bluuebunny/crossref_metadata_2025 huggingface dataset:
Oncogenes and Tumor Suppressor Genes in Breast Cancer: Potential Diagnostic and Therapeutic Applications
Authors: Osborne Cynthia , Wilson Paschal , Tripathy Debu
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Differentiate between the actions of oncogenes and tumor suppressor genes in the development of breast cancer. Describe the results of studies with antibodies and small molecule drugs that target growth factor receptors. Evaluate the current and potential roles of molecular and protein profiles of breast tumors in prognosis and in predicting response to therapy.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Oncogenes refer to those genes whose alterations cause gain-of-function effects, while tumor suppressor genes cause loss-of-function effects that contribute to the malignant phenotype. The effects of these alterations are complex due to the high number of changes in a typical case of breast cancer and the interactions of the biological pathways involved. This review focuses on the more common abnormalities in oncogenes and tumor suppressor genes in human breast cancer and their known associations with clinical outcome in terms of tumor classification, prognosis, and response to specific therapies. A better understanding of these relationships has led to new therapeutic applications. Agents that target oncogenes and their associated pathways are now in clinical use, with many more undergoing preclinical and clinical testing. The availability of antibodies, small synthetic molecules, cyotokines, gene therapy techniques, and even natural compounds that are screened for specific biological properties has greatly increased the number of candidate drugs. Nevertheless, clinical successes have been limited because of the redundancy of many cancer-related pathways as well as the high degree of variability in genotype and phenotype among individual tumors. Likewise, strategies to replace tumor suppressor gene functions face numerous technical hurdles. This review summarizes the current achievements and future prospects for the therapeutic targeting of oncogenes and tumor suppressor genes and new technology to better classify tumors and accurately predict responses to standard and novel agents.
Imaging the Liver
Authors: Sahani Dushyant V. , Kalva Sanjeeva P.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Select an appropriate imaging modality to diagnose a suspected liver tumor or stage an existing liver tumor. Describe the relative advantages and disadvantages of various imaging modalities in characterizing liver tumors. Explain the common radiological findings in the diagnosis of focal and diffuse liver disease.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Imaging of the liver is undertaken for the detection and characterization of suspected primary or secondary neoplasms, prior to planning a surgery or chemotherapy pump placement, for assessing treatment response, for evaluating biliary pathology, and for screening for liver neoplasms in high-risk groups. In this article, we review the advantages and disadvantages of various imaging modalities in the evaluation of the liver and formulate guidelines for the imaging of common clinical indications. A brief review of imaging findings in focal and diffuse liver disease is also presented.
Dilemmas in Management: The Controversial Role of Chemotherapy in PS 2 Advanced NSCLC and the Potential Role of CT-2103 (Xyotax™)
Authors: Langer Corey J.
Published: August 2004

Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.
Clinical Mimics of Lymphoma
Authors: Brown Jennifer R. , Skarin Arthur T.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Determine when lymphadenopathy is of concern and merits biopsy. Identify the benign causes of significant lymphadenopathy. Identify the unusual lymphoproliferative disorders that can cause significant lymphadenopathy.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Lymphadenopathy is a common clinical finding and is frequently benign. Warning signs suggestive of a malignant etiology include lymph nodes >2 cm in size, supraclavicular location, and generalized lymphadenopathy associated with hepatosplenomegaly or systemic symptoms. A metastatic solid tumor is always in the differential diagnosis of localized lymphadenopathy, particularly in older individuals. In the case of more generalized lymphadenopathy, in addition to the more common lymphomas, benign etiologies as well as benign and atypical lymphoproliferative disorders need to be considered. Benign etiologies of lymphadenopathy can include infections, autoimmune disorders, drug hypersensitivity reactions, sarcoidosis, and amyloidosis. Rare but benign lymphoproliferative disorders include Kikuchi's disease, Rosai-Dorfman disease, and progressive transformation of germinal centers. Atypical lymphoproliferative disorders that bear close surveillance for evolution to a more aggressive malignancy include Castleman's disease, lymphomatoid granulomatosis, and lymphomatoid papulosis. Previously considered in this category but now classified as a true lymphoma is angioimmunoblastic lymphadenopathy with dysproteinemia. Physicians need to be aware of all of these disorders when evaluating suspicious lymphadenopathy, while also considering the more common lymphomas and leukemias.
Serum CA125: A Tumor Marker for Monitoring Response to Treatment and Follow-up in Patients with Non-Hodgkin's Lymphoma
Authors: Zidan Jamal , Hussein Osamah , Basher Walid , Zohar Shmuel
Published: August 2004

