Precision Medicine and Novel Therapeutic Strategies in Detection and Treatment of Cancer: Highlights from the 58th IACR Annual Conference.

Innovation in both detection and treatment of cancer is necessary for the constant improvement in therapeutic strategies, especially in patients with novel or resistant variants of cancer. Cancer mortality rates have declined by almost 30% since 1991, however, depending on the cancer type, acquired resistance can occur to varying degrees. To combat this, researchers are looking towards advancing our understanding of cancer biology, in order to inform early detection, and guide novel therapeutic approaches. Through combination of these approaches, it is believed that a more complete and thorough intervention on cancer can be achieved. Here, we will discuss the advances and approaches in both detection and treatment of cancer, presented at the 58th Irish Association for Cancer Research (IACR) annual conference.

Liquid Biopsy: A Multi-Parametric Analysis of Mutation Status, Circulating Tumor Cells and Inflammatory Markers in EGFR-Mutated NSCLC.

The liquid biopsy has the potential to improve patient care in the diagnostic and therapeutic setting in non-small cell lung cancer (NSCLC). Consented patients with epidermal growth factor receptor (EGFR) positive disease (n = 21) were stratified into two cohorts: those currently receiving EGFR tyrosine kinase inhibitor (TKI) therapy (n = 9) and newly diagnosed EGFR TKI treatment-naïve patients (n = 12). Plasma genotyping of cell-free DNA was carried out using the FDA-approved cobas® EGFR mutation test v2 and compared to next generation sequencing (NGS) cfDNA panels. Circulating tumor cell (CTC) numbers were correlated with treatment response and EGFR exon 20 p.T790M. The prognostic significance of the neutrophil to lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) was also investigated. Patients in cohort 1 with an EGFR exon 20 p.T790M mutation progressed more rapidly than those with an EGFR sensitizing mutation, while patients in cohort 2 had a significantly longer progression-free survival (p = 0.04). EGFR exon 20 p.T790M was detected by liquid biopsy prior to disease progression indicated by computed tomography (CT) imaging. The cobas® EGFR mutation test detected a significantly greater number of exon 20 p.T790M mutations (p = 0.05). High NLR and derived neutrophil to lymphocyte ratio (dNLR) were associated with shorter time to progression and worse survival outcomes (p < 0.05). High LDH levels were significantly associated with shorter time to disease progression (p = 0.03). These data support the use of liquid biopsy for monitoring EGFR mutations and inflammatory markers as prognostic indicators in NSCLC.

Statins and prostate cancer-hype or hope? The epidemiological perspective.

BACKGROUND: Men using cholesterol-lowering statin medications have been found to have lower risks of both advanced and fatal prostate cancer in multiple registry-based studies and prospective cohort studies. Statin use has also been associated with longer survival among men already diagnosed with prostate cancer. Mechanisms responsible for purported anti-cancer effects of statins are not well understood but may offer insight into prostate cancer biology. METHODS: We summarise epidemiological data from studies of statins and prostate cancer and discuss to what extent these findings can be interpreted as causal. Additionally, lipid-mediated and non-lipid-mediated mechanisms that may contribute to potential anti-cancer effects of statins are reviewed. Finally, we consider treatment settings and molecular subgroups of men who might benefit more than others from statin use in terms of prostate cancer-specific outcomes. RESULTS: Data from prospective observational studies generally reported a lower risk of fatal prostate cancer among statin users. There is some evidence for serum cholesterol-lowering as an indirect mechanism linking statins with advanced and fatal prostate cancer. Window-of-opportunity clinical trials show measurable levels of statins in prostate tissue highlighting potential for direct effects, whilst observational data suggest possible statin-driven modulation of prostate microenvironment inflammation. Additionally, emerging data from registry studies support a potential role for statins within the context of androgen deprivation therapy and anti-androgen treatment. CONCLUSION: Prospective and registry-based studies support a lower risk of advanced and fatal prostate cancer in statin users relative to non-users, as well as better outcomes among prostate cancer patients. The few randomised-controlled trials conducted so far have short follow-up, lack identified molecular subgroups, and do not provide additional support for the observational results. Consequently, additional evidence is required to determine which men may experience greatest benefit in terms of prostate cancer-specific outcomes and how statin effects may vary according to molecular tumour characteristics.

Fusion Genes in Prostate Cancer: A Comparison in Men of African and European Descent.

Prostate cancer is one of the most prevalent cancers worldwide, particularly affecting men living a western lifestyle and of African descent, suggesting risk factors that are genetic, environmental, and socioeconomic in nature. In the USA, African American (AA) men are disproportionately affected, on average suffering from a higher grade of the disease and at a younger age compared to men of European descent (EA). Fusion genes are chimeric products formed by the merging of two separate genes occurring as a result of chromosomal structural changes, for example, inversion or trans/cis-splicing of neighboring genes. They are known drivers of cancer and have been identified in 20% of cancers. Improvements in genomics technologies such as RNA-sequencing coupled with better algorithms for prediction of fusion genes has added to our knowledge of specific gene fusions in cancers. At present AA are underrepresented in genomic studies of prostate cancer. The primary goal of this study was to examine molecular differences in predicted fusion genes in a cohort of AA and EA men in the context of prostate cancer using computational approaches. RNA was purified from prostate tissue specimens obtained at surgery from subjects enrolled in the study. Fusion gene predictions were performed using four different fusion gene detection programs. This identified novel putative gene fusions unique to AA and suggested that the fusion gene burden was higher in AA compared to EA men.

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention.

Prostate cancer is a major cause of disease for men globally. Inflammation, an established hallmark of cancer, is frequently observed in the prostate, though its contribution to prostate cancer risks and outcomes is not fully understood. Prostate cancer is biologically and clinically heterogeneous, and there is now evidence that inflammation and immunological characteristics vary by the genomic and mutational landscape of the tumor. Moreover, it is now recognized that risk factor profiles vary between tumor subgroups, as defined by histopathological and molecular features. Here, we provide a review centered around the relationship between inflammation and prostate cancer, with a consideration of molecular tumor features and a particular focus on the advanced and lethal stages of disease. We summarize findings from epidemiological studies of the etiology and role of inflammation in prostate cancer. We discuss the pathology of prostate inflammation, and consider approaches for assessing the tumor immune microenvironment in epidemiological studies. We review emerging clinical therapies targeting immune biology within the context of prostate cancer. Finally, we consider potentially modifiable risk factors and corresponding lifestyle interventions that may affect prostate inflammation, impacting outcomes. These emerging insights will provide some hints for the development of treatment and prevention strategies for advanced and lethal prostate cancer.

Characterizing and Exploiting Tumor Microenvironments to Optimize Treatment Outcomes.

Our understanding of cancer initiation, progression, and treatment is continually progressing through dedicated research achieved through laboratory investigation, clinical trials, and patient engagement. The importance and complexity of the microenvironment and its role in tumor development and behavior is pivotal to the understanding of tumor growth and the best course of treatment. The 57th Irish Association for Cancer Research (IACR) Annual Conference collected key researchers, clinicians, and patient advocates together to highlight and discuss the recognized importance of the microenvironment and treatment advances in cancer. In this article, we describe the key components of the microenvironment that influence tumor development and treatment, including the microbiome, metabolism, and immune response and the progress of preclinical models to reflect these complex environments. From a psycho-social oncology perspective, we highlight expert opinion and data on the process of shared decision-making in the context of emerging cancer treatments.

Long non-coding RNAs and their potential impact on diagnosis, prognosis, and therapy in prostate cancer: racial, ethnic, and geographical considerations.

