Purpose: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). Experimental Design: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m 2 ). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with oneway ANOVA. Results: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium.The population typical value of clearance of unbound paclitaxel was 301L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. Conclusions: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.

Immunosuppressed patients with cSCC-HN had dramatically lower outcomes compared with immunocompetent patients, despite receiving bimodality therapy. Immune status is a strong prognostic factor that should be accounted for in prognostic systems, treatment algorithms, and clinical trial design. Cancer 2017;123:2054-2060. © 2017 American Cancer Society.

Objective To evaluate whether pretreatment metabolic parameters obtained from positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) can improve risk prediction for patients with oropharyngeal squamous cell carcinoma (OPSCC) treated with definitive intensity-modulated radiation therapy (IMRT). Methods Between 2003 and 2009, 86 patients with OPSCC had FDG-PET/CT prior to treatment with definitive IMRT. Chemotherapy was administered to 90 % of the patients. Metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax), mean SUV (SUVmean), and inverse coefficient of variation (1/CoV) were analyzed for the primary tumor alone and the total of the primary tumor and involved lymph nodes. Results Median follow-up time for surviving patients was 41 months. On univariate analysis, total MTV and total TLG were significant predictors of disease-free survival (DFS) and overall survival (OS). SUVmax, SUVmean, and 1/CoV failed to predict DFS or OS. On multivariate analysis controlling for T- and N-classification, total MTV remained a significant predictor of DFS and OS. The optimal cutpoint for total MTV was 20.5 ml. A total MTV >20.5 ml was associated with a 4.13-fold increased risk of death (95 % confidence interval [CI], 2.12–8.05; p < 0.0001). Total MTV remained a significant predictor of DFS and OS for the subgroups with p16-positive (n = 25) and p16-negative (n = 18) cancer. Conclusion Total MTV is an independent predictor of DFS and OS for patients with OPSCC treated with definitive radiotherapy. Total MTV remained predictive of DFS and OS for both p16-positive and p16-negative cancer.

The data generated from the Human Genome Project has led to an explosion of technology for low-, medium-, and high-throughput genotyping methods. Pyrosequencing is a genotyping assay based on sequencing by synthesis. Short runs of sequence around each polymorphism are generated, allowing for internal controls for each sample. Pyrosequencing can also be used to identify tri-allelic, indel, and short-repeat polymorphisms, as well as determining allele percentages for methylation or pooled sample assessment. Assays details for Pyrosequencing of clinically relevant polymorphisms are described in this chapter.

BackgroundHuman cytochrome P450 3A enzymes, particularly CYP3A4 and CYP3A5, play an important role in drug metabolism. CYP3A expression exhibits substantial interindividual variation, much of which may result from genetic variation. This study describes Pyrosequencing assays for key SNPs in CYP3A4 (CYP3A4*1B, CYP3A4*2, and CYP3A4*3) and CYP3A5 (CYP3A5*3C and CYP3A5*6).MethodsGenotyping of 95 healthy European and 95 healthy African volunteers was performed using Pyrosequencing. Linkage disequilibrium, haplotype inference, Hardy-Weinberg equilibrium, and tag SNPs were also determined for these samples.ResultsCYP3A4*1B allele frequencies were 4% in Europeans and 82% in Africans. The CYP3A4*2 allele was found in neither population sample. CYP3A4*3 had an allele frequency of 2% in Europeans and 0% in Africans. The frequency of CYP3A5*3C was 94% in Europeans and 12% in Africans. No CYP3A5*6 variants were found in the European samples, but this allele had a frequency of 16% in the African samples. Allele frequencies and haplotypes show interethnic variation, highlighting the need to analyze clinically relevant SNPs and haplotypes in a variety of ethnic groups.ConclusionPyrosequencing is a versatile technique that could improve the efficiency of SNP analysis for pharmacogenomic research with the ultimate goal of pre-screening patients for individual therapy selection.

No abstract

In-transit metastasis was significantly associated with locoregional recurrence, OS, and cause-specific mortality. Efforts should be made to define in-transit metastasis in the staging system.

Purpose To report the incidence and potential predictors of fat necrosis in women with early-stage breast cancer treated with adjuvant high-dose-rate (HDR) multicatheter interstitial brachytherapy. Methods and Materials Between 2003 and 2010, 238 treated breasts in 236 women were treated with accelerated partial breast irradiation (APBI) using HDR interstitial brachytherapy. Selection criteria included patients with Tis-T2 tumors measuring ≤ 3 cm, without nodal involvement, who underwent breast-conserving surgery (BCS). 99% of treatments were to a total dose of 34 Gy. The presence and severity of fat necrosis was prospectively recorded during follow up. Cosmesis was qualitatively scored in all patients. Cosmesis was quantitatively measured via the percentage breast retraction assessment (pBRA) in 151 cases. Results Median follow-up was 56 months. The crude rate of fat necrosis was 17.6%. The rate of symptomatic fat necrosis was 10.1%. In univariate analysis acute breast infection and anthracycline-based chemotherapy, number of catheters, V100, V150, V200 and integrated reference air-kerma (IRAK) were significantly associated with fat necrosis. There was significant collinearity between the brachytherapy related factors, of these V150 was most predictive. In multivariate analysis only V150 was significantly associated with fat necrosis. At 3 years, patients with fat necrosis were more likely to have a fair/poor cosmetic outcome and a larger pBRA. Conclusions Mammary fat necrosis is a common adverse event after BCS and HDR interstitial brachytherapy. Fat necrosis is associated with worse qualitative and quantitative cosmetic outcomes. Minimizing exposure volumes such as V150 may decrease the incidence of fat necrosis and improve cosmesis.