Comparing duration of response and duration of clinical benefit between fulvestrant treatment groups in the CONFIRM trial: application of new methodology.

Comparisons of duration of response (DoR) and duration of clinical benefit (DoCB) within clinical trials are prone to biases. To address these biases, we used new methodology to prospectively analyze expected DoR and expected DoCB. Objective response rate and clinical benefit rate were calculated for fulvestrant 500 and 250 mg, and used to calculate expected DoR and expected DoCB for each dose group. The ratios for expected DoR and expected DoCB (expected DoR500/expected DoR250 and expected DoCB500/expected DoCB250) were then calculated, thereby allowing statistical comparisons of these endpoints between each arm of the COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial. Expected DoRs for fulvestrant 500 and 250 mg were 3.2 and 3.6 months, respectively. The expected DoR ratio between fulvestrant 500 and 250 mg was not statistically significant (0.89; 95 % CI, 0.48-1.67, P = 0.724). The expected DoCBs for fulvestrant 500 and 250 mg were 9.8 and 7.2 months, respectively. The expected DoCB ratio showed that the expected DoCB for fulvestrant 500 mg was significantly improved compared with the expected DoCB for fulvestrant 250 mg (1.36; 95 % CI, 1.07-1.73, P = 0.013). Analysis of the expected DoR and expected DoCB showed fulvestrant 500 mg significantly increased expected DoCB compared with fulvestrant 250 mg in the CONFIRM trial.

An attempt to prevent senescence: a mitochondrial approach.

Antioxidants specifically addressed to mitochondria have been studied to determine if they can decelerate senescence of organisms. For this purpose, a project has been established with participation of several research groups from Russia and some other countries. This paper summarizes the first results of the project. A new type of compounds (SkQs) comprising plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized. Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decyl-rhodamine 19 (SkQR1), and methylplastoquinonyldecyltriphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested in aqueous solution, detergent micelles, liposomes, BLM, isolated mitochondria, and cell cultures. In mitochondria, micromolar cationic quinone derivatives were found to be prooxidants, but at lower (sub-micromolar) concentrations they displayed antioxidant activity that decreases in the series SkQ1=SkQR1>SkQ3>MitoQ. SkQ1 was reduced by mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Nanomolar SkQ1 specifically prevented oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1, a fluorescent SkQ derivative, stained only one type of organelles, namely mitochondria. Extremely low concentrations of SkQ1 or SkQR1 arrested H(2)O(2)-induced apoptosis in human fibroblasts and HeLa cells. Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins, etc. SkQ1 manifested a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits. Moreover, the SkQ1 pretreatment of rats significantly decreased the H(2)O(2) or ischemia-induced arrhythmia of the isolated heart. SkQs strongly reduced the damaged area in myocardial infarction or stroke and prevented the death of animals from kidney ischemia. In p53(-/-) mice, 5 nmol/kgxday SkQ1 decreased the ROS level in the spleen and inhibited appearance of lymphomas to the same degree as million-fold higher concentration of conventional antioxidant NAC. Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases.

Prognostic significance of periodic acid-Schiff-positive patterns in clear cell renal cell carcinoma.

BACKGROUND: The ability of aggressive tumors to form nonendothelial tumor cell-lined microvascular channels is known as "vasculogenic mimicry" (VM). VM channels are revealed as periodic acid-Schiff (PAS)-positive patterns, and in some tumors their presence predicts clinical outcomes. OBJECTIVE: We aimed to study VM channels in clear cell renal cell carcinoma (cRCC) tumors and explore their prognostic significance and relationship to other suggested prognostic factors such as thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF) expression. METHODS: We retrospectively studied 45 patients who had undergone radical nephrectomy for clinically confined cRCC (stage T2-T3NOMO) at the Russian Cancer Research Center. The tumor sections were reviewed for disease stage, nuclear grade, perirenal fat invasion, and lymph node involvement, and we performed immunohistochemical staining for VEGF and TP expression, and PAS staining. Disease-free survival probabilities were determined by Kaplan-Meier estimates and prognostic factors were evaluated by univariate analysis. RESULTS: PAS-positive patterns observed in the cRCC tumor included back-to-back closed loops, networks, arcs, and parallel patterns. There was a significant decrease in disease-free survival among patients with PAS-positive networks (p = 0.005), but not among patients with other PAS-positive patterns. TP expression was also a significant predictor of disease-free survival (p = 0.035), but this factor did not correlate with the presence of PAS-positive networks. Notably, in our small sample, the six patients whose tumors were positive for both factors had the highest risk of cancer recurrence. CONCLUSIONS: The presence of PAS-positive networks is an independent and relevant prognostic parameter for disease-free survival in patients with cRCC. Our data suggest that the combination of PAS-positive networks and TP expression may identify patients with the highest risk of cancer recurrence.

