Comparative outcomes between robotic and abdominal radical hysterectomy for IB1 cervical cancer: Results from a single high volume institution.

OBJECTIVE: To compare the perioperative morbidity and survival between abdominal radical hysterectomy (ARH) and robotic radical hysterectomy (RRH). METHODS: A retrospective cohort of patients undergoing radical hysterectomy for cervical cancer from 2010 to 2016 was identified. Patients with stage IB1 cervical cancer were included and were grouped by ARH vs. RRH. Tumor characteristics, perioperative complications, recurrence rate, progression-free survival (PFS), and overall survival (OS) were compared between groups. RESULTS: 105 patients were identified; 56 underwent ARH and 49 underwent RRH. Those who had ARH were more likely to have lesions that were ≥2 cm (62% vs. 39%, p = 0.02) and that were higher grade (p = 0.048). Other tumor characteristics were similar between groups. There was no difference in perioperative complication rates between groups. Additionally, there were no differences in recurrence risk (RR) (14% vs. 24%, p = 0.22), progression-free survival (PFS) (p = 0.28), or overall survival (OS) (p = 0.16). However, in those with tumors ≥2 cm there was a higher risk of recurrence in the overall cohort (30% vs. 8%, p = 0.006), and a shorter PFS in the RRH group (HR 0.31, p = 0.04). On multivariate analysis patients that underwent ARH or had tumors < 2 cm had a lower likelihood of recurrence (HR 0.38, p = 0.04; HR 0.175, p = 0.002) and death (HR 0.21, p = 0.029; HR 0.15, p = 0.02). CONCLUSION: Perioperative morbidity was similar between those undergoing ARH vs. RRH for IB1 cervical cancer. Patients with tumors ≥ 2 cm undergoing RRH had a shorter PFS compared to ARH. On multivariate analysis, RRH and tumor size ≥ 2 cm were independently associated with recurrence and death in this population.

Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: implications of genetic variants on pharmacokinetics and hyperbilirubinemia.

PURPOSE: Several case reports suggest sorafenib exposure and sorafenib-induced hyperbilirubinemia may be related to a (TA)(5/6/7) repeat polymorphism in UGT1A1*28 (UGT, uridine glucuronosyl transferase). We hypothesized that sorafenib inhibits UGT1A1 and individuals carrying UGT1A1*28 and/or UGT1A9 variants experience greater sorafenib exposure and greater increase in sorafenib-induced plasma bilirubin concentration. EXPERIMENTAL DESIGN: Inhibition of UGT1A1-mediated bilirubin glucuronidation by sorafenib was assessed in vitro. UGT1A1*28 and UGT1A9*3 genotypes were ascertained with fragment analysis or direct sequencing in 120 cancer patients receiving sorafenib on five different clinical trials. Total bilirubin measurements were collected in prostate cancer patients before receiving sorafenib (n = 41) and 19 to 30 days following treatment and were compared with UGT1A1*28 genotype. RESULTS: Sorafenib exhibited mixed-mode inhibition of UGT1A1-mediated bilirubin glucuronidation (IC(50) = 18 µmol/L; K(i) = 11.7 µmol/L) in vitro. Five patients carrying UGT1A1*28/*28 (n = 4) or UGT1A9*3/*3 (n = 1) genotypes had first dose, dose-normalized areas under the sorafenib plasma concentration versus time curve (AUC) that were in the 93rd percentile, whereas three patients carrying UGT1A1*28/*28 had AUCs in the bottom quartile of all genotyped patients. The Drug Metabolizing Enzymes and Transporters genotyping platform was applied to DNA obtained from six patients, which revealed the ABCC2-24C>T genotype cosegregated with sorafenib AUC phenotype. Sorafenib exposure was related to plasma bilirubin increases in patients carrying 1 or 2 copies of UGT1A1*28 alleles (n = 12 and n = 5; R(2) = 0.38 and R(2) = 0.77; P = 0.032 and P = 0.051, respectively). UGT1A1*28 carriers showed two distinct phenotypes that could be explained by ABCC2-24C>T genotype and are more likely to experience plasma bilirubin increases following sorafenib if they had high sorafenib exposure. CONCLUSIONS: This pilot study indicates that genotype status of UGT1A1, UGT1A9, and ABCC2 and serum bilirubin concentration increases reflect abnormally high AUC in patients treated with sorafenib.

Estrogen receptor α and aromatase polymorphisms affect risk, prognosis, and therapeutic outcome in men with castration-resistant prostate cancer treated with docetaxel-based therapy.

CONTEXT: Reactive estrogen species cause genotoxicity and interfere with docetaxel-mediated tubulin polymerization resulting in shortened survival in men with castrate-resistant prostate cancer (CRPC). OBJECTIVE: We hypothesized that polymorphisms in estrogen synthesis and estrogen targets (i.e., CYP19 and ERα) would be linked to interindividual variation in CRPC risk, docetaxel response, and overall survival in men with CRPC. MATERIALS AND METHODS: Patients with CRPC (n=115) treated with docetaxel, single-agent thalidomide (n=42), or healthy controls (n=289) were genotyped for the CYP19 R264C (rs700519) and the ERα PvuII T>C (rs2234693) and XbaI A>G (rs9340799) polymorphisms. RESULTS: Patients carrying two copies of ERα polymorphisms had shorter progression-free survival on docetaxel than other patients (median survival difference ≥ 3.1 months; P ≤ 0.036). When the analysis was limited to nonobese patients, the relationship between the ERα XbaI A>G polymorphism and PFS improved (median survival difference = 3.5 months; P = 0.0078). The CYP19 R264C variant was related to the duration of survival after docetaxel in patients who were >70 years old (median survival difference =10.6 months; P=0.041). Both ERα polymorphisms were also associated with increases in CRPC risk [P ≤ 0.032; double variants vs. wild-type odds ratio ≥ 2.6], and the association with the ERα PvuII T>C also improved in those men who were <70 years old (P = 0.0073; odds ratio = 3.0). CONCLUSIONS: This study demonstrates that estrogen-related genetic variation affects docetaxel clinical response and that this relationship is dependent on age and body-type in men with CRPC. Moreover, this study suggests ERα polymorphisms confer risk of developing prostate cancer, especially in men under 70 years of age.

Pharmacogenetics of membrane transporters: an update on current approaches.

This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.