Pharmacogenetics of adjuvant breast cancer treatment with cyclophosphamide, epirubicin and 5-fluorouracil.

PURPOSE: Most adjuvant breast cancer treatment regimens include the combination of an anthracycline (epirubicin or doxorubicin) and the alkylating agent cyclophosphamide. This study sought to investigate the influence of pharmacogenetics on the pharmacokinetics and metabolism of these agents. METHODS: Blood samples were taken from patients treated with cyclophosphamide (n = 51) and epirubicin (n = 35), with or without 5-fluorouracil (5-FU). The pharmacokinetics and metabolism of the three drugs were investigated, together with pharmacogenetic investigations for cyclophosphamide and epirubicin. Cyclophosphamide and its metabolites and also epirubicin and epirubicinol were measured in plasma. DNA was extracted from whole blood and genotyping performed using RT-PCR. RESULTS: Patients with at least one variant CYP2C19*17 allele had a longer CP half-life (p = 0.007), as did homozygous variants for the CYP2B6*6 allele. There was no significant effect of GSTP1, CYP2B6*2, CYP2B6*5 or CYP2C19*2 on any pharmacokinetic parameter of CP. An NQO2 exonic SNP was associated with a higher exposure to epirubicinol relative to epirubicin (p = 0.011). Other polymorphic variants of NQO1, carbonyl reductase, UGT enzymes and transporters had no influence on epirubicin or its metabolite. CONCLUSION: Overall, pharmacogenetic factors had only a minor influence on cyclophosphamide or anthracycline-based adjuvant therapy of breast cancer.

Single-shot readout and relaxation of singlet and triplet states in exchange-coupled 31P electron spins in silicon.

We present the experimental observation of a large exchange coupling J ≈ 300 µeV between two (31)P electron spin qubits in silicon. The singlet and triplet states of the coupled spins are monitored in real time by a single-electron transistor, which detects ionization from tunnel-rate-dependent processes in the coupled spin system, yielding single-shot readout fidelities above 95%. The triplet to singlet relaxation time T(1) ≈ 4 ms at zero magnetic field agrees with the theoretical prediction for J-coupled 31P dimers in silicon. The time evolution of the two-electron state populations gives further insight into the valley-orbit eigenstates of the donor dimer, valley selection rules and relaxation rates, and the role of hyperfine interactions. These results pave the way to the realization of two-qubit quantum logic gates with spins in silicon and highlight the necessity to adopt gating schemes compatible with weak J-coupling strengths.

Pediatric treatment 2.0: ensuring a holistic response to caring for HIV-exposed and infected children.

Treatment 2.0 is an initiative launched by UNAIDS and WHO in 2011 to catalyze the next phase of treatment scale-up for HIV. The initiative defines strategic activities in 5 key areas, drugs, diagnostics, commodity costs, service delivery and community engagement in an effort to simplify treatment, expand access and maximize program efficiency. For adults, many of these activities have already been turned into treatment policies. The recent WHO recommendation to use a universal first line regimen regardless of gender, pregnancy and TB status is a treatment simplification very much in line with Treatment 2.0. But despite that fact that Treatment 2.0 encompasses all people living with HIV, we have not seen the same evolution in policy development for children. In this paper we discuss how Treatment 2.0 principles can be adapted for the pediatric population. There are several intrinsic challenges. The need for distinct treatment regimens in children of different ages makes it hard to define a one size fits all approach. In addition, the fact that many providers are reluctant to treat children without the advice of specialists can hamper decentralization of service delivery. But at the same time, there are opportunities that can be availed now and in the future to scale up pediatric treatment along the lines of Treatment 2.0. We examine each of the five pillars of Treatment 2.0 from a pediatric perspective and present eight specific action points that would result in simplification of pediatric treatment and scale up of HIV services for children.

Two minor NQO1 and NQO2 alleles predict poor response of breast cancer patients to adjuvant doxorubicin and cyclophosphamide therapy.

OBJECTIVE: A SNP in the NQO1 gene has been implicated in the response of patients with breast cancer to anthracycline containing regimens. NQO1, and its homologue NQO2, share many substrates yet retain distinct functional differences, with NQO2 being a more permissive molecule for electron accepting substrates. We aimed to determine whether functional NQO2 variants are associated with altered response to adjuvant doxorubicin and cyclophosphamide therapy, with or without tamoxifen, in the treatment of breast cancer. METHODS: Genomic DNA samples from 227 women with early breast cancer were genotyped for NQO1 and NQO2 polymorphisms. All participants were treated with an AC adjuvant therapy regimen. The functional implications of NQO2 polymorphisms were validated in in-vitro ectopic expression models. RESULTS: The NQO1 SNP (rs1800566) was associated with a poorer outcome and a lower likelihood of having a treatment delay. Patients who had ER and PR negative disease and were wild type for both the NQO1 and an NQO2 SNP (rs1143684) had 100% 5-year overall survival compared with 88% for carriers of one minor allele and 70% for carriers of two or more minor alleles (P=0.018, log rank). Carriers of minor alleles of a triallelic NQO2 promoter polymorphism were more likely to be withdrawn from tamoxifen therapy prematurely due to intolerance (P=0.009, log rank). MCF-7 cells were sensitized to growth inhibition by doxorubicin and 4OH tamoxifen, but not cyclophosphamide, by ectopic expression of NQO2. CONCLUSION: This study suggests that both NQO1 and NQO2 modulate the efficacy of AC therapy and that NQO2 is associated with tamoxifen toxicity.