Immune therapy for breast cancer in 2010—hype or hope?

The identification of numerous breast cancer antigens has generated increasing enthusiasm for the application of immune-based therapies in breast malignancies. Although the use of monoclonal antibodies has revolutionized the "targeted therapy" of breast cancer, and the immunomodulatory effects of bisphosphonates continue to be evaluated, few studies to date have demonstrated widespread utility for other forms of immunotherapy. The present review assesses modern research and explores whether the hopes for immunotherapy can overcome the hype.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar^®), vinorelbine (Navelbine^®) and irinotecan (Campto^®), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20–30% and 1-year survival rates of 30–40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-α. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar), vinorelbine (Navelbine) and irinotecan (Campto), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20-30% and 1-year survival rates of 30-40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-alpha. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.     

Gene delivery by embryonic stem cells for malignant glioma therapy: hype or hope?

Patients with glioblastomas have a poor prognosis and new treatments paradigms are needed. The futility of current treatments lies in part on the difficulty of delivering therapeutic agents to the tumor. In this article, we review and discuss current knowledge of adjuvant treatment for glioblastomas including gene therapy and viral vectors. Additionally, this review provides an update on recent progress, which has focused on improving delivery methods including the development of new approaches such as stem cells. Particular emphasis is given to laboratory data showing the use of embryonic stem cells used as vectors to deliver pro-apoptotic genes to glioblastoma cells.     

BEAC or BEAM for high-dose therapy in patients with non-Hodgkin's lymphoma? A single centre analysis on toxicity and efficacy

High-dose chemotherapy supported by autologous stem cell transplantation is widely used in patients with non-Hodgkin's lymphoma (NHL). Limited data is available on the comparative toxicity and efficacy of various high-dose regimens applied in NHL. We therefore analysed regimen-related toxicity and outcome in 71 consecutive NHL patients who received either BEAC (N = 36) or BEAM (N = 35) supported by peripheral blood progenitor cell infusion plus granulocyte colony-stimulating factor. The patients who received BEAM had significantly more often WHO grade > 2 mucositis (63 vs. 28%, P = 0.009) and diarrhoea grade >2 (29 vs. 8%, P = 0.062). Septicaemia also tended to be more frequent and the peak CRP value was higher in the BEAM group (140 vs. 113 mg/l, P = 0.034). Transplant-related mortality (< 100 d) was 3 and 9% in the BEAC and BEAM groups, respectively. No significant differences were observed in overall survival or progression free survival between these two groups. While BEAC and BEAM appears to have equal antitumour efficacy in patients with NHL, BEAM seems to be more toxic to the gastrointestinal tract. However, randomised studies are needed for more definitive conclusions on the relative merits of various high-dose regimens in patients with NHL.     

Is breast-conserving therapy a safe option for patients with tumor multicentricity and multifocality?

BackgroundWe compared outcomes after breast-conserving therapy (BCT) and mastectomy in multicentric (MC)/multifocal (MF) versus unifocal breast cancer.Patients and methodsWomen with stage I–II disease were classified as having unifocal or MC/MF disease. MC/MF and other prognostic factors were compared using binary logistic regression analysis. Univariate and multivariate analyses (MVAs) for relapse were carried out using cumulative incidence curves and Fine and Gray regression models. For the BCT group, matched analysis was added.ResultsMedian follow-up was 7.9 years, 11 983 having BCT (unifocal: 11 683, MC/MF: 300) and 7771 having mastectomy (unifocal: 6884, MC/MF: 887). MC/MF patients treated with BCT were 50–69 years old, free of extensive ductal carcinoma in situ (DCIS), and had smaller tumors. The cumulative 10-year local recurrence rates among unifocal and MC/MF disease were 4.6% [95% confidence interval (CI) 4.1% to 5.0%] versus 5.5% (95% CI 2.6% to 9.9%) for the BCT group, P = 0.76 and 5.8% (95% CI 5.2% to 6.5%) versus 6.5% (95% CI 4.7% to 8.7%) for the mastectomy group, P = 0.77. MC/MF was not a significant factor for relapse or survival on MVA. In the matched analysis, relapse rates were similar in the unifocal and MC/MF groups, P = 0.60.ConclusionBCT is a reasonable option in selected MC/MF cases, particularly those women aged 50–69 years old with small (<1 cm) MF tumors and without an extensive DCIS component.     

