Association between genetic variants in sortilin-related receptor 1 (SORL1) and Alzheimer's disease in adults with Down syndrome

Recent reports have suggested that variants in the sortilin-related receptor gene (SORL1) increase the risk of late onset Alzheimer's disease (AD) in Northern European, Hispanic, African–American and Isreali–Arab populations. SORL1 directs trafficking of amyloid precursor protein (APP) and under-expression of SORL1 may lead to over-expression of β amyloid peptides. Adults with Down syndrome (DS) over-express APP and have early onset and high risk for AD. We investigated the relation of seven variants in the gene for SORL1 to age at onset and risk for AD among 208 adults with DS, 45–70 years of age at baseline. Participants were ascertained through the New York State developmental disability service system and followed at 18-month intervals. Information from cognitive assessments, caregiver interviews, medical record review and neurological examination was used to establish the diagnosis of dementia. Homozygosity for the minor T allele in rs556349 and for the minor C allele in rs536360 was associated with later age at onset and reduced risk of AD (HR = 0.26, 95% CI: 0.08–0.86; and HR = 0.40, 95% CI: 0.16–0.98, respectively). Mean age at onset was approximately four years later in individuals who were homozygous for those alleles compared with those who had at least one major allele. These findings indicate a modest association of variants in SORL1 with AD. In addition, we did not observe the same alleles to be associated with AD compared with earlier studies, suggesting that these SNPs are in linkage disequilibrium (LD) with the putative functional variants or that expression of the SORL1 gene and hence its interaction with APP might be modified by the extremely high levels of APP characteristic of Down syndrome. Thus, further studies are needed to identify functional variants that influence risk for AD in this uniquely vulnerable population.     

Review of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy

Background

In 2006, the economic burden of metastatic renal cell carcinoma (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually. With the continuing increase of the economic burden of this disease in the United States, there is a growing need for economic analyses to guide treatment and policy decisions for this patient population.

Objective

To evaluate available comparative economic data on targeted therapies for patients with mRCC who have failed first-line targeted therapies.

Method

A broad and comprehensive literature review was conducted of US-based studies between January 1, 2005, and February 11, 2013, evaluating comparative economic evidence for targeted agents that are used as second-line therapy or beyond. Based on the specific search parameters that focused on cost-effectiveness and economic comparisons between vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) inhibitors and mammalian target of rapamycin (mTOR) inhibitors, only 7 relevant, US-based economic evaluations were found appropriate for inclusion in the analysis. All authors, who are experts in the health economics and outcomes research field, reviewed the search results. Studies of interest were those with a targeted agent, VEGF/VEGFr or mTOR inhibitor, in at least 1 study arm.

Discussion

As a group, targeted therapies were found to be cost-effective options in treating patients with refractory mRCC in the United States. Oral therapies showed an economic advantage over intravenous agents, presumably because oral therapies have a lower impact on outpatient resources. Based on 3 studies, everolimus has been shown to have an economic advantage over temsirolimus and to be cost-effective compared with sorafenib. No economic comparison between everolimus and axitinib, the only 2 drugs with a National Comprehensive Cancer Network category 1 recommendation for use after the failure of VEGFr tyrosine kinase inhibitors, is available.

Conclusion

The limited and heterogeneous sum of the currently available economic evidence does not allow firm conclusions to be drawn about the most cost-effective targeted treatment option in the second-line setting and beyond in patients with mRCC. It is hoped that ongoing head-to-head therapeutic trials and biomarker studies will help improve the economic efficiency of these expensive agents.Renal cell carcinoma (RCC) comprises 92% of all kidney cancers and has a poor prognosis, with approximately 10% of patients with metastatic disease surviving beyond 5 years.1 In 2006, the economic burden of metastatic RCC (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually.2 A recent review reported that the economic burden of RCC in the United States ranges from $600 million to $5.19 billion, with annual per-patient medical costs of between $16,488 and $43,805.3 Furthermore, these costs will likely increase with the expanded use of targeted agents, based on a 2011 pharmacoeconomic analysis showing that the annual costs to treat patients with RCC receiving these agents are 3- to 4-fold greater than the costs to treat patients who are not receiving targeted therapies.4 In addition, the incidence and prevalence of RCC are rising, in part because of improved and earlier detection, and because of increases in related risk factors, such as hypertension, diabetes, and obesity.5–7