INTRODUCTION: Advances in high-throughput sequencing have greatly advanced our understanding of long non-coding RNAs (lncRNAs) in a relatively short period of time. This has expanded our knowledge of cancer, particularly how lncRNAs drive many important cancer phenotypes via their regulation of gene expression. AREAS COVERED: Men of African descent are disproportionately affected by PC in terms of incidence, morbidity, and mortality. LncRNAs could serve as biomarkers to differentiate low-risk from high-risk diseases. Additionally, they may represent therapeutic targets for advanced and castrate-resistant cancer. We review current research surrounding lncRNAs and their association with PC. We discuss how lncRNAs can provide new insights and diagnostic biomarkers for African American men. Finally, we review advances in computational approaches that predict the regulatory effects of lncRNAs in cancer. EXPERT OPINION: PC diagnostic biomarkers that offer high specificity and sensitivity are urgently needed. PC specific lncRNAs are compelling as diagnostic biomarkers owing to their high tissue and tumor specificity and presence in bodily fluids. Recent studies indicate that PCA3 clinical utility might be restricted to men of European descent. Further work is required to develop lncRNA biomarkers tailored for men of African descent.

Circulating Tumour Cell Numbers Correlate with Platelet Count and Circulating Lymphocyte Subsets in Men with Advanced Prostate Cancer: Data from the ExPeCT Clinical Trial (CTRIAL-IE 15-21).

Interactions between circulating tumour cells (CTCs) and platelets are thought to inhibit natural killer(NK)-cell-induced lysis. We attempted to correlate CTC numbers in men with advanced prostate cancer with platelet counts and circulating lymphocyte numbers. Sixty-one ExPeCT trial participants, divided into overweight/obese and normal weight groups on the basis of a BMI ≥ 25 or <25, were randomized to participate or not in a six-month exercise programme. Blood samples at randomization, and at three and six months, were subjected to ScreenCell filtration, circulating platelet counts were obtained, and flow cytometry was performed on a subset of samples (n = 29). CTC count positively correlated with absolute total lymphocyte count (r2 = 0.1709, p = 0.0258) and NK-cell count (r2 = 0.49, p < 0.0001). There was also a positive correlation between platelet count and CTC count (r2 = 0.094, p = 0.0001). Correlation was also demonstrated within the overweight/obese group (n = 123, p < 0.0001), the non-exercise group (n = 79, p = 0.001) and blood draw samples lacking platelet cloaking (n = 128, p < 0.0001). By flow cytometry, blood samples from the exercise group (n = 15) had a higher proportion of CD3+ T-lymphocytes (p = 0.0003) and lower proportions of B-lymphocytes (p = 0.0264) and NK-cells (p = 0.015) than the non-exercise group (n = 14). These findings suggest that CTCs engage in complex interactions with the coagulation cascade and innate immune system during intravascular transit, and they present an attractive target for directed therapy at a vulnerable stage in metastasis.

Family history of prostate cancer and prostate tumor aggressiveness in black and non-black men;results from an equal access biopsy study.

PURPOSE: To test for racial differences in associations between family history (FH) of prostate cancer (PC) and prostate cancer aggressiveness in a racially diverse equal access population undergoing prostate biopsy. SUBJECTS/PATIENTS AND METHODS: We prospectively enrolled men undergoing prostate biopsy at the Durham Veterans Administration from 2007 to 2018 and assigned case or control status based on biopsy results. Race and FH of PC were self-reported on questionnaires. Logistic regression was used to test the association between FH and PC diagnosis overall and by tumor aggressiveness [high- (Grade Group 3-5) or low-grade (Grade Group 1-2) vs. no cancer], overall, and stratified by race. Models were adjusted for age and year of consent, race, PSA level, digital rectal exam findings, prostate volume, and previous (negative) biopsy receipt. RESULTS: Of 1,225 men, 323 had a FH of PC and 652 men were diagnosed with PC on biopsy. On multivariable analysis, FH was associated with increased odds of high-grade PC in black (OR 1.85, p = 0.041) and all men (OR 1.56, p = 0.057) and was unrelated to overall or low-grade PC diagnosis, overall, or stratified by race (all p ≥ 0.325). In sensitivity analyses among men without a previous biopsy, results were slightly more pronounced. CONCLUSION: In this setting of equal access to care, positive FH of PC was associated with increased tumor aggressiveness in black men, but not non-black men undergoing prostate biopsy. Further research is required to tease apart the contribution of genetics from increased PC awareness potentially influencing screening and biopsy rates in men with FH.

