Burtness B.,Chase Medical |
Bauman J.E.,University of New Mexico |
Galloway T.,Fox Chase Cancer Center
The Lancet Oncology | Year: 2013
Cancers of the head and neck that arise from habitual exposure to carcinogens have lower cure rates than those that arise from infection with human papillomavirus (HPV), and intensification of cytotoxic chemotherapy and radiation has not improved outcomes. HPV-negative head and neck cancers abundantly express EGFR, and the monoclonal antibody cetuximab, directed against EGFR, is the only targeted therapy that has improved disease survival so far. However, response rates to single-agent cetuximab are lower than 15%, and cetuximab given with chemotherapy or radiation leads to only a modest effect on survival. Thus, investigating the mechanisms of resistance to EGFR inhibition in HPV-negative head and neck cancer might help identify novel and active therapies. In this Review, we focus on therapies in development that target redundant receptor tyrosine kinases (eg, HER2 and MET), reduce or abrogate nuclear functions of EGFR, affect cellular trafficking by inhibition of histone deacetylase, or treatments that might address resistance that arises in the EGFR signalling stream (eg, aurora-kinase inhibitors and STAT decoys). © 2013 Elsevier Ltd.
Cole M.,Chase Medical |
Bromberg M.,Temple University
Oncologist | Year: 2013
Tissue factor (TF), a 47-kDa transmembrane glycoprotein that initiates blood coagulation when complexed with factor VIIa (FVIIa), is expressed in severaltumortypes.TFhasbeenshown to play a role in cell signaling, inflammation, angiogenesis, as well as tumor growth and metastasis. Activation of the TF signaling pathway has been implicated in mediating the function ofmanytumor cell types and has led to TF as a potential target in the treatment of several malignancies. Formation of the TFFVIIa complex in breast cancer cells has been shown to exert an antiapoptotic effect and play a key role in tumor growth and metastasis. Breast cancer growth is suppressed by inhibition of TF-mediated PAR2 signaling,anddeficiency inPAR2delays spontaneous breast cancer development in mice. TF is expressed in triple-negative breast cancer (TNBC), an aggressive type of breast cancer in which there is currently a paucity of available targets. Various methods of targeting TF have been investigated and include immunoconjugates or icons, anti-TF antibodies, TF pathway inhibitors, targeted photodynamic therapy, and microRNAs. These investigationsmaygive way to promising clinical therapies for breast cancer, especially in TNBC, for which there are relatively few effective treatment options. © AlphaMed Press.
Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?
Von Mehren M.,Chase Medical |
Widmer N.,University of Lausanne
Cancer Treatment Reviews | Year: 2011
Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100. ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups. © 2010.
Vadakara J.,Chase Medical |
von Mehren M.,Chase Medical
Hematology/Oncology Clinics of North America | Year: 2013
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Before the advent of tyrosine kinase inhibitors (TKIs) there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis was dismal. With the advent of imatinib and second-line TKIs the prognosis of metastatic GIST has improved dramatically; however, there is still a need for therapies for patients with disease refractory to TKI therapy. Newer agents are under investigation and may have promise. This article discusses the current standard of care in terms of standard and investigational pharmacotherapy in the management of metastatic GIST. © 2013 Elsevier Inc.
Cristofanilli M.,Chase Medical
Journal of Oncology | Year: 2012
Successful management of breast cancer in the metastatic setting is often confounded by resistance to chemotherapeutics, in particular anthracyclines and taxanes. The limited number of effective treatment options for patients with more aggressive biological subtypes, such as triple-negative metastatic breast cancer, is especially concerning. As such, a therapy clinically proven to be effective in this subtype would be of great value. Ixabepilone, a novel synthetic lactam analog of epothilone B, demonstrated better clinical outcomes in metastatic disease, particularly in triple-negative breast cancer. Most recently, studies have shown the activity of ixabepilone in the neoadjuvant setting, suggesting a role for this drug in primary disease. Notably, treating in the neoadjuvant setting might allow clinicians to explore the predictive value of biomarkers and response to treatment, as pharmacogenomic approaches to therapy continue to evolve. In this article, we review the efficacy and safety data of ixabepilone as a monotherapy and as a component of combination therapy for metastatic and primary breast cancer. Copyright © 2012 Massimo Cristofanilli.
Hall M.J.,Chase Medical
JNCCN Journal of the National Comprehensive Cancer Network | Year: 2010
Inherited mutations in 1 of 4 known mismatch repair genes (MLM, MSH2, MSH6, PMS2) are associated with various cancer risks collectively referred to as Lynch syndrome. Roughly 3 of every 100 new colorectal cancers (CRCs) have an underlying Lynch mutation. Tumor-based screening for Lynch among all patients with newly diagnosed CRC could theoretically improve the ability to identify Lynch and prevent cancer among at-risk family members, but the patient-level and social implications of this approach must be carefully considered before adopting this strategy. Poorly addressed issues include the role/timing of informed consent for testing, access and cost barriers associated with genetic counseling and DNA testing, psychosocial burdens to the thousands of middle-aged and elderly patients with CRC coping with surgical and chemotherapy treatments and poor prognosis, the need for providers to warn third-party relatives of risk for Lynch syndrome, limited effectiveness of screening, and the cost burden to society when poor DNA testing uptake, test limitations, and modest screening compliance are considered. Diverse barriers to the success of a population-based Lynch screening program in the United States remain (e.g., clinical resource needs, financial limitations, clinical expertise gaps, educational deficits). Data supporting clinical efficacy (feasibility) and effectiveness (real-life performance) are critical before important policy changes are adopted, especially where issues of hereditary cancer risk and genetic privacy are involved. © Journal of the National Comprehensive Cancer Network.