KEY POINTS

• ▸ The growing economic burden of renal cell carcinoma (RCC) in the United States indicates the need for economic analyses of current therapies to guide treatment decisions for this disease.
• ▸ This article is based on a comprehensive review of 7 studies that were identified within the search criteria for US-based economic data related to targeted therapies for metastatic RCC (mRCC) after failure of first-line therapies.
• ▸ Targeted therapies were shown to be cost-effective for the treatment of refractory mRCC.
• ▸ Oral therapies showed an economic advantage over intravenous agents, presumably because of their lower impact on outpatient resources.
• ▸ No economic comparison is yet available for the only 2 drugs (ie, everolimus and axitinib) with an NCCN category 1 recommendation for use after a vascular endothelial growth factor receptor TKI.
• ▸ Ongoing head-to-head therapeutic trials and biomarker studies may help to improve the economic efficiency of targeted treatments in the second-line setting and beyond for mRCC.

Clear-cell RCC, the most common histology, constitutes 75% of cases of RCC.8 The majority of patients with clear-cell RCC experience a loss of the functional von Hippel-Lindau gene, resulting in the accumulation of hypoxia-inducible factor-1α, an angiogenic factor whose protein synthesis is regulated by mammalian target of rapamycin (mTOR).9 The net effect is overproduction of downstream proteins that promote RCC progression by stimulating cell growth and proliferation, cellular metabolism, and angiogenesis (ie, vascular endothelial growth factor [VEGF], platelet-derived growth factor, and epidermal growth factor).9Abnormal functioning of the mTOR pathway is therefore thought to play a role in the pathogenesis of RCC; inhibition of mTOR globally decreases protein production, suppresses VEGF synthesis, and induces cell cycle arrest.10 Knowledge of the critical role of VEGF and mTOR in RCC pathogenesis drove the development of targeted agents in the treatment of this disease. The US Food and Drug Administration (FDA) approval of axitinib in January 2012 brings the total of approved targeted agents for RCC to 7 in the past 7 years, making this one of the most prolific areas of cancer drug development (11–25 The need for clarity regarding the optimal sequential use of these agents is stronger than ever, particularly given the high price of these agents.

Table 1

Targeted Agents Approved for RCC and Pivotal Phase 3 Clinical Trials

United States-based practice patterns and resource utilization in advanced neuroendocrine tumor treatment

AIM: To assess advanced neuroendocrine tumor (NET) treatment patterns and resource utilization by tumor progression stage and tumor site in the United States. METHODS: United States Physicians meeting eligibility criteria were provided with online data extraction forms to collect patient chart data on recent NET patients. Resource utilization and treatment pattern data were collected over a baseline period (after diagnosis and before tumor progression), as well as initial and secondary progression periods, with progression defined according to measureable radiographic evidence of tumor progression. Resource categories used in the analysis include: Treatments (e.g. , surgery, chemotherapy, radiotherapy, targeted therapies), hospitalizations and physician visits, diagnostic tests (biomarkers, imaging, laboratory tests). Comparisons between categories of resource utilization and tumor progression status were examined using univariate (by tumor site) and multivariate analyses (across all tumor sites). RESULTS: Fifty-five physicians were included in the study and completed online data extraction forms using the charts of 110 patients. The physician sample showed a relatively even distribution for those affiliated with academic versus community hospitals (46% vs 55%). Forty (36.3%) patients were reported to have pancreatic NET (pNET), while 70 (63.6%) patients had gastrointestinal tract (GI)/Lung as the primary NET site. Univariate analysis showed the proportion of patients hospitalized increased from 32.7% during baseline to 42.1% in the progression stages. While surgeries were performed at similar proportions overall at baseline and progression, pNET patients, were more likely than GI/Lung NET patients to have undergone surgery during the baseline (33.3% vs 25.0%) and any progression periods (26.7% vs 23.4%). While peptide-receptor radionuclide and targeted therapy utilization was low across NET types and tumor stages, GI/Lung types exhibited greater utilization of these technologies compared to pNET. Chemotherapy u