Epidemiology of Basal-like and Luminal Breast Cancers among Black Women in the AMBER Consortium.

BACKGROUND: Evidence suggests etiologic heterogeneity among breast cancer subtypes. Previous studies with six-marker IHC classification of intrinsic subtypes included small numbers of black women. METHODS: Using centralized laboratory results for estrogen receptor (ER), progesterone receptor, HER2, proliferation marker, Ki-67, EGFR, and cytokeratin (CK)5/6, we estimated case-only and case-control ORs for established breast cancer risk factors among cases (n = 2,354) and controls (n = 2,932) in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. ORs were estimated by ER status and intrinsic subtype using adjusted logistic regression. RESULTS: Case-only analyses by ER status showed etiologic heterogeneity by age at menarche, parity (vs. nulliparity), and age at first birth. In case-control analyses for intrinsic subtype, increased body mass index and waist-to-hip ratio (WHR) were associated with increased risk of luminal A subtype, whereas older age at menarche and parity, regardless of breastfeeding, were associated with reduced risk. For basal-like cancers, parity without breastfeeding and increasing WHR were associated with increased risk, whereas breastfeeding and age ≥25 years at first birth were associated with reduced risk among parous women. Basal-like and ER-/HER2+ subtypes had earlier age-at-incidence distribution relative to luminal subtypes. CONCLUSIONS: Breast cancer subtypes showed distinct etiologic profiles in the AMBER consortium, a study of more than 5,000 black women with centrally assessed tumor biospecimens. IMPACT: Among black women, high WHR and parity without breastfeeding are emerging as important intervention points to reduce the incidence of basal-like breast cancer.

Platelet cloaking of circulating tumour cells in patients with metastatic prostate cancer: Results from ExPeCT, a randomised controlled trial.

BACKGROUND: Circulating tumour cells (CTCs) represent a morphologically distinct subset of cancer cells, which aid the metastatic spread. The ExPeCT trial aimed to examine the effectiveness of a structured exercise programme in modulating levels of CTCs and platelet cloaking in patients with metastatic prostate cancer. METHODS: Participants (n = 61) were randomised into either standard care (control) or exercise arms. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analysed for the presence of CTCs, CTC clusters and platelet cloaking. CTC data was correlated with clinico-pathological information. RESULTS: Changes in CTC number were observed within group over time, however no significant difference in CTC number was observed between groups over time. Platelet cloaking was identified in 29.5% of participants. A positive correlation between CTC number and white cell count (WCC) was observed (p = 0.0001), in addition to a positive relationship between CTC clusters and PSA levels (p = 0.0393). CONCLUSION: The presence of platelet cloaking has been observed in this patient population for the first time, in addition to a significant correlation between CTC number and WCC. TRIAL REGISTRATION: ClincalTrials.gov identifier NCT02453139.

Abdominal and pelvic adipose tissue distribution and risk of prostate cancer recurrence after radiation therapy.

BACKGROUND: Fat distribution varies between individuals of similar body mass index (BMI). We hypothesized that visceral obesity is more strongly associated with poor prostate cancer outcomes than overall obesity defined by BMI. MATERIALS AND METHODS: We quantified abdominal visceral and subcutaneous fat area (VFA and SFA), and pelvic periprostatic adipose tissue area (PPAT), using computed tomography scans from radiation-treated prostate cancer patients at the Durham North Carolina Veterans Administration Hospital. Multivariable-adjusted Cox regression examined associations between each adiposity measure and risk of recurrence, overall and stratified by race and receipt of androgen deprivation therapy (ADT). RESULTS: Of 401 patients (59% black) treated from 2005 to 2011, 84 (21%) experienced recurrence during 9.3 years median follow-up. Overall, obesity defined by BMI was not associated with recurrence risk overall or stratified by race or ADT, nor was any measure of fat distribution related to the risk of recurrence overall or by race. However, higher VFA was associated with increased risk of recurrence in men who received radiation only (hazard ratio [HR], 1.79; 95% confidence interval [CI], 0.87-3.66), but inversely associated with recurrence risk in men treated with radiation and ADT (HR, 0.49; 95% CI, 0.24-1.03; P-interaction = .002), though neither association reached statistical significance. Similar patterns of ADT-stratified associations were observed for PPAT and SFA. CONCLUSIONS: Associations between abdominal and pelvic adiposity measures and recurrence risk differed significantly by ADT receipt, with positive directions of association observed only in men not receiving ADT. If confirmed, our findings suggest that obesity may have varying effects on prostate cancer progression risk dependent on the hormonal state of the individual.

