Male breast cancer: a disease distinct from female breast cancer.

PURPOSE: Male breast cancer (BC) is rare, representing approximately 1% of cancers that occur in men and approximately 1% of all BCs worldwide. Because male BC is rare, not much is known about the disease, and treatment recommendations are typically extrapolated from data available from clinical trials enrolling female BC patients. METHODS: We review the epidemiology, risk factors, prognosis, and the varied molecular and clinicopathologic features that characterize male BC. In addition, we summarize the available data for the use of systemic therapy in the treatment of male BC and explore the ongoing development of targeted therapeutic agents for the treatment of this subgroup of BCs. RESULTS: There are important biological differences between male and female BC. Male BC is almost exclusively hormone receptor positive (+), including the androgen receptor (AR), and is associated with an increased prevalence of BRCA2 germline mutations, especially in men with increased risk for developing high-risk BC. Additional research is warranted to better characterize male BC. To accomplish this, a multi-national consortium approach, such as the International Male Breast Cancer Program, is needed in response to the scarcity of patients. This approach allows the pooling of information from a large number of men with BC and the creation of registries for future therapeutic-focused clinical trials. CONCLUSIONS: Given the unique biology of BC in men, promising new therapeutic targets are currently under investigation, including the use of poly-ADP-ribose polymerase inhibitors or AR-targeted agents either as monotherapy or in combination with other agents.

Phase I Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer.

Purpose: Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with antitumor activity in vitro and in vivo This open-label phase I clinical study evaluated the safety, tolerability, pharmacokinetics and activity of once-daily seviteronel in male chemotherapy-naïve subjects with castration-resistant prostate cancer (CRPC).Patients and Methods: Seviteronel was administered at 600 mg once daily with dose titration (DT) and in modified 3 + 3 dose escalation once-daily cohorts at 600, 750, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability, and the MTD of seviteronel in chemotherapy-naïve subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA), and enzalutamide. Secondary objectives were to assess pharmacokinetics, PSA, tumor response, and endocrine results.Results: Twenty-one subjects were enrolled. No dose-limiting toxicities (DLT) were observed through 750 mg once daily. Most treatment-emergent adverse events (AE) reported at grade 1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), blurred vision (38%), and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption.Conclusions: Once-daily seviteronel was generally well tolerated in this phase I study of men with CRPC, a majority of which had progressed on prior AA or enzalutamide, or both. Of the doses evaluated, 600 mg once daily was chosen as the recommended phase II dose for future studies in subjects with CRPC. Clin Cancer Res; 24(21); 5225-32. ©2018 AACR.

Phase 1 study of seviteronel, a selective CYP17 lyase and androgen receptor inhibitor, in women with estrogen receptor-positive or triple-negative breast cancer.

PURPOSE: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer. METHODS: Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24). RESULTS: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported. CONCLUSIONS: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.

Harnessing a Different Dependency: How to Identify and Target Androgen Receptor-Positive Versus Quadruple-Negative Breast Cancer.

The androgen receptor (AR) is a promising therapeutic target for a subset of triple-negative breast cancers (TNBCs) in which AR is expressed. However, the mechanistic action of AR and the degree to which primary and metastatic tumors depend on AR, both before and after conventional treatment, remain to be defined. We discuss preclinical and clinical data for AR+ TNBC, the difficulties in monitoring AR protein levels, new methods for determining AR status, the influence of AR on "stemness" in the context of TNBC, the role of combined inhibition of sex steroid production and AR, and the role of AR in regulation of the immune system. Although the exact role of AR in subsets of TNBC is still being characterized, new therapies that target AR and the production of androgens may provide additional options for patients with TNBC for whom chemotherapy is currently the sole treatment option.

Treatment patterns and characteristics of European patients with castration-resistant prostate cancer.

