Clinical utility of tumour marker velocity of cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) in breast cancer surveillance.

BACKGROUND: Serum tumour markers, cancer antigen 15-3 (CA 15-3) and carcinoembryonic antigen (CEA) are not routinely recommended for detecting breast cancer recurrence and monitoring treatment. In this study, we aim to evaluate the diagnostic accuracy of absolute CA 15-3 and CEA levels and report on the clinical utility of tumour marker velocity in breast cancer surveillance. METHODS: 67 consecutive patients over a 15-year period (1998-2012) with available serial serum CA 15-3 and CEA measurements at recurrence were matched to a control group of patients. Tumour marker velocity was derived from the average change in consecutive tumour marker values over time, expressed in unit/year. Logistic regression analysis was performed to investigate the association between tumour characteristics, tumour marker velocity and disease recurrence. RESULTS: Using the Youden index values, the optimal cut-off values for absolute CA 15-3 and CEA corresponded to the normal assay reference range while tumour marker velocity values were derived to be 2.5U/mL/year and 1.2ng/mL/year respectively. CA 15-3 velocity > 2.5U/mL/year had the highest AUROC value of 0.85 than CEA velocity alone. When either tumour marker velocity exceeded threshold values, the sensitivity, specificity, negative predictive value and positive predictive value were 94.0%, 73.1%, 92.5%, and 77.8% respectively. In the multivariate logistic regression analysis, having both CA 15-3 and CEA velocity exceeding the cut-off values was shown to be a significant predictor for disease recurrence (p = 0.01). CONCLUSION: These findings highlighted the clinical utility of serial tumour markers measurements and its velocity in breast cancer surveillance.

Population Pharmacokinetic and Pharmacodynamic Modeling of LY2510924 in Patients With Advanced Cancer.

The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C-X-C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a two-compartment model with first-order absorption and dose-dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1.17). The dynamics of CD34+ cell counts were best characterized with a precursor model with reversible transfer from the precursor to the central compartment and LY2510924-driven stimulation of cell mobilization. Model-based simulations show that once-daily doses of 20 mg LY2510924 produce maximum CD34+ cell response and that peak effect typically occurs after three daily doses and slowly wanes over time.

An accessible pharmacodynamic transcriptional biomarker for notch target engagement.

γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.

Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of trabectedin (ET-743, Yondelis) induced neutropenia.

Myelosuppression was found to be one of the main toxicities of trabectedin (ET-743, Yondelis) during phase I/II studies. Our objective was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model that describes the time course of the absolute neutrophil counts (ANCs) in cancer patients receiving trabectedin. Data from 699 patients who received intravenous trabectedin as monotherapy (dose range: 0.006-1.8 mg/m2) as a 1-, 3-, or 24-h infusion every 21 days; 1- or 3-h infusion on days 1, 8, and 15 every 28 days; or a 1-h infusion daily for 5 consecutive days every 21 days were used to develop (N=405; ANCs=7,291) and validate (N=294; ANCs=5,029) the model. The PK/PD model comprised a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (Circ0), mean transit time in bone marrow (MTT), and a feedback parameter (gamma). A first-order process quantified by the rate constant k(e0) described the trabectedin concentrations at the effect compartment (C(e)), which were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to the function alphaC(e)beta. The model was qualified and simulations were undertaken to evaluate the neutropenia schedule dependency and the effects of selected covariates. NONMEM software was used to perform the modeling and simulation analyses. For a typical man of 70 kg, the mean values (between-subject variability; %) of the Circ0, MTT, gamma, k(e0), alpha, and beta were estimated to be 4.46 x 10(9)/l (37.9%), 4.0 days (37.5%), 0.218 (41.8%), 2.09 h(-1) (77.9%), 2.00 l/microg (85.1%), and 1.26, respectively. Although in women, k(e0) was reduced by 29% and a 25% increase in body weight resulted in a 12.6% reduction in the beta parameter, the clinical relevance of these effects is limited. The model evaluation procedure indicated accurate prediction of the observed incidence of neutropenia grades 3 and 4 across the dosing regimens evaluated. Simulations indicated that trabectedin dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model-predicted time course of the ANC and its variability confirmed that neutropenia is reversible, of short duration, and non-cumulative. The extent and time course of neutropenia following six different dosing regimens of trabectedin were well predicted by the semiphysiological PK/PD model.

Peri-operative risk factors for acute lung injury after elective oesophagectomy.

Acute lung injury after oesophagectomy is well recognized but the risk factors associated with its development are poorly defined. We analysed retrospectively the effect of a number of pre-, peri- and post-operative risk factors on the development of lung injury in 168 patients after elective oesophagectomy performed at a single centre. The acute respiratory distress syndrome (ARDS) developed in 14.5% of patients and acute lung injury in 23.8%. Mortality in patients developing ARDS was 50% compared with 3.5% in the remainder. Features associated with the development of ARDS included a low pre-operative body mass index, a history of cigarette smoking, the experience of the surgeon, the duration of both the operation and of one-lung ventilation, and the occurrence of a post-operative anastomotic leak. Peri-operative cardiorespiratory instability (measured by peri-operative hypoxaemia, hypotension, fluid and blood requirements and the need for inotropic support) was also associated with ARDS. Acute lung injury after elective oesophagectomy is associated with intraoperative cardiorespiratory instability.