Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.

BackgroundIn the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.MethodsFrom 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.FindingsWe found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.InterpretationWe showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT

Targeting the mTOR Pathway for the Prevention of ER-negative Breast Cancer

Our results show that everolimus delays mammary tumor formation in multiple mouse models, suggesting that mTOR inhibitors will be useful for the prevention of ER-negative and triple-negative breast cancer in humans. See related Spotlight, p. 787

Treatment Strategies and Mechanisms Associated with the Prevention of NASH-Associated HCC by a Toll-like Receptor 4 Inhibitor.

We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations.Prevention relevanceMeans to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC

Alternative dosing of exemestane in postmenopausal women with ER-positive breast cancer. Design and methods of a randomized presurgical trial.

IntroductionAromatase inhibitors are effective in lowering breast cancer incidence among postmenopausal women, but adverse events represent a barrier to their acceptability and adherence as a preventive treatment. This study aims to assess whether lowering exemestane schedule may retain biological activity while improving tolerability in breast cancer patients.Methods/designWe are conducting a, pre-surgical, non-inferiority phase IIb study in postmenopausal women with newly diagnosed estrogen receptor-positive breast cancer. Participants are randomized to receive either exemestane 25 mg/day or 25 mg/three times-week or once a week for 4 to 6 weeks prior to surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery comparing the three arms. Sample size of 180 women was calculated assuming a 6% non-inferiority of the percent change of estradiol in the lower dose arms compared with the 80% decrease predicted in the full dose arm, with 80% power and using a one-sided 5% significance level and a two-sample t-test. Main secondary outcomes are: safety; change in Ki-67 in cancer and adjacent pre-cancer tissue, circulating sex hormones, adipokines, lipid profile, insulin and glucose changes, in correlation with drug and metabolites concentrations.Results and discussionThe present paper is focused on methodology and operational aspects of the study. A total of 180 participants have ben enrolled. The trial is still blinded, and the analyses are ongoing. Despite the short term duration, results may have relevant implications for clinical management of women at increased risk of developing a ER positive breast cancer

Alternative dosing of exemestane in postmenopausal women with ER-positive breast cancer. Design and methods of a randomized presurgical trial.

IntroductionAromatase inhibitors are effective in lowering breast cancer incidence among postmenopausal women, but adverse events represent a barrier to their acceptability and adherence as a preventive treatment. This study aims to assess whether lowering exemestane schedule may retain biological activity while improving tolerability in breast cancer patients.Methods/designWe are conducting a, pre-surgical, non-inferiority phase IIb study in postmenopausal women with newly diagnosed estrogen receptor-positive breast cancer. Participants are randomized to receive either exemestane 25 mg/day or 25 mg/three times-week or once a week for 4 to 6 weeks prior to surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery comparing the three arms. Sample size of 180 women was calculated assuming a 6% non-inferiority of the percent change of estradiol in the lower dose arms compared with the 80% decrease predicted in the full dose arm, with 80% power and using a one-sided 5% significance level and a two-sample t-test. Main secondary outcomes are: safety; change in Ki-67 in cancer and adjacent pre-cancer tissue, circulating sex hormones, adipokines, lipid profile, insulin and glucose changes, in correlation with drug and metabolites concentrations.Results and discussionThe present paper is focused on methodology and operational aspects of the study. A total of 180 participants have ben enrolled. The trial is still blinded, and the analyses are ongoing. Despite the short term duration, results may have relevant implications for clinical management of women at increased risk of developing a ER positive breast cancer

Tissue Effects in a Randomized Controlled Trial of Short-term Finasteride in Early Prostate Cancer.

BackgroundIn the Prostate Cancer Prevention Trial, finasteride selectively suppressed low-grade prostate cancer and significantly reduced the incidence of prostate cancer in men treated with finasteride compared with placebo. However, an apparent increase in high-grade disease was also observed among men randomized to finasteride. We aimed to determine why and hypothesized that there is a grade-dependent response to finasteride.MethodsFrom 2007 to 2012, we randomized dynamically by intranet-accessible software 183 men with localized prostate cancer to receive 5mg finasteride or placebo daily in a double-blind study during the 4-6weeks preceding prostatectomy. As the primary end point, the expression of a predefined molecular signature (ERβ, UBE2C, SRD5A2, and VEGF) differentiating high- and low-grade tumors in Gleason grade (GG) 3 areas of finasteride-exposed tumors from those in GG3 areas of placebo-exposed tumors, adjusted for Gleason score (GS) at prostatectomy, was compared. We also determined androgen receptor (AR) levels, Ki-67, and cleaved caspase 3 to evaluate the effects of finasteride on the expression of its downstream target, cell proliferation, and apoptosis, respectively. The expression of these markers was also compared across grades between and within treatment groups. Logistic regression was used to assess the expression of markers.FindingsWe found that the predetermined molecular signature did not distinguish GG3 from GG4 areas in the placebo group. However, AR expression was significantly lower in the GG4 areas of the finasteride group than in those of the placebo group. Within the finasteride group, AR expression was also lower in GG4 than in GG3 areas, but not significantly. Expression of cleaved caspase 3 was significantly increased in both GG3 and GG4 areas in the finasteride group compared to the placebo group, although it was lower in GG4 than in GG3 areas in both groups.InterpretationWe showed that finasteride's effect on apoptosis and AR expression is tumor grade dependent after short-term intervention. This may explain finasteride's selective suppression of low-grade tumors observed in the PCPT

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease.

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187

CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer.

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention.SignificanceDuctal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell-mediated tumor regression. See related commentary by DelGiorno, p. 977