Sleep quality and prostate cancer aggressiveness: Results from the REDUCE trial.

BACKGROUND: Disrupted sleep has been associated with increased risk of certain cancers. Little data exist in prostate cancer. We tested the association between sleep quality and prostate cancer diagnosis overall and by tumor grade in the Reduction by Dutasteride of Prostate Cancer Events chemoprevention trial. We hypothesized that worse sleep quality would be associated with increased tumor aggressiveness. METHODS: At baseline, 5614 men completed a validated six-item questionnaire on sleep quality. We generated a composite score categorized into tertiles to measure overall sleep quality and assessed each sleep quality question individually. Logistic regression was used to test associations between baseline sleep quality and overall, low-grade and high-grade prostate cancer diagnosis at 2-year study-mandated biopsy. Models were stratified by nocturia. RESULTS: Overall sleep quality was unrelated to overall or low-grade prostate cancer. Worse overall sleep quality was associated with elevated odds of high-grade prostate cancer (odds ratio [OR]T3vsT1 1.15; 95% confidence interval [CI]: 0.83-1.60 and ORT2vsT1 1.39; 95% CI: 1.01-1.92). Men reporting trouble falling asleep at night sometimes vs never had elevated odds of high-grade prostate cancer (OR: 1.51; 95% CI: 1.08-2.09) while trouble staying awake during the day was associated with decreased odds of low-grade prostate cancer (OR: 0.65; 95% CI: 0.49-0.86). Results were similar within strata of nocturia severity. CONCLUSIONS: Overall, associations between sleep quality and prostate cancer were inconsistent. However, there was some evidence for a positive association between insomnia and high-grade prostate cancer, and an inverse relationship between daytime sleepiness and low-grade prostate cancer; findings that should be validated by future studies.

Asian Race and Risk of Prostate Cancer: Results from the REDUCE Study.

BACKGROUND: Global prostate cancer incidence rates are lower in Asian men than Caucasian men. Whether this is the result of less screening in Asian men remains to be determined. We examined whether Asian race was associated with prostate cancer diagnosis in the Reduction by Dutasteride of Cancer Events (REDUCE) study. METHODS: REDUCE was a 4-year, multicenter, randomized trial of dutasteride versus placebo for prostate cancer prevention among men who underwent prostate-specific antigen (PSA)-independent biopsies at 2 and 4 years. Eligible men were ages 50 to 75 years, had PSA between 2.5 and 10 ng/mL, and a negative prestudy prostate biopsy. We tested the association between Asian and Caucasian race and prostate cancer diagnosis using logistic regression. RESULTS: Of 8,122 men in REDUCE, 5,755 (71%) were Caucasian and 105 (1.8%) were Asian. Asians had lower body mass index (24.8 vs. 26.9 kg/m2, P < 0.001), had smaller prostate volume (35.0 vs. 43.5 cc, P < 0.001), and were less likely to have abnormal digital rectal exams (P = 0.048), but were similar in baseline age, PSA, family history of prostate cancer, and smoking status compared with Caucasian men (all P ≥ 0.164). Asian men were equally likely to receive any on-study biopsy compared with Caucasian men (P = 0.634). After adjusting for potential confounders, Asian men were less likely to be diagnosed with prostate cancer during the 4-year study (OR = 0.49; 95% confidence interval, 0.28-0.88; P = 0.016), compared with Caucasian men. CONCLUSIONS: In REDUCE, where all men underwent biopsies largely independent of PSA, Asian race was associated with lower prostate cancer diagnosis. IMPACT: These findings suggest that lower prostate cancer risk in Asian men may be due to biological, genetic, and/or lifestyle factors.

