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Abstract: This was a single institution phase I/II study to determine the maximum tolerated dose (MTD) and efficacy of pegylated liposomal doxorubicin (PLD) and gemcitabine in Asian women with metastatic breast cancer. PLD was administered on day 1 and gemcitabine on days 1 and 8 every 3 weeks at escalating doses from 25mg/m2 and 1000mg/m2 onwards respectively. The median age was 56 years with a median disease-free interval of 43 months. Majority of the patients had visceral involvement. At PLD 35mg/m2 and gemcitabine 1200mg/m2, the overall response rate for 23 evaluable patients was 83% (1 CR, 18 PR, 3 SD, 1 PD). Six had prior adjuvant anthracyclines (3 PR, 1 SD). The median follow-up was 81 weeks and progression free interval was 29 weeks. Overall survival was 23.9 months. The dose limiting toxicities were mucositis and myelosuppression. This regimen is active and reasonably tolerated as first-line therapy. [Copyright &y& Elsevier]

The aim of this exploratory study was to investigate associations between irinotecan pharmacokinetic parameters and allelic variants in genes encoding for drug transporters and drug metabolizing enzymes that are involved in irinotecan disposition in Asian patients with cancer.Irinotecan was administered at 100 mg m−2 over 90 min on a weekly schedule to 29 nasopharyngeal carcinoma patients and pharmacokinetic analysis was performed during the first cycle. All patients were genotyped for allelic variants in genes encoding drug metabolizing enzymes (CYP3A4,CYP3A5,UGT1A1) and drug transporters (ABCB1,ABCC2andABCG2) that are involved in irinotecan disposition.Of the six candidate genes that were analyzed, 11 genetic variants were found. Significant genotypic–phenotypic associations were apparent only for transporter genes. TheCmax of irinotecan was significantly lower in patients carrying the CC genotype at exon 26 of theABCB1gene compared with those harbouring at least one variant allele (P = 0.047). Patients harbouring the wild typeABCG2CTCA genotype were associated with significantly higher values for relative extent of conversion (REC) of irinotecan to SN-38 compared with patients carrying at least one deletion CTCA allele (P = 0.019).The present exploratory study shows that genetic polymorphisms in drug transporter genes, particularly inABCB1andABCG2genes, may be important in influencing the pharmacokinetics of irinotecan and its metabolites. The predictive value of the identified allelic variants in theABCG2andABCB1genes on irinotecan disposition should be further investigated in a larger patient population as well as in other ethnic populations. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Recently, several genome-wide association studies have demonstrated a cumulative association of 5 polymorphic variants in chromosomes 8q24 and 17q with prostate cancer (CaP) risk in Caucasians, particularly those harboring aggressive clinicopathologic characteristics. The purpose of this study was to evaluate the influence of these variants on CaP susceptibility in Singaporean Asian men. Materials and methods: We performed a case-control study in 289 Chinese CaP patients and 412 healthy subjects (144 Chinese, 134 Malays, and 134 Indians), and examined the association of the 5 single nucleotide polymorphisms (SNPs) with CaP. Results: In the healthy subjects, rs16901979 A-allele frequency was highest amongst Chinese (0.32) compared with Malays (0.13; P < 0.0001) or Indians (0.09; P < 0.0001); rs6983267 G-allele was highest in Indians (0.51) compared with Chinese (0.42; P = 0.041) or Malays (0.43; P = 0.077); whereas rs1859962 G-allele frequency was highest amongst Indians (0.56) compared with Chinese (0.40; P = 0.0002) or Malays (0.38; P < 0.0001). Individuals with the rs4430796 TT genotype were at increased CaP risk in the Chinese via a recessive model (odds ratios (OR) = 1.56, 95% CI = 1.04–2.33). Significant associations were observed for rs4430796 TT with Gleason scores of ≥7 (OR = 1.76, 95% CI = 1.14–2.73) and prostate-specific antigen (PSA) levels of ≥10 ng/ml at diagnosis (OR = 1.63, 95% CI = 1.01–2.63), as well as for rs6983267 GG with stage 3–4 CaPs (OR = 1.91, 95% CI = 1.01–3.61). A cumulative gene interaction influence on disease risk, which approximately doubled for individuals with at least 2 susceptibility genotypes, was also identified (OR = 2.18, 95% CI = 1.10–4.32). Conclusions: This exploratory analysis suggests that the 5 genetic variants previously described may contribute to prostate cancer risk in Singaporean men. [Copyright &y& Elsevier]

Introduction: Most international clinical practice guidelines for prostate cancer (PCa) are driven by data derived in a Western setting. However, tumour biology and clinical disease progression are likely to differ in the Asian population. We compare the performance of the revised American Joint Committee on Cancer (AJCC) prognostic groups with the commonly used D'Amico Risk Classification and conventional predictors for PCa, in a large cohort of Asian patients., Materials and Methods: We retrospectively reviewed data for 404 consecutive Singaporean patients receiving definitive radiotherapy at our centre between December 1996 and October 2006. The primary outcome was biochemical relapse-free survival (BRFS), defined using the Phoenix definition. The secondary outcome was overall survival (OS). Prognostic risk groups were defined using AJCC 7th edition (AJCC7) and 6th edition (AJCC6). Univariate analysis (UVA) and multivariate analysis (MVA) were performed for the following putative risk factors: age, Gleason score, prognostic grouping, tumour classification, radiation delivery technique, radiotherapy dose, hormonal therapy and initial PSA value., Results: For the cohort, median age was 69 years. Median follow-up was 66.3 months. Five-year BRFS rate was 84.3% with 71 biochemical relapses and 5-year OS rate was 89.1% with 54 deaths. The concordance-indices for BRFS prediction were 0.588, 0.550 and 0.567 for AJCC7, AJCC6 and D'Amico respectively. Initial PSA, T-stage and AJCC7 were prognostic for BRFS on UVA. Comparison of AJCC7 vs. D'Amico showed no statistical additional value of either classification system although D'Amico was superior when compared to AJCC6 in predicting BRFS. T-stage ≥3 and D'Amico were significant prognostic factors for BRFS on MVA., Conclusion: In our local, predominantly Chinese population, neither AJCC6 nor AJCC7 demonstrated a high predictive accuracy for BRFS although AJCC7 has a slightly better predictive ability than AJCC6.

Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients.