The combination of serum insulin, osteopontin, and hepatocyte growth factor predicts time to castration-resistant progression in androgen dependent metastatic prostate cancer- an exploratory study.

Background: We hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic androgen-dependent prostate cancer (mADPC).

Methods: Serum samples from treatment-naïve men participating in a randomized phase 3 trial of ADT +/- chemotherapy were retrospectively analyzed using multiplex assays for insulin and multiple other soluble factors. Cox proportional hazards regression models were used to identify associations between individual factor levels and PFS.

A Phase l Study of a Tumor-targeted Systemic Nanodelivery System, SGT-94, in Genitourinary Cancers.

Gene therapy development has been limited by our inability to target multifocal cancer with systemic delivery. We developed a systemically administered, tumor-targeted liposomal nanodelivery complex (SGT-94) carrying a plasmid encoding RB94, a truncated form of the RB gene. In preclinical studies, RB94 showed marked cytotoxicity against tumor but not normal cells.

Polymorphisms in DNA repair genes, traffic-related polycyclic aromatic hydrocarbon exposure and breast cancer incidence.

Vehicular traffic polycyclic aromatic hydrocarbons (PAHs) have been associated with breast cancer incidence in epidemiologic studies, including our own. Because PAHs damage DNA by forming adducts and oxidative lesions, genetic polymorphisms that alter DNA repair capacity may modify associations between PAH-related exposures and breast cancer risk. Our goal was to examine the association between vehicular traffic exposure and breast cancer incidence within strata of a panel of nine biologically plausible nucleotide excision repair (NER) and base excision repair (BER) genotypes.

A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naïve Urothelial Cancer is Predictive of Clinical Outcomes from Neoadjuvant Chemotherapy: A Phase 2 Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in Urothelial Cancer.

Background: Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy.

Objective: To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype.

Rational Manual and Automated Scoring Thresholds for the Immunohistochemical Detection of TP53 Missense Mutations in Human Breast Carcinomas.

Missense mutations in TP53 are common in human breast cancer, have been associated with worse prognosis, and may predict therapy effect. TP53 missense mutations are associated with aberrant accumulation of p53 protein in tumor cell nuclei. Previous studies have used relatively arbitrary cutoffs to characterize breast tumors as positive for p53 staining by immunohistochemical assays.

Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults.

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants.

Vehicular Traffic-Related Polycyclic Aromatic Hydrocarbon Exposure and Breast Cancer Incidence: The Long Island Breast Cancer Study Project (LIBCSP).

Background: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants, known human lung carcinogens, and potent mammary carcinogens in laboratory animals. However, the association between PAHs and breast cancer in women is unclear. Vehicular traffic is a major ambient source of PAH exposure.

Targeting the interleukin-11 receptor α in metastatic prostate cancer: A first-in-man study.

Background: Receptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors ("vascular zip codes") within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature.

Phase I trial of sunitinib and temsirolimus in metastatic renal cell carcinoma.

Background: Preclinical data suggest that anti-vascular endothelial growth factor agents combined with mammalian target of rapamycin inhibitors yield synergistic antitumor effects. A phase I trial with a 3+3 dose escalation design of S with T was stopped after the first dose pair led to 2 of 3 patients experiencing dose-limiting toxicity (DLT).

Patients And Methods: To explore multiple potential dosing pairs of S and T, a 2-stage outcome-adaptive Bayesian dose-finding method was designed.

Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects.

Purpose: To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina.

Methods: Cases (n = 1,972) were women 20-74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n = 1,776) were frequency matched to cases by age and race.

Genetic variation in cell cycle regulatory gene AURKA and association with intrinsic breast cancer subtype.

AURKA is a putative low-penetrance tumor susceptibility gene due to its prominent role in cell cycle regulation and centrosomal function. Germline variation in AURKA was evaluated for association with breast cancer and intrinsic breast cancer subtypes in the Carolina Breast Cancer Study (CBCS), a population-based case-control study of African Americans (AA) and Caucasians (Cau). Tag and candidate single nucleotide polymorphisms (SNPs) on AURKA were genotyped in 1946 cases and 1747 controls.

DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival.

Introduction: Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood.

Methods: A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer.

Genome-wide scan of 29,141 African Americans finds no evidence of directional selection since admixture.

The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture.

Polymorphisms in the carcinogen detoxification genes CYB5A and CYB5R3 and breast cancer risk in African American women.