Purpose. Serum CA125 is an important prognostic factor in patients with non-Hodgkin's lymphoma (NHL). Elevation of CA125 level correlates with advanced disease, poor response to treatment, and poor survival rates. The aim of the current study is to evaluate CA125 levels in patients with NHL and to investigate the correlations between high CA125 level and other presenting features.

Materials and Methods. Thirty-eight patients (14 with low-grade and 24 with aggressive histologically proven NHL) were studied prospectively. Serum CA125 assessment was done at diagnosis, during treatment, and at follow-up. The associations between CA125 levels and other presenting features were examined.

Results. CA125 levels were elevated in 43% of patients with low-grade NHL and in 46% of patients with aggressive NHL (i.e., 45% of all patients). A higher CA125 level was associated with advanced disease, bone marrow involvement, extranodal involvement, poor performance status, the presence of B symptoms, and high serum lactate dehydrogenase level. Complete responses occurred in 86% of patients with normal CA125 levels and in 59% of patients with elevated CA125 levels. In both low-grade and aggressive NHL, the estimated 5-year overall survival rate was higher in patients with normal CA125 levels than in patients with elevated CA125 levels (88% versus 50% and 70% versus 27%, respectively).

Conclusion. High serum CA125 is an important prognostic factor in NHL and correlates with more advanced disease, low response rates, and worse survival. CA125 measurements may be used for staging, monitoring response to treatment, and follow-up of patients with NHL.
Conformal Radiation Therapy for Childhood CNS Tumors
Authors: Kirsch David G. , Tarbell Nancy J.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the difference between conventional and conformal radiation therapy. Explain why conformal radiation therapy may decrease the long-term side effects of treatment. Compare the potential risks for a radiation-induced malignancy from proton radiation therapy and intensity-modulated radiation therapy with photons (x-rays).

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Radiation therapy plays a central role in the management of many childhood brain tumors. By combining advances in brain tumor imaging with technology to plan and deliver radiation therapy, pediatric brain tumors can be treated with conformal radiation therapy. Through conformal radiation therapy, the radiation dose is targeted to the tumor, which can minimize the dose to normal brain structures. Therefore, by limiting the radiation dose to normal brain tissues, conformal radiation therapy offers the possibility of limiting the long-term side effects of brain irradiation.

In this review, we describe different approaches to conformal radiation therapy for pediatric central nervous system tumors including: A) three-dimensional conformal radiation therapy; B) stereotactic radiation therapy with arc photons; C) intensity-modulated radiation therapy; and D) proton beam radiation therapy. We discuss the merits and limitations of these techniques and describe clinical scenarios in which conformal radiation therapy offers advantages over conventional radiation therapy for treating pediatric brain tumors.
Effectiveness of Darbepoetin Alfa Versus Epoetin Alfa in Patients with Chemotherapy-Induced Anemia Treated in Clinical Practice
Authors: Patton Jeffrey , Reeves Timothy , Wallace Joel
Published: August 2004

Primary Purpose. The objective of this retrospective observational cohort study was to compare the effectiveness of darbepoetin alfa with that of epoetin alfa in patients with chemotherapy-induced anemia using data from noncontemporaneous chart audits conducted at a community-based oncology practice.