Melanoma vasculogenic mimicry is strongly related to reactive oxygen species level.

The concept of 'vasculogenic mimicry' (VM) was introduced to describe the unique ability of highly invasive tumor cells to form capillary-like structures (CLS) and matrix-rich patterned network in three-dimensional culture that mimic embryonic vasculogenic network. Recently, we have shown that CLS formation requires apoptotic cell death through activation of caspase-3-dependent mechanism. In this study, to identify some molecular determinants driving aggressive melanoma cells to express a latent 'angiogenic program' that recapitulates the early events of CLS formation, we focused on the involvement of antioxidants (AOs) in the process of melanoma VM. We have studied the effects of resveratrol, (-)-epigallocathechin gallate, N-acetyl-cysteine (NAC) and Trolox on the ability of melanoma cells to form/destroy CLS. We observed that the formation of CLS was strongly related to reactive oxygen species level. In vivo animal experiments confirmed the involvement of reactive oxygen species level in melanoma VM. To understand the molecular mechanisms of this phenomenon, we specifically looked for induction of apoptosis and vascular endothelial growth factor (VEGF) release. Western blot analysis revealed that the level of VEGF, VEGF receptors (VEGF-Rs) and active caspase-3 dramatically decreased in cells treated with AOs. Here, we also report further experiments designed to determine whether the crosstalk between AOs and apoptosis exists in melanoma VM.

Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial.

PURPOSE: To evaluate the efficacy and tolerability of fulvestrant (Faslodex; AstraZeneca Pharmaceuticals LP, Wilmington, DE), a new estrogen receptor (ER) antagonist that downregulates ER and has no agonist effects, versus tamoxifen, an antiestrogen with agonist and antagonist effects, for the treatment of advanced breast cancer in postmenopausal women. PATIENTS AND METHODS: In this multicenter, double-blind, randomized trial, patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were randomly assigned to receive either fulvestrant (250 mg, via intramuscular injection, once monthly; n = 313) or tamoxifen (20 mg, orally, once daily; n = 274). Patients' tumors were positive for ER (ER+) and/or progesterone receptor (PgR+), or had an unknown receptor status. RESULTS: At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression (TTP; median TTP, 6.8 months and 8.3 months, respectively; hazard ratio, 1.18; 95% CI, 0.98 to 1.44; P =.088). In a prospectively planned subset analysis of patients with known ER+ and/or PgR+ tumors ( approximately 78%), median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen (hazard ratio, 1.10; 95% CI, 0.89 to 1.36; P =.39). The objective response rate for the overall population was 31.6% with fulvestrant and 33.9% with tamoxifen, and 33.2% and 31.1%, respectively, in the known hormone receptor-positive subgroup. Both treatments were well tolerated. CONCLUSION: In the overall population, between-group differences in efficacy end points favored tamoxifen, and statistical noninferiority of fulvestrant could not be demonstrated. However, in patients with hormone receptor-positive tumors, fulvestrant had similar efficacy to tamoxifen and was well tolerated.

Humoral immune response to thymidylate synthase in colon cancer patients after 5-FU chemotherapy.