BACKGROUND: European treatment guidelines recommend the use of hormonal therapy for the treatment of advanced prostate cancer, including castration-resistant prostate cancer (CRPC), but there is little understanding of how common practices in prostate cancer treatment compare across Europe. The aim of this analysis was to evaluate the management of CRPC patients across five European countries (France, Germany, Italy, Spain and the UK). METHODS: Data were drawn from the Adelphi Real World Prostate Cancer Disease Specific Programme (DSP), a cross-sectional survey of patients undertaken between December 2009 and May 2010. The study is based on physician interviews, physician-completed detailed patient record forms, and a patient-completed questionnaire. RESULTS: A total of 348 physicians (191 urologists and 157 oncologists) reported on 3477 patients with prostate cancer. Of the 3477 patients, 1405 (40%) were categorised as having CRPC, and 1119 of these had metastatic CRPC. Bone metastases were the most common (78%), followed by liver (37%) and lung (30%). The mean age of CRPC patients was 71 years, 35% were current or ex-smokers and 10% had a family history of prostate cancer. CRPC patients had a mean of 1.8 comorbidities; 66% had hypertension and 32% had diabetes. Most physicians estimated their patients would stop responding to initial hormone therapy after 19-24 months. Overall, addition of an anti-androgen to a luteinising-hormone-releasing hormone (LHRH) agonist was the most commonly prescribed therapy when patients failed initial LHRH agonist therapy, although there were considerable variations between countries. While 72% of physicians in Europe would choose chemotherapy as the next treatment option after diagnosis of CRPC, 31% of this group would initially prescribe this without an LHRH agonist. CONCLUSIONS: Results from this analysis highlight inconsistencies in common hormonal therapy treatment patterns for CRPC and hormonal therapy across the EU.

Preliminary report of the Hepatic Encephalopathy Assessment Driving Simulator (HEADS) score.

INTRODUCTION: Audiovisual simulations of real-life driving (ie, driving simulators) have been used to assess neurologic dysfunction in a variety of medical applications. However, the use of simulated driving to assess neurologic impairment in the setting of liver disease (ie, hepatic encephalopathy) is limited. OBJECTIVES: The aim of this analysis was to develop a scoring system based on simulated driving performance to assess mild cognitive impairment in cirrhotic patients with hepatic encephalopathy. METHODS: This preliminary analysis was conducted as part of the Hepatic Encephalopathy Assessment Driving Simulator (HEADS) pilot study. Cirrhotic volunteers initially underwent a battery of neuropsychological tests to identify those cirrhotic patients with mild cognitive impairment. Performance during an audiovisually simulated course of on-road driving was then compared between mildly impaired cirrhotic patients and healthy volunteers. A scoring system was developed to quantify the likelihood of cognitive impairment on the basis of data from the simulated on-road driving. RESULTS: Mildly impaired cirrhotic patients performed below the level of healthy volunteers on the driving simulator. Univariate logistic regression and correlation models indicated that several driving simulator variables were significant predictors of cognitive impairment. Five variables (run time, total map performance, number of collisions, visual divided attention response, and average lane position) were incorporated into a quantitative model, the HEADS scoring system. The HEADS score (0-9 points) showed a strong correlation with cognitive impairment as measured by area under the receiver-operator curve (.89). CONCLUSION: The HEADS system appears to be a promising new tool for the assessment of mild hepatic encephalopathy.

Matching graft to recipient by predicted survival: can this be an acceptable strategy to improve utilization of deceased donor kidneys?

A new kidney allocation scheme is needed to address the current shortage of deceased donor kidneys for transplantation in the United States. With this goal in mind, we have derived a novel utility-based system to balance supply and demand. Our system uses a North American-based recipient risk score and the deceased donor score to maximize the total number of years of renal allograft function as a means to improve allocation of kidneys from deceased donors. Essentially, donor renal allografts are matched to a wait-listed candidate with similar predicted survival, which poses an ethical issue. However, this novel utility-based system is practical and could improve deceased donor renal allocation by minimizing both waste and need for retransplantation.

Constitutive androstane receptor agonist, TCPOBOP, attenuates steatohepatitis in the methionine choline-deficient diet-fed mouse.