Materials and Methods. For the first chart audit, data were collected from consecutive patients with nonmyeloid malignancies with diagnoses of chemotherapy-induced anemia and hemoglobin levels ≤10.5 g/dl who were receiving concurrent chemotherapy and had at least 5 weeks of visits from July-September 2000. After therapeutic substitution of darbepoetin alfa for epoetin alfa for all patients with chemotherapy-induced anemia, data were collected from consecutive darbepoetin alfa-treated patients with diagnoses of chemotherapy-induced anemia and at least 8 weeks of visits from June-October 2002 (darbepoetin alfa was approved in July 2002).

Results. Most (86%) of the 212 epoetin alfa-treated patients had received an initial dose of 40,000 U once weekly, and most (85%) of the 196 darbepoetin alfa-treated patients had received a fixed dose of either 100 μg once weekly (49%) or 200 μg every 2 weeks (36%). At 8 weeks, the mean change in hemoglobin level was 1.1 g/dl for the darbepoetin alfa patient group and 1.0 g/dl for the epoetin alfa patient group.

Discussion. Utilization, dose escalation rates, and clinical outcomes were considered comparable for the darbepoetin alfa and epoetin alfa patient groups.

Conclusions. Darbepoetin alfa, 100 μg once weekly or 200 μg every 2 weeks, appears to be as effective as epoetin alfa, 40,000 U once weekly, for the treatment of chemotherapy-induced anemia in the clinical practice setting.
The Molecular Perspective: Polycyclic Aromatic Hydrocarbons
Authors: Goodsell David S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Gain a basic understanding of the role of polycyclic aromatic hydrocarbons in cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Breast Cancer Highlights: Key Findings from the San Antonio Breast Cancer Symposium: A U.S. Perspective
Authors: Cristofanilli Massimo , Hortobágyi Gabriel N.
Published: August 2004

The San Antonio Breast Cancer Symposium has become one of the leading forums for communication of important discoveries in breast cancer research. Over the past couple of years, seminal, practice-changing results have been presented at this meeting. The aromatase inhibitors represent the most effective endocrine interventions for postmenopausal women with hormone receptor-positive breast cancer. Their introduction into the adjuvant therapy of primary breast cancer was prompted by evidence from the ATAC trial. Progress in adjuvant chemotherapy included the introduction to taxanes, and more recently, the demonstration that the dose-dense administration of paclitaxel in association with doxorubicin and cyclophosphamide resulted in significant improvements in relapse-free and overall survival rates. Molecular targets have become accepted as rational targets, and targeted therapies are proceeding through clinical trials. The success of trastuzumab elicited much excitement, but a number of theoretical and practical hurdles must be overcome before other molecularly targeted agents are incorporated into standard therapy of primary and metastatic breast cancer.
Targeted Therapy of Colorectal Cancer: Clinical Experience with Bevacizumab
Authors: Fernando Nishan H. , Hurwitz Herbert I.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the clinical experience of bevacizumab in colorectal cancer. Explain the relevant biology and preclinical drug development of bevacizumab in colorectal cancer. Discuss future directions of research.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com

Advanced colorectal cancer remains an urgent health concern, despite improvements in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy with minimal side effects. Angiogenesis (the formation of new blood vessels) is essential for tumor growth and metastasis and may be an ideal target in the search for new antineoplastic agents. Vascular endothelial growth factor is one of the best characterized of the proangiogenic growth factors that regulate angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab (AvastinTM; Genentech Inc.; South San Fransisco, CA), a humanized murine monoclonal antibody directed at vascular endothelial growth factor, is being evaluated in the treatment of various types of cancer. It has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer. Addition of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus leucovorin) resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal safety concerns, but were manageable. Further phase II/III studies of bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without irinotecan and/or oxaliplatin, in colorectal cancer, are under way.
Non-Small Cell Lung Cancer and Antiangiogenic Therapy: What Can Be Expected of Bevacizumab?
Authors: Herbst Roy S. , Sandler Alan B.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Identify the role of angiogenesis in non-small cell lung cancer (NSCLC). Explain the role of bevacizumab in apparently producing greater response, time to progression, and overall survival rates in a randomized phase II trial comparing carboplatin, paclitaxel, and bevacizumab with carboplatin and paclitaxel without bevacizumab and the limitations of this interpretation. Define the main toxicity concerns with the use of bevacizumab in the treatment of NSCLC.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com

