Using the AR-V7 biomarker to determine treatment in metastatic castrate resistant prostate cancer, a feasibility randomised control trial, conclusions from the VARIANT trial [version 2; peer review: 2 approved]

Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS).  Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials

Adipocyte hypertrophy, fatty liver and metabolic risk factors in South Asians: the Molecular Study of Health and Risk in Ethnic Groups (mol-SHARE).

OBJECTIVE: We sought to determine if differences in the distribution and characteristics of adipose tissue between South Asians and white Caucasians account for differences in risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: We recruited 108 healthy South Asians (36.8 years) and white Caucasians (34.2 years) within three BMI strata. Body composition, adipocyte size, abdominal fat area, and hepatic adiposity were assessed and related to fasting glucose, insulin, lipids and adiponectin. RESULTS: After adjustment for age, sex, and BMI, South Asians compared to white Caucasians had higher ln fasting insulin (mean difference (MD): 0.44; 95% CI: 0.20-0.69), lower HDL cholesterol (md: -0.13; 95% CI:-0.26 to -0.01), and lower adiponectin (md: -2.38; 95% CI: -3.59 to -1.17). South Asians also had more body fat (md: 2.69; 95% CI: 0.70 to 4.69), lower lean muscle mass (md: -3.25; 95%CI: -5.35 to -1.14), increased waist to hip ratio (md: 0.03; 95% CI: 0.01-0.05), less superficial subcutaneous abdominal adipose tissue (md: -2.94; 95% CI: -5.56 to-0.32), more deep/visceral to superficial adipose tissue ratio (md 0.34; 95% CI: 0.02 to 0.65), and more liver fat (md: 7.43%; 95% CI: 2.30 to 12.55%). Adipocyte area was increased in South Asians compared to white Caucasians (md: 64.26; 95% CI: 24.3 to 104.1) units(2). Adjustment for adipocyte area attenuated the ethnic differences in insulin (md: 0.22; 95% CI: -0.07 to 0.51), HDL (md: -0.01; 95% CI: -0.16 to 0.13) and adiponectin (md: -1.11; 95% CI: -2.61 to 0.39). Adjustment for differences in adipocyte area and fat distribution attenuated the ethnic difference in liver fat (md: 5.19; 95% CI: 0.31 to 10.06). CONCLUSION: South Asians have an increased adipocyte area compared to white Caucasians. This difference accounts for the ethnic differences in insulin, HDL cholesterol, adiponectin, and ectopic fat deposition in the liver

Adipose and lean tissue characteristics of participants.

<p>* Means (± SE) are adjusted for age and BMI,</p><p>† Means (± SE) are adjusted for age, sex and BMI,</p><p>|| Total fat area refers to: superficial + deep+visceral fat by MRI,</p><p>‡ p<0.05 comparing South Asians to Europeans overall,</p><p>§ p<0.05 comparing South Asian women to European women,</p><p>¶ p<0.05 comparing South Asian men to European men,</p><p>Note: There was no change in the IMCL change after adjustment for peak exercise capacity i.e. Vo2 max at 15 mins.</p

BMI: Body Mass Index, error bars represent the standard error.

<p>BMI: Body Mass Index, error bars represent the standard error.</p

Baseline characteristics of participants.

<p>* Means (± SE) are adjusted for age,</p><p>† Means (± SE) are adjusted for age, sex, BMI ‡ p<0.05 comparing South Asians to Europeans overall,</p><p>§ p<0.05 comparing South Asian women to European women,</p><p>|| p<0.05 comparing South Asian men to European men; Physical activity score derived from the SHARE activity index (14).</p

HDL: High Density Lipoprotein, CRP: C-reactive protein.

<p>HDL: High Density Lipoprotein, CRP: C-reactive protein.</p