Systemic treatment in EGFR-ALK NSCLC patients：second line therapy and beyond

Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer（NSCLC） has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few ＂mountains＂ [representing the most commonly mutated genes like KRAS, epidermal growth factor（EGFR）, and anaplastic lymphoma kinase（ALK）] and a vast number of ＂hills＂（representing low frequency but potentially actionable mutations）. Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.     

Genomics and circulating tumor cells: promising tools for choosing and monitoring adjuvant therapy in patients with early breast cancer?

PURPOSE OF REVIEW: Gene expression profiling using a class discovery approach has consistently shown that breast cancer emerges as a group of different disease entities: the basal-like, the human epidermal growth factor receptor 2 type, the normal breast-like, and at least two different hormone receptor positive or luminal types. Initial reports have also suggested that certain expression patterns are associated with relapse. Current data on adjuvant therapy are only beginning to consider this biologic heterogeneity (estrogen receptor and human epidermal growth factor receptor 2 status). Similarly, the search for isolated tumor cells in blood or bone marrow has been regarded as another approach for defining prognosis and tailoring adjuvant therapies. The purpose of this review is to highlight the recent data emerging from both approaches as a means of assessing prognosis and tailoring therapy in patients with early breast cancer. RECENT FINDINGS: The initial reports on prognosis assessment of breast cancer using the expression profile have been corroborated, but the differences between the actual genes selected for the different prognostic signatures remain difficult to explain. Others have introduced added signatures, such as those associated with proliferation or with wound healing, or selected subgroups on the basis of, for example, estrogen receptor level prior to class comparison. The data on the quantification of expression of a limited number of selected genes are promising for both prognosis and prediction. The segregation of histological grade 2 tumors into genetically defined grade 1 or 3 tumors and its associated prognostic significance is a critical observation. The standardization of methods for measuring isolated tumor cells in blood or bone marrow has resulted in validated data both on prognosis in early breast cancer and in the advanced setting. Methylation of circulating DNA might become another method for selecting patients for extended adjuvant regimens. SUMMARY: The new molecular knowledge must be incorporated into prospective clinical studies in patients with early breast cancer. This is the challenge for the years to come.     

Plexin D1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy?

We previously reported that during mouse embryogenesis, plexin D1 (plxnD1) is expressed on neuronal and endothelial cells. Endothelial cells gradually loose plxnD1 expression during development. Here we describe, using in situ hybridization, that endothelial plxnD1 expression is regained during tumor angiogenesis in a mouse model of brain metastasis. Importantly, we found PLXND1 expression also in a number of human brain tumors, both of primary and metastatic origin. Apart from the tumor vasculature, abundant expression was also found on tumor cells. Via panning of a phage display library, we isolated two phages that carry single-domain antibodies with specific affinity towards a PLXND1-specific peptide. Immunohistochemistry with these single-domain antibodies on the same tumors that were used for in situ hybridization confirmed PLXND1 expression on the protein level. Furthermore, both these phages and the derived antibodies specifically homed to vessels in brain lesions of angiogenic melanoma in mice after i.v. injection. These results show that PLXND1 is a clinically relevant marker of tumor vasculature that can be targeted via i.v. injections.     

What is the optimal therapy for patients with metastatic renal cell carcinoma who progress on an initial VEGFr-TKI?