AIM: To ascertain whether constitutive androstane receptor (CAR) activation by 1,4-bis-[2-(3,5,-dichloropyridyloxy)] benzene (TCPOBOP) modulates steatohepatitis in the methionine choline-deficient (MCD) diet-fed animal. METHODS: C57/BL6 wild-type mice were fed the MCD or standard diet for 2 wk and were treated with either the CAR agonist, TCPOBOP, or the CAR inverse agonist, androstanol. RESULTS: Expression of CYP2B10 and CYP3A11, known CAR target genes, increased 30-fold and 45-fold, respectively, in TCPOBOP-treated mice fed the MCD diet. TCPOBOP treatment reduced hepatic steatosis (44.6 +/- 5.4% vs 30.4 +/- 4.5%, P < 0.05) and serum triglyceride levels (48 +/- 8 vs 20 +/- 1 mg/dL, P < 0.05) in MCD diet-fed mice as compared with the standard diet-fed mice. This reduction in hepatic steatosis was accompanied by an increase in enzymes involved in fatty acid microsomal omega-oxidation and peroxisomal beta-oxidation, namely CYP4A10, LPBE, and 3-ketoacyl-CoA thiolase. The reduction in steatosis was also accompanied by a reduction in liver cell apoptosis and inflammation. In contrast, androstanol was without effect on any of the above parameters. CONCLUSION: CAR activation stimulates induction of genes involved in fatty acid oxidation, and ameliorates hepatic steatosis, apoptosis and inflammation.

A recipient risk score for deceased donor renal allocation.

BACKGROUND: The current shortage of deceased donor kidneys makes it difficult to design a kidney allocation scheme that balances optimal utility with supply. The aim of this study is to derive a recipient risk score (RRS) that could be used with the deceased donor score (DDS) to maximize the total number of years of renal allograft function as a means to improve allocation. METHODS: We retrospectively reviewed 47,535 adult recipients of deceased donor renal transplants between 1995 and 2002 from the United Network for Organ Sharing Standard Transplant Analysis and Research Files. Multivariable Cox regression models were used to derive an RRS and estimate recipient and graft survival as a function of RRS. Annual rates of organ supply and recipient demand for deceased donor kidneys were estimated from expectancy data and expressed in renal years (years provided by a functioning kidney allograft). Renal-year analyses were used to optimize allocation. RESULTS: The strongest predictors of recipient survival after transplantation used in the RRS were recipient age, history of diabetes mellitus, history of angina, and time on dialysis therapy. When used with DDS, RRS provided a utility-based allocation system for deceased donor kidneys that theoretically increased the annual (2002) rate of supply by 15%. CONCLUSION: The RRS is a practical system that, when combined with a method to assess donor organs, such as DDS, may improve deceased donor renal allocation.

Improving utilization of deceased donor kidneys by matching recipient and graft survival.

Younger renal transplant recipients often outlive their allografts, whereas older recipients often die before their allograft fails. Thus, our aim was to assess the utility of matching recipient and graft survival to improve allocation of deceased donor kidneys. We reviewed the records of 49,206 patients (United Network for Organ Sharing, 1995-2002). Donor grafts were stratified by Deceased Donor Score (DDS). We observed a disparity between recipient survival and renal graft survival which contributed to an annual gap between supply and demand of renal transplants. Utilization of DDS and distribution of marginal kidneys to older recipients would improve allocation.

Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins.

