Impact of the Cell Cycle Progression Test on Physician and Patient Treatment Selection for Localized Prostate Cancer.

PURPOSE: The cell cycle progression test is a validated molecular assay that assesses prostate cancer specific disease progression and mortality risk when combined with clinicopathological parameters. We present the results from PROCEDE-1000, a large, prospective registry designed to evaluate the impact of the cell cycle progression test on shared treatment decision making for patients newly diagnosed with prostate cancer. MATERIALS AND METHODS: Untreated patients with newly diagnosed prostate adenocarcinoma were enrolled in the study and the cell cycle progression test was performed on the initial prostate biopsy tissue. A set of 4 sequential surveys tracked changes relative to initial therapy recommendations (before cell cycle progression) based on clinicopathological parameters following physician review of the cell cycle progression test result, physician/patient review of the cell cycle progression test results and a minimum of 3 months of clinical followup (actual treatment). RESULTS: Of the 1,596 patients enrolled in this registry 1,206 were eligible for analysis. There was a significant reduction in the treatment burden recorded at each successive evaluation (p <0.0001), with the mean number of treatments per patient decreasing from 1.72 before the cell cycle progression test to 1.16 in actual followup. The cell cycle progression test caused a change in actual treatment in 47.8% of patients. Of these changes 72.1% were reductions and 26.9% were increases in treatment. For each clinical risk category there was a significant change in treatment modality (intervention vs nonintervention) before vs after cell cycle progression testing (p=0.0002). CONCLUSIONS: The cell cycle progression test has a significant impact in assisting physicians and patients reach personalized treatment decisions.

Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer.

BACKGROUND: This study assessed BRCA1 and BRCA2 mutation prevalence in an unselected cohort of patients with triple-negative breast cancer (BC). METHODS: One hundred ninety-nine patients were enrolled. Triple negativity was defined as <1% estrogen and progesterone staining by immunohistochemistry and HER-2/neu not overexpressed by fluorescence in situ hybridization. Having given consent, patients had BRCA1 and BRCA2 full sequencing and large rearrangement analysis. Mutation prevalence was assessed among the triple-negative BC patients and the subset of patients without a family history of breast/ovarian cancer. Independent pathological review was completed on 50 patients. RESULTS: Twenty-one deleterious BRCA mutations were identified--13 in BRCA1 and 8 in BRCA2 (prevalence, 10.6%). In 153 patients (76.9%) without significant family history (first-degree or second-degree relatives with BC aged <50 years or ovarian cancer at any age), 8 (5.2%) mutations were found. By using prior National Comprehensive Cancer Network (NCCN) guidelines recommending testing for triple-negative BC patients aged <45 years, 4 of 21 mutations (19%) would have been missed. Two of 21 mutations (10%) would have been missed using updated NCCN guidelines recommending testing for triple-negative BC patients aged <60 years. CONCLUSIONS: The observed mutation rate was significantly higher (P = .0005) than expected based on previously established prevalence tables among patients unselected for pathology. BRCA1 mutation prevalence was lower, and BRCA2 mutation prevalence was higher, than previously described. Additional mutation carriers would have met new NCCN testing guidelines, underscoring the value of the updated criteria. Study data suggest that by increasing the age limit to 65 years, all carriers would have been identified.

Modeling the 5-fluorouracil area under the curve versus dose relationship to develop a pharmacokinetic dosing algorithm for colorectal cancer patients receiving FOLFOX6.

BACKGROUND: 5-Fluorouracil (5-FU) is administered based on standard body surface area (BSA) dosing. BSA administration results in highly variable exposure, measured as the area under the concentration-time curve (AUC). An immunoassay (OnDose®; Myriad Genetic Laboratories, Inc., Salt Lake City, UT) that measures plasma 5-FU concentration and reports an AUC in mg · h/L has been developed to optimize therapy using pharmacokinetic (PK) dosing. The results of an analysis to model the 5-FU AUC-dose relationship are presented. METHODS: A set of 589 sequential patients from a clinical database receiving 5-FU, leucovorin, and oxaliplatin (the FOLFOX6 regimen) for colorectal cancer (CRC) treatment was analyzed. A subset including only patients who had at least two consecutive cycles tested, received 1,600-3,600 mg/m2 of continuous infusion 5-FU during the initial test cycle, and had a blood sample collected after ≥18 hours, was used to conduct regression modeling of the change in AUC versus change in dose. RESULTS: A simple regression model with R(2) = 0.51 developed over n = 307 cycle-pair observations characterizes the AUC-Dose relationship as: change in AUC = 0.02063 * dose change. The model suggests that dose changes in the range of 145-727 mg/m2 would be sufficient to adjust the AUC to a potential therapeutic threshold of >20 mg · h/L for most patients. CONCLUSIONS: 5-FU is an ideal candidate for PK dose optimization. Because individual factors other than dose change may also affect the change in AUC, longitudinal PK monitoring in all cycles and dose adjustment to ensure AUC in the desired range of 20-30 mg · h/L are recommended.

Biomass and nutrient concentrations of sporocarps produced by mycorrhizal and decomposer fungi in Abies amabilis stands.

Sporocarps and sclerotia were collected for a one-year period in 23- and 180-year-old Abies amabilis stands in western Washington. All sporocarps were classified and chemically analyzed for N, P, K, Ca, Mg, Na and Fe. Lactarius sp. and Cortinarius sp. contributed the largest proportion of the total annual epigeous sporocarp production in both stands. Annual epigeous production was 34 kg/ha in the young stand and 27 kg/ha in the mature stand. Hypogeous sporocarp production increased from 1 kg ha-1 yr-1 to 380 kg ha-1 yr-1 with increasing stand age. High sclerotia biomass occurred in the young (2,300 kg/ha) and mature (3,000 kg/ha) stands. Peak sclerotia and epigeous sporocarp biomass in the young stand and epigeous and hypogeous sporocarp biomass in the mature stand coincided with the fall peak of mycorrhizal root biomass.In the young stand, sporocarps produced by decomposer fungi concentrated higher levels of Ca and Mn than those produced by mycorrhizal fungi. In the mature stand, sporocarps of decomposer fungi concentrated higher levels of N, P, Mn, Ca and Fe than sporocarps of mycorrhizal fungi. Epigeous and hypogeous sporocarps concentrated higher levels of N, P, and K than sclerotia or mycelium. The highest concentration of N (4.36%), P (0.76%), K (3.22%) and Na (1,678 ppm) occurred in epigeous sporocarps. Highest Mn (740 ppm) and Ca (20,600 ppm) concentrations occurred in mycelium, while highest Mg (1,929 ppm) concentrations were in hypogeous sporocarps and highest Fe (4,153 ppm) concentrations were in sclerotia.