Thymidylate synthase (TYMS), the critical enzyme for DNA synthesis and a target for chemotherapy, was recently characterized as an oncogene and a potential target for specific immunotherapy. Here we report TYMS-specific antibody response in a fraction of colon cancer patients. Humoral immune response to TYMS is induced by chemotherapy using TYMS inhibitors, such as 5-fluorouracil (5-FU), and may be associated with tumor burden. Therefore, TYMS may serve as a useful serological biomarker for monitoring the course of disease and treatment in cancer patients.

Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial.

BACKGROUND: At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died. A final analysis of OS was subsequently planned for when 75% of patients had died. METHODS: Patients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on days 0, 14, and 28 and every 28 (±3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo injections only), and 28 and every 28 (±3) days thereafter. OS was analyzed using an unadjusted log-rank test. No adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy were also reported. All statistical tests were two-sided. RESULTS: In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500 mg (n = 362) or 250 mg (n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for fulvestrant 500 mg and 22.3 months for 250 mg (hazard ratio = 0.81; 95% confidence interval = 0.69-0.96; nominal P = .02). There were no clinically important differences in SAE profiles between the treatment groups; no clustering of SAEs could be detected in either treatment group. Type of first subsequent therapy and objective responses to first subsequent therapy were well balanced between the two treatment groups. CONCLUSIONS: In patients with locally advanced or metastatic estrogen receptor-positive breast cancer, fulvestrant 500 mg is associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulvestrant 250 mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified.

First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study.

PURPOSE: To investigate whether sunitinib plus docetaxel improves clinical outcomes for patients with human epidermal growth factor receptor 2 (HER2)/neu-negative advanced breast cancer (ABC) versus docetaxel alone. PATIENTS AND METHODS: In this phase III study, patients were randomly assigned to open-label combination therapy (sunitinib 37.5 mg/d, days 2 to 15 every 3 weeks; and docetaxel 75 mg/m(2), day 1 every 3 weeks) or monotherapy (docetaxel 100 mg/m(2) every 3 weeks). Progression-free survival (PFS) was the primary end point. RESULTS: Two hundred ninety-six patients were randomly assigned to combination therapy, and 297 patients were assigned to monotherapy. Median PFS times were 8.6 and 8.3 months with combination therapy and monotherapy, respectively (hazard ratio, 0.92; one-sided P = .265). The objective response rate (ORR) was significantly higher with the combination (55%) than with monotherapy (42%; one-sided P = .001). Duration of response was similar in both arms (7.5 months with the combination v 7.2 months with monotherapy). Median overall survival (OS) times were 24.8 and 25.5 months with combination therapy and monotherapy, respectively (one-sided P = .904). There were 107 deaths with the combination and 91 deaths with monotherapy. The frequency of common adverse events (AEs) was higher with the combination, as were treatment discontinuations caused by AEs. CONCLUSION: The combination of sunitinib plus docetaxel improved ORR but did not prolong either PFS or OS compared with docetaxel alone when given to an unselected HER2/neu-negative cohort as first-line treatment for ABC. Sunitinib combination therapy may also have resulted in AEs that yield an unfavorable risk-benefit ratio. The sunitinib-docetaxel regimen evaluated in this study is not recommended for further use in ABC.

Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer.

PURPOSE: We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy. PATIENTS AND METHODS: Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). RESULTS: PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. CONCLUSION: Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg.

Antibody response to a non-conserved C-terminal part of human histone deacetylase 3 in colon cancer patients.

Antibodies to cancer antigens can often be detected in the sera of patients, although the mechanism of the underlying humoral immune response is poorly understood. Using immunoscreening of tumor-derived cDNA expression libraries (SEREX), we identified human histone deacetylase 3 (HDAC3) as serologically defined antigen in colon cancer. Closely related HDAC1 and HDAC2 do not elicit humoral response in colon cancer patients. We show that the C-terminal region of HDAC3 protein lacking the homology to other Class I HDAC contains at least 3 distinct B-cell epitopes that are recognized by the serum antibodies. HDAC3 in combination with other SEREX antigens may become a useful molecular biomarker with diagnostic or prognostic value for a subset of colon cancer patients.