The constitutive androstane receptor (CAR) modulates xeno- and endobiotic hepatotoxicity by regulating detoxification pathways. Whether activation of CAR may also protect against liver injury by directly blocking apoptosis is unknown. To address this question, CAR wild-type (CAR+/+) and CAR knockout (CAR-/-) mice were treated with the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and then with the Fas agonist Jo2 or with concanavalin A (ConA). Following the administration of Jo2, hepatocyte apoptosis, liver injury, and animal fatalities were abated in TCPOBOP-treated CAR+/+ but not in CAR-/- mice. Likewise, acute and chronic ConA-mediated liver injury and fibrosis were also reduced in wild-type versus CAR(-/-) TCPOBOP-treated mice. The proapoptotic proteins Bak (Bcl-2 antagonistic killer) and Bax (Bcl-2-associated X protein) were depleted in livers from TCPOBOP-treated CAR+/+ mice. In contrast, mRNA expression of the antiapoptotic effector myeloid cell leukemia factor-1 (Mcl-1) was increased fourfold. Mcl-1 promoter activity was increased by transfection with CAR and administration of TCPOBOP in hepatoma cells, consistent with a direct CAR effect on Mcl-1 transcription. Indeed, site-directed mutagenesis of a putative CAR consensus binding sequence on the Mcl-1 promoter decreased Mcl-1 promoter activity. Mcl-1 transgenic animals demonstrated little to no acute liver injury after administration of Jo2, signifying Mcl-1 cytoprotection. In conclusion, these observations support a prominent role for CAR cytoprotection against Fas-mediated hepatocyte injury via a mechanism involving upregulation of Mcl-1 and, likely, downregulation of Bax and Bak.

Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse.

Proteasome inhibition has recently been demonstrated to inhibit hepatic fibrogenesis in the bile duct-ligated (BDL) mouse by blocking stellate cell NF-kappaB activation. The effect of proteasome inhibition on liver injury, however, is unclear. Our aims were to assess the effect of the proteasome inhibitor bortezomib on liver injury in the BDL mouse. Liver injury was assessed in 7-day BDL mice treated with a single dose of bortezomib on day 4 after bile duct ligation. Despite NF-kappaB inhibition by bortezomib, liver injury and hepatocyte apoptosis were reduced in treated BDL mice. The antiapoptotic effect of bortezomib was likely mediated by an increase in hepatic cellular FLICE inhibitory protein (c-FLIP) levels, a potent antiapoptotic protein. Unexpectedly, numerous mitotic hepatocytes were observed in the bortezomib-treated BDL mice liver specimens. Consistent with this observation, PCNA immunoreactivity and cyclin A protein expression were also increased with bortezomib treatment. Bortezomib therapy was also associated with a decrease in numbers and activation of Kupffer cells/macrophages. In conclusion, these data suggest that the proteasome inhibitor bortezomib reduces hepatocyte injury in the BDL mouse by mechanisms associated with a reduction in hepatocyte apoptosis, a decrease in Kupffer cell/macrophage number and activation, and increased hepatocyte proliferation.

Liver transplantation for gastroenteropancreatic neuroendocrine cancers: Defining selection criteria to improve survival.

Liver transplantation for gastroenteropancreatic neuroendocrine cancer (GEP) is controversial. The aim of this study was to assess patient outcomes after liver transplantation for hepatic metastases from GEP. Medical records of patients who underwent liver transplantation for GEP were reviewed. Immunohistochemistry for assessing the Ki67 proliferation index was performed on explanted liver tissue. Nineteen patients who underwent liver transplantation had a mean follow-up of 22 months with a range of 0 to 84 months. There was 1 intraoperative death, and 3 patients had disease recurrence after liver transplantation leading to death in 1 patient. Overall estimated 1-year survival for 17 patients included in the treatment protocol (mean follow-up, 15 months) was 87% with an estimated 1-year recurrence-free rate (conditional on survival) of 77%. Three of 11 patients with pancreatic islet cell GEP developed disease recurrence, whereas all 8 patients with carcinoid GEP remain free of disease. Analysis of the Ki67 proliferation index in 18 patients did not differentiate those with recurrence from those without disease recurrence. In conclusion, liver transplantation for patients with hepatic metastases from GEP is a viable therapeutic option in highly selected patients.

Proteasome inhibition induces hepatic stellate cell apoptosis.

