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Chan M.,National Cancer Center | Ji S.M.,National Cancer Center | Yeo Z.X.,National Cancer Center | Gan L.,Defence Medical and Environmental Research Institute | And 8 more authors.
Journal of Molecular Diagnostics | Year: 2012

In a clinical setting, next-generation sequencing (NGS) approaches for the enrichment and resequencing of DNA targets may have limitations in throughput, cost, or accuracy. We evaluated an NGS workflow for targeted DNA sequencing for mutation detection. Targeted sequence data of the BRCA1 and BRCA2 genes, generated using a PCR-based, multiplexed NGS approach using the SOLiD 4 (n = 24) and Ion Torrent PGM (n = 20) next-generation sequencers, were evaluated against sequence data obtained by Sanger sequencing. The overall sensitivity for SOLiD and PGM were 97.8% (95% CI = 94.7 to 100.0) and 98.9% (95% CI = 96.8 to 100.0) respectively. The specificity for the SOLiD platform was high, at 100.0% (95% CI = 99.3 to 100.0). PGM correctly identified all 3 indels, but 68 false-positive indels were also called. Equimolar normalization of amplicons was not necessary for successful NGS. Both platforms are highly amenable to scale-up, potentially reducing the reagent cost for BRCA testing to Source

Wong N.-S.,National Cancer Center | Seah E.Z.H.,National University of Singapore | Wang L.-Z.,Cancer Science Institute | Yeo W.-L.,National University of Singapore | And 10 more authors.
Pharmacogenetics and Genomics | Year: 2011

OBJECTIVES: Vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. METHODS: Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. Results: Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. Conclusion: UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat, and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Ravaud A.,Hopital Saint Andre Bordeaux University Hospital | Barrios C.H.,Pontifical Catholic University of Rio Grande do Sul | Alekseev B.,Hertzen Cancer Research Institute | Tay M.-H.,OncoCare Cancer Center | And 10 more authors.
Annals of Oncology | Year: 2015

Background: The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. Patients and methods: Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results: Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69-1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. Conclusions: The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Yeo Z.X.,National Cancer Center Singapore | Chan M.,National Cancer Center Singapore | Yap Y.S.,National Cancer Center Singapore | Ang P.,National Cancer Center Singapore | And 3 more authors.
PLoS ONE | Year: 2012

The emergence of benchtop sequencers has made clinical genetic testing using next-generation sequencing more feasible. Ion Torrent's PGMTM is one such benchtop sequencer that shows clinical promise in detecting single nucleotide variations (SNVs) and microindel variations (indels). However, the large number of false positive indels caused by the high frequency of homopolymer sequencing errors has impeded PGMTM's usage for clinical genetic testing. An extensive analysis of PGMTM data from the sequencing reads of the well-characterized genome of the Escherichia coli DH10B strain and sequences of the BRCA1 and BRCA2 genes from six germline samples was done. Three commonly used variant detection tools, SAMtools, Dindel, and GATK's Unified Genotyper, all had substantial false positive rates for indels. By incorporating filters on two major measures we could dramatically improve false positive rates without sacrificing sensitivity. The two measures were: B-Allele Frequency (BAF) and VARiation of the Width of gaps and inserts (VARW) per indel position. A BAF threshold applied to indels detected by UnifiedGenotyper removed ~99% of the indel errors detected in both the DH10B and BRCA sequences. The optimum BAF threshold for BRCA sequences was determined by requiring 100% detection sensitivity and minimum false discovery rate, using variants detected from Sanger sequencing as reference. This resulted in 15 indel errors remaining, of which 7 indel errors were removed by selecting a VARW threshold of zero. VARW specific errors increased in frequency with higher read depth in the BRCA datasets, suggesting that homopolymer-associated indel errors cannot be reduced by increasing the depth of coverage. Thus, using a VARW threshold is likely to be important in reducing indel errors from data with higher coverage. In conclusion, BAF and VARW thresholds provide simple and effective filtering criteria that can improve the specificity of indel detection in PGMTM data without compromising sensitivity. © 2012 Yeo et al. Source

Chay W.Y.,National Cancer Center Singapore | Ong W.S.,National Cancer Center Singapore | Tan P.H.,Singapore General Hospital | Jie Leo N.Q.,National Cancer Center Singapore | And 8 more authors.
Breast Cancer Research | Year: 2012

Introduction: The Gail model (GM) is a risk-assessment model used in individual estimation of the absolute risk of invasive breast cancer, and has been applied to both clinical counselling and breast cancer prevention studies. Although the GM has been validated in several Western studies, its applicability outside North America and Europe remains uncertain. The Singapore Breast Cancer Screening Project (SBCSP) is a nation-wide prospective trial of screening mammography conducted between Oct 1994 and Feb 1997, and is the only such trial conducted outside North America and Europe to date. With the long-term outcomes from this study, we sought to evaluate the performance of GM in prediction of individual breast cancer risk in a Asian developed country.Methods: The study population consisted of 28,104 women aged 50 to 64 years who participated in the SBSCP and did not have breast cancer detected during screening. The national cancer registry was used to identify incident cases of breast cancer. To evaluate the performance of the GM, we compared the expected number of invasive breast cancer cases predicted by the model to the actual number of cases observed within 5-year and 10-year follow-up. Pearson's Chi-square test was used to test the goodness of fit between the expected and observed cases of invasive breast cancers.Results: The ratio of expected to observed number of invasive breast cancer cases within 5 years from screening was 2.51 (95% confidence interval 2.14 - 2.96). The GM over-estimated breast cancer risk across all age groups, with the discrepancy being highest among older women aged 60 - 64 years (E/O = 3.53, 95% CI = 2.57-4.85). The model also over-estimated risk for the upper 80% of women with highest predicted risk. The overall E/O ratio for the 10-year predicted breast cancer risk was 1.85 (1.68-2.04).Conclusions: The GM over-predicts the risk of invasive breast cancer in the setting of a developed Asian country as demonstrated in a large prospective trial, with the largest difference seen in older women aged between 60 and 64 years old. The reason for the discrepancy is likely to be multifactorial, including a truly lower prevalence of breast cancer, as well as lower mammographic screening prevalence locally. © 2011 Chay et al.; licensee BioMed Central Ltd. Source

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