There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC), as progress with current chemotherapy regimens has been limited. The roles of vascular endothelial growth factor (VEGF) in promoting tumor angiogenesis, maintaining existing vasculature, and contributing to resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (AvastinTM; Genentech Inc., South San Fransisco, CA), a monoclonal antibody directed against VEGF, has shown promise in treating a number of different cancers. In a recent phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy produced a significantly longer time to progression (32.1 versus 18.4 weeks) and greater response rate (31% versus 19% [not significant]) than chemotherapy alone. In the subset of patients with nonsquamous histologies, response rates and survival were further enhanced, with a mean survival time of 17.9 months versus 12.3 months with chemotherapy alone.

Bevacizumab was generally well tolerated and did not appear to increase the incidences or severities of the nausea/vomiting, neuropathy, and renal toxicity that are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) appear to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor.

Further work is needed to identify the best way to use bevacizumab in NSCLC, including use in combination with other biologic agents and in the adjuvant setting.
Vascular Endothelial Growth Factor as a Target for Anticancer Therapy
Authors: Ferrara Napoleone
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Explain the biology of angiogenesis. Identify the role of VEGF in normal and tumor angiogenesis. Describe the key ways in which VEGF has been targeted in cancer therapy.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com

The development of a vascular supply is a critical factor in the growth and metastatic spread of malignant tumors. Of the multitude of growth factors that regulate physiological and pathological angiogenesis, vascular endothelial growth factor (VEGF) is believed to be the most important. There is evidence that overexpression of VEGF is correlated with an adverse prognosis, at least in some tumors. Tumor-expressed VEGF is particularly attractive as a target for anticancer therapy because its angiogenesis-promoting activity is at the level of the endothelial cell and, compared with agents that directly target tumor cells, tumor penetration is less critical for VEGF inhibitors. Moreover, recent work has shown that inhibiting tumor angiogenesis increases the effectiveness of coadministered chemotherapy and radiotherapy. This suggests that drugs that target VEGF or its receptors can be combined with traditional treatment modalities to ensure maximum effectiveness. A variety of agents aimed at blocking VEGF or its receptor-signaling system are currently being developed for the treatment of cancer. Of these, bevacizumab, a humanized monoclonal antibody directed at VEGF, is the most advanced in clinical development and has shown promising results in clinical trials.
Expanding the Clinical Development of Bevacizumab
Authors: Chen Helen X.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the clinical development of bevacizumab. Summarize the clinical trials conducted using bevacizumab. Discuss the anticipated role of bevacizumab in cancer treatment and future directions for research.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com

Bevacizumab (AvastinTM; Genentech, Inc.; South San Francisco, CA) is a recombinant, humanized monoclonal antibody to vascular endothelial growth factor, a key regulator of tumor angiogenesis. Bevacizumab demonstrated potent antitumor activity in preclinical models and has also shown biologic activity and clinical benefit in clinical studies. Notably, a randomized, placebo-controlled phase II trial in renal cell carcinoma demonstrated a significantly longer time to tumor progression with bevacizumab monotherapy. Furthermore, in a phase III trial for untreated advanced colorectal cancer, the addition of bevacizumab to chemotherapy led to significantly longer overall survival and progression-free survival times than chemotherapy alone. The clinical development of bevacizumab has been expanded to include confirmatory phase III trials and exploratory phase II trials in a variety of solid tumors and hematologic malignancies. Treatment regimens being examined include bevacizumab alone and in combination with conventional chemotherapy, radiation, immune therapy, and biologically targeted agents.
Maximizing the Potential of Bevacizumab in Cancer Treatment
Authors: Bergsland Emily , Dickler Maura N.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Identify the major side effects of bevacizumab treatment. Describe the drug combinations, doses, and sequencing options that have been investigated to date and discuss further studies that are needed to fully define optimal therapy. Explain the challenges to using biological surrogates as outcome measures.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com

