Patterns of finasteride and dutasteride use in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial cohort: effects of socio-demographic factors and a black box warning

Background: Five-alpha reductase inhibitors (5-ARIs), specifically finasteride and dutasteride, have been shown to significantly reduce prostate cancer incidence. However, these agents were also associated with a significant increase in the detection of high-grade prostate cancer leading to an FDA black box warning in 2011. Little is known about the effect of this warning on the subsequent use of these 5-ARIs. The purpose of this analysis was to assess use patterns of finasteride and dutasteride before and after the black box warning. Methods: This cohort study evaluated men enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial who had ≥12 months of Medicare Part D coverage from 2008 to 2015, and had not been diagnosed with prostate cancer through 2007. Socio-demographic factors and benign prostatic hyperplasia (BPH) status were ascertained from follow-up questionnaires, while medication use was ascertained from linkage to Medicare Part D claims data. Results: Of 14,833 eligible men, 88.7% identified as non-Hispanic white, 1.7% as African-American, 5.2% as Asian/Pacific Islander and 1.7% as Hispanic. The median age was 72 years; 41.8% reported a BPH diagnosis. Only 13.6% and 4% of the population took finasteride or dutasteride, respectively, at any time from 2008 to 2015. During this period, finasteride use significantly increased from 3.6% to 9.7% and was highest among men with BPH; dutasteride use remained low and decreased from 2.8% to 1.9%. Conclusions: Finasteride use significantly increased after the FDA’s 2011 black box warning, while dutasteride use remained low and steady throughout the study period

Association of MTHFR gene polymorphisms with breast cancer survival

BACKGROUND: Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women. METHODS: African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival. RESULTS: We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.05–4.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.31–1.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.17–6.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.12–1.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, p(interaction )= 0.088; C677T, p(interaction )= 0.026). CONCLUSION: We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival

Differences in the Tumor Microenvironment between African-American and European-American Breast Cancer Patients

Background: African-American breast cancer patients experience higher mortality rates than European-American patients despite having a lower incidence of the disease. We tested the hypothesis that intrinsic differences in the tumor biology may contribute to this cancer health disparity. Methods and Results: Using laser capture microdissection, we examined genome-wide mRNA expression specific to tumor epithelium and tumor stroma in 18 African-American and 17 European-American patients. Numerous genes were differentially expressed between these two patient groups and a two-gene signature in the tumor epithelium distinguished between them. To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed. Several biological processes were identified which may contribute to enhanced disease aggressiveness in African-American patients, including angiogenesis and chemotaxis. African-American tumors also contained a prominent interferon signature. The role of angiogenesis in the tumor biology of African-American

Autoimmunity and hematologic malignancies: associations and mechanisms

Although the true prevalence of autoimmune diseases remains to be better defined, in Western countries the current estimates indicate that at least 5% of the population is affected by an autoimmune disorder. Over the last few decades, autoimmune diseases have been associated with an elevated risk of developing lymphoproliferative malignancies, particularly non-Hodgkin lymphomas. Some studies have found the relationship between autoimmunity and lymphoproliferative tumors to be bi-directional. Although substantial work has been carried out to characterise the associations between autoimmunity and lymphoproliferation, current insights regarding underlying biological mechanisms remain limited and hence present a gap in the literature. In this article, we review reported main associations between selected common autoimmune diseases and lymphoproliferative neoplasms. We also discuss potential underlying mechanisms that have been proposed to connect these two disorders. Finally, we provide future directions for new research studies aimed to improve our understanding of inflammation and the dysregulated immune system in the development of autoimmunity and hematologic malignancies

Household income is associated with the p53 mutation frequency in human breast tumors.

A study from Scotland reported that the p53 mutation frequency in breast tumors is associated with socio-economic deprivation.We analyzed the association of the tumor p53 mutational status with tumor characteristics, education, and self-reported annual household income (HI) among 173 breast cancer patients from the greater Baltimore area, United States.p53 mutational frequency was significantly associated with HI. Patients with < $15,000 HI had the highest p53 mutation frequency (21$15,000 and $60,000 (18$60,000 HI had the fewest mutations (5%). When dichotomized at $60,000, 26 out of 135 patients in the low income category had acquired a p53 mutation, while only 2 out of 38 with a high income carried a mutation (P < 0.05). In the adjusted logistic regression analysis with 3 income categories (trend test), the association between HI and p53 mutational status was independent of tumor characteristics, age, race/ethnicity, tobacco smoking and body mass. Further analyses revealed that HI may impact the p53 mutational frequency preferentially in patients who develop an estrogen receptor (ER)-negative disease. Within this group, 42$15,000 HI) carried a mutation, followed by the middle income group (21%), while those above $60,000 HI did not carry mutations (Ptrend < 0.05).HI is associated with the p53 mutational frequency in patients who develop an ER-negative disease. Furthermore, high income patients may acquire fewer p53 mutations than other patients, suggesting that lifetime exposures associated with socio-economic status may impact breast cancer biology

Kaplan-Meier survival curves for 5-year breast cancer-specific survival by annual household income (HI) of the patients.

<p>Log-rank test: <i>P</i> < 0.05. Within this follow-up period, 38 of the 173 patients (22%) died from breast cancer.</p

Relationship between tumor p53 status and annual household income in the adjusted analysis.

<p>OR  =  odds ratio; CI  =  confidence interval; IHC  =  immunohistochemistry</p>*<p>Trend test. Shown is the OR for the stepwise increase in household income (reference: low income). Income coded as 0 (< $15,000), 1 ($15,000 to $60,000), and 2 (>$60,000); adjustments: smoking (pack years), age, and body mass index (BMI) were used as continuous data; other covariates were dichotomized for the analysis, as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057361#pone-0057361-t001" target="_blank">Table 1</a></p>**<p>adjusted for race/ethnicity, node status, tumor estrogen receptor status, and tumor grade</p

Association of patient characteristics with tumor p53 mutational status.

*<p><i>P</i> value comparing patient characteristics by tumor p53 mutational status</p>**<p>Cases with missing information are not included</p>***<p>Mann-Whitney rank sum test</p><p>Annual household income, race/ethnicity, and education are self-reported. Tumor-associated macrophages were counted as CD68-positive cells. Pack years: (packs smoked per day) x (years as a smoker). BMI  =  kg/m²; SD  =  standard deviation, IHC  =  immunohistochemistry.</p

Association of household income with a mutant p53 tumor status by estrogen receptor status.

<p>Association of household income with a mutant p53 tumor status by estrogen receptor status.</p