Induction of hepatic stellate cell (HSC) apoptosis attenuates hepatic fibrosis, and, therefore, mechanisms to induce HSC cell death are of therapeutic interest. Proteasome inhibitors induce apoptosis in transformed cells, especially those cells dependent upon nuclear factor kappa B (NF-kappaB) activation. Because stimulated HSCs also trigger NF-kappaB activation, the aim of this study was to determine if proteasome inhibitors induce HSC apoptosis. The immortalized human HSC line, LX-2, and primary rat HSCs were treated with the proteasome inhibitors bortezomib and MG132. Both proteasome inhibitors induced HSC apoptosis. Proteasome inhibition blocked NF-kappaB activation and, more importantly, NF-kappaB inhibition by Bay11-7082-triggered HSC apoptosis. Activated HSC survival is dependent upon the NF-kappaB target gene A1, an anti-apoptotic Bcl-2 family member, as siRNA targeted knockdown of A1-induced HSC apoptosis. In contrast, proteasome inhibition-induced alterations in TRAIL, death receptor 5, and Bim could not be implicated in the apoptotic response. The relevance of these findings was confirmed in the bile-duct-ligated mouse where bortezomib reduced hepatic markers of stellate cell activation and fibrosis. In conclusion, proteasome inhibition is a potential therapeutic strategy for inducing HSC apoptosis and inhibiting liver fibrogenesis.

Improving the prediction of donor kidney quality: deceased donor score and resistive indices.

BACKGROUND: The deceased donor score (DDS), expanded criteria donor (ECD) definition, and resistive index (RI) were developed for pretransplant evaluation of donors. DDS and ECD are determined by a calculation of risk from donor variables, while RI is determined from flow characteristics of kidneys during machine preservation (MP). This study was designed to compare DDS, ECD status, and RI as predictors of outcome after deceased donor transplantation. We were also interested to see if DDS or ECD could identify kidneys most likely to benefit from MP. METHODS: We retrospectively reviewed 48,952 deceased donor renal transplants reported to UNOS from 1997-2002. DDS (0-39 pts.), ECD status (+ or -), and preservation technique (MP vs. cold storage [CS]) were determined in all cases. RI during MP was studied in a single-center cohort of 425 transplants. RESULTS: DDS was superior to ECD status and RI in its correlation with early and late renal function after transplantation. DDS identified a subgroup of ECD- kidneys, those with DDS > or = 20 pts, that functioned significantly below expectation and similar to ECD+ kidneys. Benefits of MP, which include improved early graft function and a trend towards longer graft survival, were greatest in the group of kidneys with DDS > or = 20 pts. CONCLUSIONS: DDS was the best predictor of outcome after deceased donor renal transplantation and may be useful in identifying kidneys most likely to benefit from MP.

United Network for Organ Sharing's expanded criteria donors: is stratification useful?

The United Network for Organ Sharing (UNOS) Expanded Criteria Donor (ECD) system utilizes pre-transplant variables to identify deceased donor kidneys with an increased risk of graft loss. The aim of this study was to compare the ECD system with a quantitative approach, the deceased donor score (DDS), in predicting outcome after kidney transplantation. We retrospectively reviewed 49 111 deceased donor renal transplants from the UNOS database between 1984 and 2002. DDS: 0-39 points; >or=20 points defined as marginal. Recipient outcome variables were analyzed by ANOVA or Kaplan-Meier method. There was a 90% agreement between the DDS and ECD systems as predictors of renal function and graft survival. However, DDS identified ECD- kidneys (10.7%) with a significantly poorer outcome than expected (DDS 20-29 points, n = 5,252). Stratification of ECD+ kidneys identified a group with the poorest outcome (DDS >or=30 points). Predictability of early post-transplant events (i.e. need for hemodialysis, decline of serum creatinine and length of hospital stay) was also improved by DDS. DDS predicted outcome of deceased donor renal transplantation better than the ECD system. Knowledge obtained by stratification of deceased donor kidneys can allow for improved utilization of marginal kidneys which is not achieved by the UNOS ECD definition alone.