Promising results have been obtained with bevacizumab (AvestinTM; Genentech, Inc.; South San Francisco, CA) in clinical trials in patients with a range of solid tumors; however, to maximize the potential of this agent, further research is needed to clarify a number of important issues. These include the optimization of bevacizumab dosage and schedule of administration, the potential value of this agent in combination with other treatment modalities like chemotherapy and radiation, the management of toxicities, and the selection of patients most likely to benefit from treatment. Intriguing results from two recent phase III trials highlight the need for a better understanding of the best ways to incorporate bevacizumab into clinical practice. Ultimately, maximizing the potential value of this agent may require a more thorough understanding of bevacizumab's mechanism of action and the pathways mediating resistance.
Bevacizumab in the Treatment of Breast Cancer: Rationale and Current Data
Authors: Rugo Hope S.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Explain the role of VEGF in the tumor biology of breast cancer. Outline the data from clinical trials of bevacizumab conducted in patients with breast cancer. Discuss the interpretation of the phase III study of capecitabine alone or in combination with bevacizumab.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors.

Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (AvastinTM; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.
Taxane-Platinum Combinations in Advanced Non-Small Cell Lung Cancer: A Review
Authors: Rigas James R.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the rationale for and use of taxanes in NSCLC. Identify key efficacy findings from the four large randomized trials assessing platinum-taxane combinations in advanced NSCLC. Discuss adverse event and quality-of-life results from four large randomized trials assessing platinum-taxane combinations in advanced NSCLC.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Platinum-based chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC). As a result of their single-agent activities and synergistic effects, taxane-platinum combinations are often used as first-line therapy for this disease. Four large, multicenter, randomized phase III clinical trials (the TAX 326 trial, the Southwest Oncology Group 9509 trial, the Italian Lung Cancer Project, and the Eastern Cooperative Oncology Group 1594 trial) have compared taxane-platinum combinations (docetaxel and paclitaxel) with other platinum combinations (vinorelbine and gemcitabine) in chemotherapy-naïve patients with good performance status scores and advanced disease. The end points for these large randomized clinical trials were survival, response rate, adverse events, and quality of life (QOL). Of the taxane-platinum combinations tested, docetaxel-cisplatin was the only platinum combination to yield survival and response rates superior to another platinum combination. In adverse event terms, the taxane-platinum combination of paclitaxel-carboplatin demonstrated less grade 3 or 4 neutropenia and lower rates of febrile neutropenia than other taxane-platinum combinations but higher rates of irreversible grade 3 or 4 peripheral neuropathy than any of the other taxane-platinum combinations. Additional differences emerged when QOL data were evaluated. The docetaxel-platinum combination demonstrated broad QOL benefits for patients receiving this combination, and this benefit was not observed with the other platinum or taxane-platinum combinations. As our use of these taxane-platinum combinations expands, these differences in survival, response rate, adverse events, and QOL will permit us to better balance our treatment goals for all patients with all stages of NSCLC.
Docetaxel and Paclitaxel in the Treatment of Breast Cancer: A Review of Clinical Experience
Authors: Crown John , O'Leary Michael , Ooi Wei-Seong
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe randomized trial data from studies evaluating taxanes in anthracycline-naïve or anthracycline-pretreated metastatic breast cancer patients. Discuss recent findings of randomized trials evaluating docetaxel as neoadjuvant therapy. Compare and contrast efficacy end point data from three adjuvant taxane trials with mature results.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