Purpose: Cytochrome b 5 (encoded by CYB5A) and NADH cytochrome b 5 reductase (encoded by CYB5R3) detoxify aromatic and heterocyclic amine mammary carcinogens found in cigarette smoke. We hypothesized that CYB5A and CYB5R3 polymorphisms would be associated with breast cancer risk in women.

Methods: We characterized the prevalence of 18 CYB5A and CYB5R3 variants in genomic DNA from African American (AfrAm) and Caucasian (Cauc) women from the Carolina Breast Cancer Study population (1,946 cases and 1,747 controls) and determined their associations with breast cancer risk, with effect modification by smoking.

A comprehensive examination of breast cancer risk loci in African American women.

Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women.

Meta-analysis of loci associated with age at natural menopause in African-American women.

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied.

Replication of breast cancer susceptibility loci in whites and African Americans using a Bayesian approach.

Genome-wide association studies (GWAS) and candidate gene analyses have led to the discovery of several dozen genetic polymorphisms associated with breast cancer susceptibility, many of which are considered well-established risk factors for the disease. Despite attempts to replicate these same variant-disease associations in African Americans, the evaluable populations are often too small to produce precise or consistent results. We estimated the associations between 83 previously identified single nucleotide polymorphisms (SNPs) and breast cancer among Carolina Breast Cancer Study (1993-2001) participants using maximum likelihood, Bayesian, and hierarchical methods.

Breast cancer subtypes and previously established genetic risk factors: a bayesian approach.

Background: Gene expression analyses indicate that breast cancer is a heterogeneous disease with at least five immunohistologic subtypes. Despite growing evidence that these subtypes are etiologically and prognostically distinct, few studies have investigated whether they have divergent genetic risk factors. To help fill in this gap in our understanding, we examined associations between breast cancer subtypes and previously established susceptibility loci among white and African-American women in the Carolina Breast Cancer Study.

Trends in stage-specific incidence rates for urothelial carcinoma of the bladder in the United States: 1988 to 2006.

Background: Bladder cancer is notable for a striking heterogeneity of disease-specific risks. Among the approximately 75% of incident cases found to be superficial to the muscularis propria at the time of presentation (non-muscle-invasive bladder cancer), the risk of progression to the lethal phenotype of muscle-invasive disease is strongly associated with stage and grade of disease. Given the suggestion of an increasing percentage of low-risk cases in hospital-based registry data in recent years, the authors hypothesized that population-based data may reveal changes in the stage distribution of early-stage cases.

Mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis in patients with renal cell cancer: predictors, management, and outcomes.

Objective: To characterise the incidence, onset, management, predictors, and clinical impact of mammalian target of rapamycin (mTOR) inhibitor-associated non-infectious pneumonitis (NIP) on patients with metastatic renal cell carcinoma (mRCC).

Patients And Methods: Retrospective review of 310 patients with mRCC who received temsirolimus and/or everolimus between June 2007 and October 2010. Clinical correlations were made with serial radiological imaging.

Association between mammographic density and basal-like and luminal A breast cancer subtypes.

Introduction: Mammographic density is a strong risk factor for breast cancer overall, but few studies have examined the association between mammographic density and specific subtypes of breast cancer, especially aggressive basal-like breast cancers. Because basal-like breast cancers are less frequently screen-detected, it is important to understand how mammographic density relates to risk of basal-like breast cancer.

Methods: We estimated associations between mammographic density and breast cancer risk according to breast cancer subtype.

Refining patient selection for neoadjuvant chemotherapy before radical cystectomy.

Purpose: We evaluated the survival of patients with muscle invasive bladder cancer undergoing radical cystectomy without neoadjuvant chemotherapy to confirm the utility of existing clinical tools to identify low risk patients who could be treated with radical cystectomy alone and a high risk group most likely to benefit from neoadjuvant chemotherapy.

Materials And Methods: We identified patients with muscle invasive bladder cancer who underwent radical cystectomy without neoadjuvant chemotherapy at our institution between 2000 and 2010. Patients were considered high risk based on the clinical presence of hydroureteronephrosis, cT3b-T4a disease, and/or histological evidence of lymphovascular invasion, micropapillary or neuroendocrine features on transurethral resection.

Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk.

The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single-strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated.

Determinants of breast cancer treatment delay differ for African American and White women.

Background: Timeliness of care may contribute to racial disparities in breast cancer mortality. African American women experience greater treatment delay than White women in most, but not all studies. Understanding these disparities is challenging as many studies lack patient-reported data and use administrative data sources that collect limited types of information.