Bimodal age distribution at diagnosis in breast cancer persists across molecular and genomic classifications.

PURPOSE: Female breast cancer demonstrates bimodal age frequency distribution patterns at diagnosis, interpretable as two main etiologic subtypes or groupings of tumors with shared risk factors. While RNA-based methods including PAM50 have identified well-established clinical subtypes, age distribution patterns at diagnosis as a proxy for etiologic subtype are not established for molecular and genomic tumor classifications. METHODS: We evaluated smoothed age frequency distributions at diagnosis for Carolina Breast Cancer Study cases within immunohistochemistry-based and RNA-based expression categories. Akaike information criterion (AIC) values compared the fit of single density versus two-component mixture models. Two-component mixture models estimated the proportion of early-onset and late-onset categories by immunohistochemistry-based ER (n = 2860), and by RNA-based ESR1 and PAM50 subtype (n = 1965). PAM50 findings were validated using pooled publicly available data (n = 8103). RESULTS: Breast cancers were best characterized by bimodal age distribution at diagnosis with incidence peaks near 45 and 65 years, regardless of molecular characteristics. However, proportional composition of early-onset and late-onset age distributions varied by molecular and genomic characteristics. Higher ER-protein and ESR1-RNA categories showed a greater proportion of late age-at-onset. Similarly, PAM50 subtypes showed a shifting age-at-onset distribution, with most pronounced early-onset and late-onset peaks found in Basal-like and Luminal A, respectively. CONCLUSIONS: Bimodal age distribution at diagnosis was detected in the Carolina Breast Cancer Study, similar to national cancer registry data. Our data support two fundamental age-defined etiologic breast cancer subtypes that persist across molecular and genomic characteristics. Better criteria to distinguish etiologic subtypes could improve understanding of breast cancer etiology and contribute to prevention efforts.

Serum Lipids prior to Starting Androgen Deprivation Therapy and Risk of Castration Resistant Prostate Cancer and Metastasis: Results from the SEARCH Database.

PURPOSE: We tested the association of serum lipid levels prior to androgen deprivation therapy with the risk of castration resistant prostate cancer and metastasis. MATERIALS AND METHODS: We identified 302 men in the SEARCH (Shared Equal Access Regional Cancer Hospital) database who received androgen deprivation therapy after radical prostatectomy for nonmetastatic disease, had never received statins before androgen deprivation therapy and had available serum lipid data within 2 years prior to androgen deprivation therapy. Cox proportional hazards models were used to test associations between total cholesterol (less than 200 vs 200 mg/dl or greater), low density lipoprotein (less than 130 vs 130 mg/dl or greater), high density lipoprotein (40 or greater vs less than 40 mg/dl) and triglycerides (less than 150 vs 150 mg/dl or greater) and the risk of castration resistant prostate cancer and metastasis after androgen deprivation therapy while adjusting for potential confounders. Subanalyses were restricted to men who remained statin nonusers after androgen deprivation therapy. RESULTS: Median followup after androgen deprivation therapy was 67 months. Castration resistant prostate cancer and metastasis developed in 42 and 44 men, respectively. Men with elevated cholesterol received androgen deprivation therapy in an earlier year and had longer followup and a higher rate of statin use after androgen deprivation therapy. On multivariable analysis total cholesterol and low density lipoprotein were unrelated to castration resistant prostate cancer. Low high density lipoprotein (less than 40 vs 40 mg/dl or greater) was suggestively linked to an increased risk of castration resistant prostate cancer (HR 1.86, 95% CI 0.99-3.48). The association was stronger in men who remained statin nonusers after androgen deprivation therapy (HR 3.64, 95% CI 1.45-9.17). Results for metastasis were similar to those for castration resistant prostate cancer. CONCLUSIONS: Among men with nonmetastatic prostate cancer who started androgen deprivation therapy serum cholesterol was unrelated to castration resistant prostate cancer or metastasis. Low high density lipoprotein was suggestively associated with risks of increased castration resistant prostate cancer and metastasis, particularly in statin never users. Further studies are needed to explore a potential role for lipids in prostate cancer progression after androgen deprivation therapy.