In the 10 years since their initial licensing in Europe, the taxanes, paclitaxel and docetaxel, have emerged as fundamental drugs in the treatment of breast cancer. Clinically meaningful benefits were first shown in the metastatic setting, and large-scale exploration of their roles in the adjuvant therapy of early-stage disease is ongoing. Benefits have been seen in the neoadjuvant setting as well, mainly with docetaxel. This paper reviews the current roles of the taxanes in the treatment of metastatic and early-stage breast cancer. Also addressed are outstanding issues involving optimal dosing and sequencing, as well as a discussion of the relative merits of each agent in this setting. Clinicians should choose a taxane-based regimen for their patients with breast cancer based on consideration of the pharmacokinetics, clinical activity, and dosing schedule that best meets the patients' needs. At the current time, the pharmacokinetic profile, consistent positive clinical results, and convenience of an intermittent, short-infusion schedule have made docetaxel the preferred taxane for many clinicians treating patients with breast cancer.
Preclinical Pharmacology of the Taxanes: Implications of the Differences
Authors: Gligorov Joseph , Lotz Jean Pierre
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Identify the differences in molecular pharmacology of the taxanes. Describe the impact of the pharmacokinetic and pharmacodynamic profiles of the taxanes on their administration and toxicity. Outline the toxicity profiles of paclitaxel and docetaxel.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Taxanes are one of the most powerful classes of compounds among all chemotherapeutic drugs. Only 30 years separate the isolation of the first taxane from the results of direct clinical comparisons in metastatic breast, ovarian, and lung cancer between the two taxanes available in routine clinical practice. These results suggest a more favorable benefit-to-risk ratio for docetaxel compared to paclitaxel when these drugs are used as single agents or in combination with other chemotherapeutic agents in an every-3-week dosing regimen. Pharmacological data support the difference between the taxanes, likely explaining the clinical results. Considering the molecular pharmacology of the two drugs, docetaxel appears to bind to β-tubulin with greater affinity and has a wider cell cycle activity than paclitaxel. Docetaxel also appears to have direct antitumoral activity via an apoptotic effect mediated by bcl-2 phosphorylation. In addition, docetaxel has a longer retention time in tumor cells than paclitaxel because of greater uptake and slower efflux. Pharmacokinetics and pharmacodynamics of the taxanes show both agents to be extensively metabolized in the liver, and paclitaxel has a nonlinear pharmacokinetic behavior while docetaxel has linear pharmacokinetics. These differences explain the more simple treatment schedule and favorable results for docetaxel as a single agent and in combination therapy. Last, but not least, there is a pharmacokinetic interaction between paclitaxel and the anthracyclines, an active class of compounds commonly used in the treatment of breast cancer. This pharmacokinetic interaction is associated with greater cardio- and myelotoxicities, which are sequence dependent. These pharmacological data likely explain the different clinical development strategies for the two molecules as well as the different clinical results from individual trials and direct comparisons.
The Treatment of Advanced Gastric Cancer: New Findings on the Activity of the Taxanes
Authors: Van Cutsem Eric
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Explain the role and evolution of chemotherapy for advanced gastric cancer. Discuss results of phase II trials evaluating taxanes in advanced gastric cancer. Describe the results and clinical implications of a phase III trial of docetaxel, cisplatin, and fluorouracil in advanced gastric cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Globally, gastric cancer is one of the most common types of cancer and one of the most frequent causes of cancer-related death. Despite many advances in the diagnosis and treatment of this disease, the prognosis for gastric cancer remains poor, especially in more advanced stages. In metastatic disease, benefits in survival and quality of life have been demonstrated in patients with unresectable or metastatic gastric cancer receiving chemotherapy plus best supportive care versus best supportive care alone. The taxanes, which are among the most promising cytotoxic agents in clinical use, have shown encouraging activity in early-phase studies as single agents and in combination regimens in the treatment of advanced gastric cancer. Recently, interim results of a randomized phase III trial comparing the triplet of docetaxel, cisplatin, and 5-fluorouracil with a standard reference regimen of cisplatin and 5-fluorouracil were reported. Patients treated with the docetaxel-containing regimen had a statistically superior response rate and time to disease progression as well as a clinically significant prolongation of survival. This study underscores the importance of developing new therapeutic options for patients with advanced gastric cancer.
Dual Kinase Inhibition in the Treatment of Breast Cancer: Initial Experience with the EGFR/ErbB-2 Inhibitor Lapatinib
Authors: Burris Howard A.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Identify the rationale for the development of dual ErbB receptor inhibitors. Describe safety data from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib. Describe evidence of biologic and clinical activity from early-phase clinical trials of the dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for ≥4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.
The Role of ErbB Inhibitors in Trastuzumab Resistance
Authors: Miller Kathy D.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Discuss mechanisms of resistance to EGFR inhibitor monotherapy. Cite potential treatment strategies and ongoing clinical trials to prevent or delay the development of resistance to EGFR inhibitors. Describe results of clinical trials using EGFR inhibitors in patients with metastatic breast cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

