Methodological and practical challenges for personalized cancer therapies
Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Nature Reviews Clinical Oncology
(Impact Factor: 14.18).
03/2011; 8(3):135-41. DOI: 10.1038/nrclinonc.2011.2
Many experts agree that personalized cancer medicine, defined here as treatment based on the molecular characteristics of a tumor from an individual patient, has great potential in the therapy of many types of cancer. Although targeted therapy agents are increasingly available for clinical applications, many of these promising drugs have produced disappointing results when tested in clinical trials, indicating that there are many challenges that must be addressed to advance this field. We propose that a new generation of clinical trials requiring biopsies to obtain relevant tumor specimens, as well as novel statistical designs, will be essential to improve treatment outcomes. However, these novel clinical trials will only be successful if appropriate biomarkers are identified to help guide the selection of the most beneficial treatments for the participating patients. Although biomarkers based on single gene mutations are the most commonly used in clinical applications today, gene-expression or protein-expression 'signatures' and new imaging technologies have the potential to play important roles as biomarkers in the future. Therefore, it is of crucial importance that we identify and resolve existing challenges that may impede the rapid identification and translation of validated biomarkers with acceptable sensitivity and specificity from the laboratory to the clinic. These challenges include limitations of current biomarker development methodologies and regulatory and reimbursement policies and practices.
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- "Lung cancer continues to be the most common and deadly malignant cancers worldwide . Although important progress in the management of this disease has been observed over the last decade, non-small cell lung cancer (NSCLC) remains a lethal disease, and improving poor prognosis (5-year survival of approximately 15%) remains a challenge . Multiple independent prognostic factors, such as performance status, disease stage, age, sex and amount of weight lost, have previously been identified for predicting survival . "
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The prognostic value of the copy number (GCN) and protein expression of the mesenchymal-epithelial transition (MET) gene for survival of patients with non-small cell lung cancer (NSCLC) remains controversial. This study aims to comprehensively and quantitatively asses the suitability of MET GCN and protein expression to predict patients' survival.
PubMed, Embase, Web of Science and Google Scholar were searched for articles comparing overall survival in patients with high MET GCN or protein expression with those with low level. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed.
Eighteen eligible studies enrolling 5,516 patients were identified. Pooled analyses revealed that high MET GCN or protein expression was associated with poor overall survival (OS) (GCN: HR = 1.90, 95% CI 1.35–2.68, p<0.001; protein expression: HR = 1.52, 95% CI 1.08–2.15, p = 0.017). In Asian populations (GCN: HR = 2.22, 95% CI 1.46–3.38, p<0.001; protein expression: HR = 1.89, 95% CI 1.34–2.68, p<0.001), but not in the non-Asian subset. For adenocarcinoma, high MET GCN or protein expression indicated decreased OS (GCN: HR = 1.49, 95% CI 1.05–2.10, p = 0.025; protein expression: HR = 1.69, 95% CI 1.31–2.19, p<0.001). Results were similar for multivariate analysis (GCN: HR = 1.61, 95% CI 1.15–2.25, p = 0.005; protein expression: HR = 2.18, 95% CI 1.60–2.97, p<0.001). The results of the sensitivity analysis were not materially altered and did not draw different conclusions.
Increased MET GCN or protein expression was significantly associated with poorer survival in patients with surgically resected NSCLC; this information could potentially further stratify patients in clinical treatment.
- "However, despite initially encouraging results, breast cancer studies have reported that anti-angiogenic treatment increases progression free survival but not overall survival compared to standard cytostatic treatment . Finding reliable and accurate methods to individualize therapy is a high priority for cancer treatment of the future  and critical for increasing the overall benefit of anti-angiogenic therapy. Determining the extent to which these methods can identify and quantify molecular dysfunctions and therapeutic responses in preclinical models is a key step toward accelerating future translation to human studies. "
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ABSTRACT: Vascular endothelial growth factor receptor 2 (VEGFR2) is a crucial mediator of tumour angiogenesis. High expression levels of the receptor have been correlated to poor prognosis in cancer patients. Reliable imaging biomarkers for stratifying patients for anti-angiogenic therapy could therefore be valuable for increasing treatment success rates. The aim of this study was to investigate the pharmacokinetics and angiogenesis imaging abilities of the VEGFR2-targeting positron emission tomography (PET) tracer (R)-[11C]PAQ.
(R)-[11C]PAQ was evaluated in the mouse mammary tumour virus-polyoma middle T (MMTV-PyMT) model of metastatic breast cancer. Mice at different stages of disease progression were imaged with (R)-[11C]PAQ PET, and results were compared to those obtained with [18 F]FDG PET and magnetic resonance imaging. (R)-[11C]PAQ uptake levels were also compared to ex vivo immunofluorescence analysis of tumour- and angiogenesis-specific biomarkers. Additional pharmacokinetic studies were performed in rat and mouse.
A heterogeneous uptake of (R)-[11C]PAQ was observed in the tumorous mammary glands. Ex vivo analysis confirmed the co-localization of areas with high radioactivity uptake and areas with elevated levels of VEGFR2. In some animals, a high focal uptake was observed in the lungs. The lung uptake correlated to metastatic and angiogenic activity, but not to uptake of [18 F]FDG PET. The pharmacokinetic studies revealed a limited metabolism and excretion during the 1-h scan and a distribution of radioactivity mainly to the liver, kidneys and lungs. In rat, a high uptake was additionally observed in adrenal and parathyroid glands.
The results indicate that (R)-[11C]PAQ is a promising imaging biomarker for visualization of angiogenesis, based on VEGFR2 expression, in primary tumours and during metastasis development.
Available from: Cecilia Nardini
- "When patients that have the same kind of tumour, but harbouring different molecular lesions, are exposed to a targeted compound, the response can vary dramatically to the point that not only the magnitude, but also the direction of the treatment effect may be different across molecularly identified subgroups. This is particularly relevant for the testing of such drugs, as it means that the beneficial effect of the targeted agent in trial is often restricted to a small class of the initially eligible patients, and the class of patients that would benefit often cannot be determined prior to beginning the study . Thus, in a study testing a targeted agent, only a small fraction of the participating patients have a prospect to benefit from the experimental treatment at all. "
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ABSTRACT: Over the past decades, randomised controlled trials (RCTs) have prevailed over clinical judgement, case reports, and observational studies and became the gold evidential standard in medicine. Furthermore, during the same time frame, RCTs became a crucial part of the regulatory process whereby a new therapeutic can gain access to the drug market. Today, clinical trials are large and tightly regulated enterprises that have to comply with ethical requirements while maintaining high epistemic standards, a balance that becomes increasingly difficult as the research questions become more sophisticated. In this review, the author will discuss some of the most important ethical issues surrounding RCTs, with an eye to the most recent debates and the context of oncological research in particular.
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