain, calponin, p63 and high molecular weight keratins, which can characterize the myoepithelial cell layer. With respect to radiographic evaluation of papillary carcinoma, ultrasonography is the most extensively studied imaging modality, though magnetic resonance mammography has potential utility. Available data suggest improved outcome for papillary carcinoma as compared to invasive ductal carcinoma. Treatment-related information for patients with papillary carcinoma is limited, and patterns noted in available series suggest a variable approach to this disease. The scarcity of information underscores the need for further treatment- and outcome-related studies in papillary carcinoma of the breast.
papillary; breast carcinoma; male breast cancer; breast ultrasonography; breast magnetic resonance mammography
Over the past decade, a multitude of targeted agents have been explored in the treatment of advanced non-small cell lung cancer (NSCLC). Thus far, two broad classes of agents have been implemented in clinical practice: (1) vascular endothelial growth factor (VEGF)-directed therapies and (2) antagonists of the epidermal growth factor receptor (EGFR). In the former category, the agent bevacizumab (a monoclonal antibody) has shown landmark improvements in survival when added to cytotoxic therapy. Small molecule tyrosine kinase inhibitors (TKIs) targeting the VEGF receptor (i.e., sunitinib, sorafenib, and vandetanib) show activity in phase II clinical studies. With respect to EGFR-directed therapies, the TKIs gefitinib and erlotinib have demonstrated significant benefit, and have uncovered valuable information regarding the biology of lung cancer. Outside of therapies directed specifically at VEGF- and EGFR-mediated signaling, trials evaluating insulin-like growth factor-1 receptor (IGF-IR)-targeting agents, cyclooxygenase-2 (COX-2) inhibitors, c-met inhibitors, irreversible pan-HER inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors are ongoing. Inhibitors of ALK show great promise in patients with the relevant gene translocation. Herein, the clinical development of novel therapies for NSCLC is described, including some discussion of relevant biomarkers and determination of synergy with both cytotoxic therapy and other targeted agents.
With the FDA approval of six novel targeted agents since December 2005 and limited comparative trials to discern relative efficacy, the treatment of metastatic renal cell carcinoma (RCC) has become immensely complex. The research community must look to novel ways in which to identify appropriate candidates for selected targeted therapies; one potential strategy is the use of clinical and molecular biomarkers. A growing body of knowledge related VHL-driven pathways in this disease has highlighted the potential role of hypoxia-inducible factor (HIF) subtypes in distinguishing RCC patients clinically. Techniques applied in other malignancies, such as gene expression and proteomic profiling, may also ultimately allow for clinical stratification. An emerging understanding of immunologic phenomena that may affect cancer progression (i.e., tumor infiltration by CD68 lymphocytes, memory T-cells, etc.) has unveiled a number of other potential biomarkers of response. Several vascular endothelial growth factor (VEGF) receptor-directed therapies classically thought to function as antiangiogenics may also have complex effects upon the tumor microenvironment, including the associated immune cell milieu. As such, immunologic parameters could potentially predict response to current therapies. Finally, clinical biomarkers such as hypertension may predict the efficacy of several currently available targeted agents, although implementation of such biomarkers remains challenging. Herein, the clinical relevance of putative RCC biomarkers is examined in detail.
sunitinib; renal cell carcinoma; mechanism; angiogenesis; STAT3; KIT; bevacizumab; breast cancer
The agents currently approved for use in metastatic renal cell carcinoma (mRCC) can be divided broadly into two categories: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.
metastatic renal cell carcinoma; mRCC; mTOR inhibitors
Within the past two years, three agents have garnered approval from the US FDA for the specific treatment of metastatic castration resistant prostate cancer (mCRPC) – (1) abiraterone, (2) cabazitaxel and (3) sipuleucel-T. In separate phase III studies, each agent led to an improvement in overall survival (OS) of 2–4 months over a suitable comparator. With these costly therapies all having potential application in the patient with mCRPC, multiple entities (industry, government, and the general public) must strategize to determine how the cost burden of these agents can be balanced with the potential gains for the individual patient. Herein, we provide a framework with which to approach this dilemma.