The ErbB family of receptors and ligands is a complex, delicately balanced system involved in the growth and differentiation of normal human cells as well as neoplasms. Targeting this system with therapies that inhibit ErbB receptor activity in cancer patients has been somewhat successful, but resistance to ErbB inhibitor monotherapy is substantial. An understanding of the biology of ErbB receptor inhibitors is necessary to determine how best to utilize them in treatment regimens. Experimental evidence has provided valuable insights regarding mechanisms involved in resistance, and indicates that resistance can be reversed in some models. Ongoing studies in patients are evaluating whether agents that target both the epidermal growth factor (EGFR, ErbB-1) and ErbB-2 (HER-2) receptors can prevent or delay resistance in patients with metastatic breast cancer that overexpresses HER-2. With a better understanding of the biology of breast cancer, and with several novel ErbB receptor inhibitors in development, continued progress for improved patient outcomes is expected.
Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition
Authors: Ellis Matthew
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Discuss patterns of resistance to endocrine therapy for breast cancer. Relate differences in resistance patterns in early and advanced disease settings. Identify potential treatment strategies to overcome resistance and/or restore endocrine therapy efficacy.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR+) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a small “proof of concept” phase II study of letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated durable responses despite tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacy was variable, however, despite the selection of patients on the basis of ER and ErbB-2 coexpression. Complicating matters further, resistance often occurs in the absence of any evidence for ErbB TK family member expression. In the absence of a clear target, common downstream signal transduction proteins that are known to intersect with the ER pathway can be inhibited to address resistance, including G proteins with farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with rapamycin analogues. With a number of phase III clinical trials now under way, major advances in the endocrine treatment of advanced disease are possible.
Monoclonal Antibodies, Small Molecules, and Vaccines in the Treatment of Breast Cancer
Authors: Esteva Francisco J.
Published: August 2004

Learning Objectives

After completing this course, the reader will be able to:

Describe the specificity and benefits of the monoclonal antibody trastuzumab in treating patients with metastatic breast cancer. Identify the potential advantages of dual HER tyrosine kinase inhibitors over single HER receptor inhibitors for treating metastatic breast cancer. Explain the design considerations of clinical trials for therapeutic vaccines to assess effect in patients with various stages of breast cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

The human epidermal growth factor receptor (HER, ErbB) family of receptors is considered an important therapeutic target, and various types of molecularly based small molecules, including monoclonal antibodies, protein tyrosine kinase inhibitors, and therapeutic vaccines, are in development as potential therapies for metastatic breast cancer. Trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA), the first approved monoclonal antibody for HER-2 (ErbB-2)-overexpressing metastatic breast cancer, provided the proof of principle that targeting specific receptors results in clinical benefit. Other monoclonal antibodies and the small molecule dual protein tyrosine kinase inhibitors show great promise as treatments for metastatic breast cancer but require evaluation in clinical trials to assess their benefits. Therapeutic vaccines may have a role, particularly in early-stage disease, but they are associated with greater limitations and study design issues that make their evaluation difficult. Optimum combination therapy regimens with a variety of novel approaches that incorporate small molecule targeted therapies need to be developed, and the population most likely to benefit from targeted therapies needs to be identified.
Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2
Authors: Prior Thomas W. , Swoboda Kathryn J. , Scott H. Denman , Hejmanowski Ashley Q.
Published: August 2004