Statin use and longitudinal changes in prostate volume; results from the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial.

OBJECTIVE: To test the association between statin use and prostate volume (PV) change over time using data from the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, a 4-year randomised controlled trial testing dutasteride for prostate cancer chemoprevention. SUBJECTS/PATIENTS AND METHODS: We identified men with a baseline negative prostate biopsy from REDUCE who did not undergo prostate surgery or develop prostate cancer over the trial period. Men reported statin use at baseline. PV was determined from transrectal ultrasonography performed to guide prostate biopsy at baseline, and 2- and 4-years after randomisation. Multivariable generalised estimating equations tested differences in PV change over time by statin use, overall and stratified by treatment arm. We tested for interactions between statins and time in association with PV using the Wald test. RESULTS: Of 4106 men, 17% used statins at baseline. Baseline PV did not differ by statin use. Relative to non-users, statin users had decreasing PVs over the trial period (P = 0.027). Similar patterns were seen in the dutasteride and placebo arms, although neither reached statistical significance. The mean estimated PV was modestly but significantly lower in statin users relative to non-users in the dutasteride arm at 2-years (4.5%, P = 0.032) and 4-years (4.0%, P = 0.033), with similar (3-3.3%) but non-significant effects in the placebo arm. CONCLUSION: If confirmed, our present findings support a role for statins in modestly attenuating PV growth, with a magnitude of effect in line with previously reported prostate-specific antigen-lowering effects of statins (~4%). Future studies are needed to assess whether this putative role for statins in PV growth could impact lower urinary tract symptom development or progression.

Borderline Estrogen Receptor-Positive Breast Cancers in Black and White Women.

BACKGROUND: Some breast tumors expressing greater than 1% and less than 10% estrogen receptor (ER) positivity (ER-borderline) are clinically aggressive; others exhibit luminal biology. Prior ER-borderline studies included few black participants. METHODS: Using the Carolina Breast Cancer Study (phase I: 1993-1996; 2: 1996-2001; 3: 2008-2013), a population-based study that oversampled black women, we compared ER-borderline (n = 217) to ER-positive (n = 1885) and ER-negative (n = 757) tumors. PAM50 subtype and risk of recurrence score (ROR-PT, incorporates subtype, proliferation, tumor size) were measured. Relative frequency differences (RFD) were estimated using multivariable linear regression. Disease-free interval (DFI) was evaluated by ER category and endocrine therapy receipt, overall and by race, using Kaplan Meier and Cox models. Statistical tests were two-sided. RESULTS: ER-borderlines were more frequently basal-like (RFD = +37.7%, 95% confidence interval [CI] = 27.1% to 48.4%) and high ROR-PT (RFD = +52.4%, 95% CI = 36.8% to 68.0%) relative to ER-positives. Having a high ROR-PT ER-borderline tumor was statistically significantly associated with black race (RFD = +26.2%, 95% CI = 9.0% to 43.3%). Compared to ER-positives, DFI of ER-borderlines treated with endocrine therapy was poorer but not statistically significantly different (hazard ratio [HR] = 2.03, 95% CI = 0.89% to 4.65%), whereas DFI was statistically significantly worse for ER-borderlines without endocrine therapy (HR = 3.33, 95% CI = 1.84% to 6.02%). However, black women with ER-borderline had worse DFI compared to ER-positives, even when treated with endocrine therapy (HR = 2.77, 95% CI = 1.09% to 7.04%). CONCLUSIONS: ER-borderline tumors were genomically heterogeneous, with survival outcomes that differed by endocrine therapy receipt and race. Black race predicted high-risk ER-borderlines and may be associated with poorer endocrine therapy response.