Smith M.R.,Chase Medical
Future Oncology | Year: 2011
Mantle cell lymphoma (MCL) is an uncommon subtype of B-cell lymphomathat is characterized by monoclonal B cells that express CD5 on their surface, but not CD23, and harbor the t(11:14) chromosomal translocation that leads to dysregulated expression of cyclin D1. MCL is a biologically and clinically heterogeneous disease. It has the unfavorable characteristics of both aggressive and indolent lymphoma in that MCL is not curable with current standard therapy, yet patients have a shorter survival compared with other indolent histology. MCL is incurable, yet more intensive therapy does lead to longer disease-free intervals; therefore, treatment must be designed to optimize survival while maintaining quality of life. Thus, therapy should be individualized based on both the clinical behavior of the lymphoma and the patient's status. While there is no clear standard therapy that can be recommended for all patients, there may be an optimal choice for each patient. Knowledge of the expected clinical benefits and toxicities of various approaches will allow the physician and patient to appropriately select the therapy. © 2011 Future Medicine Ltd.
Held-Warmkessel J.,Chase Medical
Oncology nursing forum | Year: 2014
A patient being treated for metastatic adenocarcinoma of the pancreas presents to the clinic for a routine appointment. A complete blood count reveals hemoglobin of 6.5 g/dl and a platelet count of 30,000 K/mm3 thought to be from the last of many doses of gemcitabine. On assessment, the only complaint was fatigue with no evidence of bleeding or other abnormal physical findings other than pallor. Past medical history includes hypertension managed with three antihypertensive agents. Additional laboratory tests reveal elevated blood urea nitrogen (69 mg/dl), creatinine (2.76 mg/dl), and lactic dehydrogenase (LDH), was well as indirect bilirubin (2.1 mg/dl). The patient is admitted and transfused with packed red blood cells (pRBCs). The next day, the platelet count drops to 9,000 K/mm3 and the hemoglobin increases, appropriately, to 8.9 g/dl. Urinalysis is positive for hemoglobin (+ 3). The peripheral blood smear is positive for schistocytes (fragmented RBCs). A pheresis catheter is placed after the patient was evaluated by a hematologist and a nephrologist. A presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) with hemolytic uremic syndrome (HUS) was made.
Blay J.-Y.,University of Lyon |
Von Mehren M.,Chase Medical
Seminars in Oncology | Year: 2011
The development of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myelogenous leukemia (CML) was based on the discovery that CML stem and progenitor cells overexpress the abnormal fusion protein kinase BCR-ABL. The prototype TKI, imatinib, selectively inhibits BCR-ABL, as well as several other kinases, including stem cell factor receptor (KIT), discoidin domain receptor (DDR), platelet-derived growth factor receptor (PDGFR), and colony-stimulating factor receptor-1 (CSF-1R). Although the management of CML improved dramatically with the introduction of imatinib, not all patients benefit from treatment because of resistance or intolerance. Consequently, research efforts have focused on developing more potent TKIs with the ability to circumvent imatinib resistance. Nilotinib, a second-generation oral TKI, was rationally designed based on the crystal structure of imatinib to be highly active against a wide range of imatinib-resistant BCR-ABL mutants and is approved for the treatment of newly diagnosed or imatinib-resistant or -intolerant CML, and has shown superiority over imatinib in first-line treatment for newly diagnosed CML. Furthermore, the activity of nilotinib against KIT and PDGFRα has led to its evaluation in advanced gastrointestinal stromal tumors (GIST). The purpose of this review is to describe the development of nilotinib, providing a structural explanation for the differential activity of nilotinib and imatinib in GIST. Activity of nilotinib against KIT and PDGFR and emerging evidence of differences in cellular uptake between nilotinib and imatinib are discussed. © 2011 Elsevier Inc. All rights reserved.
Dotan E.,Chase Medical |
Cohen S.J.,Chase Medical
Seminars in Oncology | Year: 2011
Approximately one third of patients diagnosed with early-stage colon cancer will present with lymph node involvement (stage III) and about one quarter with transmural bowel wall invasion but negative lymph nodes (stage II). Adjuvant chemotherapy targets micrometastatic disease to improve disease-free (DFS) and overall survival (OS). While beneficial for stage III patients, the role of adjuvant chemotherapy is unestablished in stage II disease. This likely relates to the improved outcome of these patients, and the difficulties in developing studies with sufficient power to document benefit in this patient population. However, recent investigation also suggests that molecular differences may exist between stage II and III cancers and within stage II patients. Validated pathologic prognostic markers are useful at identifying stage II patients at high risk for recurrence for whom the benefit from adjuvant chemotherapy may be greater. Such high-risk features include higher T stage (T4 v T3), suboptimal lymph node retrieval, presence of lymphovascular invasion, bowel obstruction, or bowel perforation, and poorly differentiated histology. However, for the majority of patients who do not carry any of these adverse features and are classified as "average-risk" stage II patients, the benefit of adjuvant chemotherapy remains unproven. Emerging understanding of the underlying biology of stage II colon cancer has identified molecular markers that may change this paradigm and improve our risk assessment and treatment choices for stage II disease. Assessment of microsatellite stability (MSI), which serves as a marker for DNA mismatch repair (MMR) system function, has emerged as a useful tool for risk stratification of patients with stage II colon cancer. Patients with high frequency of MSI have been shown to have increased OS and limited benefit from 5-fluorouracil (5-FU)-based chemotherapy. Additional research is necessary to clearly define the most appropriate way to use this marker and others in routine clinical practice. © 2011 Elsevier Inc. All rights reserved.