Spinal muscular atrophy is a common autosomal recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The absence of the SMN1 gene has been shown to occur in all types of SMA, childhood and adult forms. In rare cases, asymptomatic family members have also been found with homozygous mutations in the SMN1 gene, suggesting a role for phenotypic modifiers. We describe three unrelated asymptomatic individuals, with family histories of SMA, who were shown to have the homozygous SMN1 deletion. Quantitative studies indicated that the three individuals all had increased SMN2 copy numbers. These cases not only support the role of SMN2 in modifying the phenotype, but our data also demonstrate that expression levels consistent with five copies of the SMN2 genes maybe enough to compensate for the absence of the SMN1 gene. Lastly, in cases similar to the ones described, the measurement of the SMN2 gene copy number may provide valuable prognostic information. © 2004 Wiley‐Liss, Inc.
Genome scan for loci involved in nonsyndromic cleft lip with or without cleft palate in families from West Bengal, India
Authors: Field L. Leigh , Ray Ajit K. , Cooper Margaret E. , Goldstein Toby , Shaw Diana F. , Marazita Mary L.
Published: August 2004

In order to identify genes or regions involved in nonsyndromic cleft lip with or without cleft palate (CL/P) in families from India, we analyzed 38 multiplex families (DNA from 272 individuals, 82 affected with CL/P, 190 unaffected) for 285 genome‐wide markers (average spacing 12.6 cM), including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 that have been implicated in other studies of CL/P. LOD scores (two‐point and multipoint), and model‐free association (TDT) and linkage (NPL) statistics, were calculated between each of the markers and a hypothetical CL/P susceptibility locus. The most statistically significant two‐point linkage results were with markers on chromosome 7 (LOD = 1.89 with D7S435, 7p15, 47 cM), chromosome 5 (LOD = 1.76 with D5S407, 5q11, 65 cM), chromosome 15 (LOD = 1.55 with D15S652, 15q26, 90 cM), and chromosome 20 (LOD = 1.46 with STS155130, 20q13, 54 cM). The most significant multipoint linkage result was on chromosome 5q, again near D5S407 (HLOD = 1.40). Regions on chromosomes 1p, 1q, 7q, 12q, 16q, 18q, and Xp also had a LOD or HLOD ≥ 1.0. Of seven candidate markers and regions with previous positive reports in the literature (TGFA, MSX1, D4S175, F13A1, TGFB3, D17S250, and APOC2), none had a significant linkage result, but one (the APOC2 region) had a significant association result and three others (TGFA, MSX1, F13A1) had suggestive results. The results are consistent with the involvement of multiple loci in CL/P expression in this West Bengal population, which concurs with results found in other CL/P study populations. © 2004 Wiley‐Liss, Inc.
Lay people's understanding of and preference against the word “mutation”
Authors: Condit Celeste M. , Dubriwny Tasha , Lynch John , Parrott Roxanne
Published: August 2004

Lay understandings of the term “mutation” are explored using three methodologies and three population bases. A community based sample (n = 848) employing a written survey to assess knowledge and understanding indicated good lay understanding of the basic concept of mutation. However, lay people associated mutation with reproductive outcomes, but not with changes in genes across the life span. A student sample (n = 241) employed a written survey to assess connotations of the term mutation. It showed a strong negative response to mutation. A community based sample (n = 120) employing focus groups also showed strong negative reactions to the term mutation and rejection of use of the term mutation in public service announcements (PSAs). The term variation had better response and is recommended as an alternative in genetic counseling and public media. © 2004 Wiley‐Liss, Inc.
Control of hepatocyte metabolism by sympathetic and parasympathetic hepatic nerves
Authors: Püschel Gerhard P.
Published: August 2004

More than any other organ, the liver contributes to maintaining metabolic equilibrium of the body, most importantly of glucose homeostasis. It can store or release large quantities of glucose according to changing demands. This homeostasis is controlled by circulating hormones and direct innervation of the liver by autonomous hepatic nerves. Sympathetic hepatic nerves can increase hepatic glucose output; they appear, however, to contribute little to the stimulation of hepatic glucose output under physiological conditions. Parasympathetic hepatic nerves potentiate the insulin‐dependent hepatic glucose extraction when a portal glucose sensor detects prandial glucose delivery from the gut. In addition, they might coordinate the hepatic and extrahepatic glucose utilization to prevent hypoglycemia and, at the same time, warrant efficient disposal of excess glucose. © 2004 Wiley‐Liss, Inc.