Sequential treatment with targeted therapies is the current standard of care for patients with metastatic renal cell carcinoma (mRCC). Most patients are initially treated with a first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI), but will eventually develop resistance and subsequent disease progression. Patients with mRCC whose disease progresses during initial VEGFr-TKI therapy may continue treatment with a different VEGFr-TKI or they may switch to treatment with a mammalian target of rapamycin (mTOR) inhibitor which has a different mechanism of action. Based on positive results of the phase III RECORD-1 trial, clinical guidelines in the United States and Europe recommend use of everolimus, an mTOR inhibitor, in patients with VEGFr-TKI–refractory mRCC. Positive results of the phase III AXIS trial led to recent approval in the United States of the VEGFr-TKI axitinib for use in patients with mRCC who failed one previous therapy. VEGFr-TKIs and mTOR inhibitors have distinct clinical effects with differing safety profiles, but to date, no head-to-head comparisons in the post-VEGFr-TKI second-line setting are available. This review discusses multiple factors that should be considered when selecting a second-line therapy for patients with VEGFr-TKI–refractory mRCC, including evidence-based guidelines, efficacy, safety, patient profile, and clinician familiarity with available agents.     

Relapse after high-dose therapy in relapsed Ewing's tumor patients: effects of maintenance chemotherapy in two selected patients?

BACKGROUND: The prognosis for patients with high-risk Ewing's tumor, i.e. primarily multifocal or early relapsed disease, is extremely poor with conventional relapse therapy. High-dose radio/chemotherapy (HDC) with subsequent stem cell transplantation seems to improve outcome in this patient cohort. In spite of this intensified therapy however, relapse remains the most frequent cause of death. In the majority of patients the time to second relapse after HDC is shorter than the time to first relapse after conventional therapy (3.4 vs. 18 months). Event-free survival in Ewing's tumor patients who suffer a second relapse after first-line therapy (EICESS 92) is 2% after 18 months. CASE REPORT: The present report describes the clinical course of two girls who relapsed after HDC and subsequently received low-dose oral trofosfamide and etoposide. The patient with very late multifocal relapse after first-line treatment and a second localized relapse 30 months after HDC remains disease-free for 5 years after the last relapse. However, the other patient with 2 early relapses after first-line treatment and HDC, respectively, did not benefit from this regime. CONCLUSION: We propose that low-dose maintenance therapy may be beneficial in the subgroup of Ewing's tumor patients with late relapse after HDC.     

Nestin involvement in tissue injury and cancer - a potential tumor marker?

Background

In eukaryotic cells, the cytoskeleton contains three major filamentous components: actin microfilaments, microtubules and intermediate filaments. Nestin represents one of the class VI intermediate filament proteins. Clinical and molecular analyses have revealed substantial information regarding the presence of Nestin in cells with progenitor or stem cell properties. During tissue injury Nestin is expressed in cells with progenitor cell-like properties. These cells may serve as a tissue reserve and, as such, may contribute to tissue repair. Based on currently available data, Nestin also appears to be implicated in two oncogenic processes. First, Nestin has been found to be expressed in cancer stem-like cells and poorly differentiated cancer cells and, as such, Nestin is thought to contribute to the aggressive behavior of these cells. Second, Nestin has been found to be involved in tumor angiogenesis through an interaction of cancer cells and blood vessel endothelial cells and, as such, Nestin is thought to facilitate tumor growth.

Conclusions

We conclude that Nestin may serve as a promising tumor marker and as a potential therapeutic target amenable to tumor suppression and angiogenesis inhibition.     

Has first-line therapy had an impact on general outcome in metastatic breast cancer?

According to the WHO World Cancer Report, 2003, breast cancer is a global public health burden with more than one million new cases diagnosed worldwide each year. Despite the diminished frequency of advanced-stage disease at initial diagnosis in some parts of the world, a significant proportion of women with early-stage disease eventually experience distant recurrences. Metastatic breast cancer is generally incurable and treatment is aimed at extending survival and improving quality-of-life. Efforts to optimize these paradigms are ongoing. In the last 30 years, significant innovations in drug delivery, scheduling and biologic therapies have resulted in significant improvements in disease-specific outcomes in the metastatic setting. One hopes that ongoing innovations, particularly in targeted therapy, will continue to translate into further improvements in this population.