Treatment with abiraterone and enzalutamide does not overcome poor outcome from metastatic castration-resistant prostate cancer in men with the germline homozygous HSD3B1 c.1245C genotype.

BACKGROUND: In men with castration-sensitive prostate cancer (CSPC), the HSD3B1 c.1245A>C variant has been reported to be associated with shorter responses to first-line androgen-deprivation therapy (ADT). Here, we evaluated the association between the inherited HSD3B1 c.1245A>C variant and outcomes from metastatic castration-resistant prostate cancer (mCRPC) after first-line treatment with abiraterone (Abi) or enzalutamide (Enza). PATIENTS AND METHODS: Patients with mCRPC (n = 266) were enrolled from two centers at the time of starting first-line Abi/Enza. Outcomes after Abi/Enza included best prostate-specific antigen (PSA) response, treatment duration, and overall survival (OS). Outcomes after first-line ADT were determined retrospectively, and included treatment duration and OS. As was prespecified, we compared patients with the homozygous variant HSD3B1 genotype (CC genotype) versus the combined group with the heterozygous (AC) and homozygous wild-type (AA) genotypes. RESULTS: Among the 266 patients, 22 (8.3%) were homozygous for the HSD3B1 variant (CC). The CC genotype had no association with PSA response rate; the median Abi/Enza treatment duration was 7.1 months for the CC group and 10.3 months for the AA/AC group (log rank P = 0.34). Patients with the CC genotype had significantly worse OS, with median survival at 23.6 months for the CC group and 30.7 months for the AA/AC group (log rank P = 0.02). In multivariable analysis adjusting for age, Gleason score, PSA, prior chemotherapy, and M1 disease, the association between the CC genotype and OS remained significant (hazard ratio 1.78, 95% confidence interval 1.03-3.07, P = 0.04). Poor outcome after first-line ADT in the CC group was also observed when evaluating retrospective ADT duration data for the same combined cohort. CONCLUSIONS: In this large two-center study evaluating the HSD3B1 c.1245 genotype and outcomes after first-line Abi/Enza, homozygous variant (CC) HSD3B1 genotype was associated with worse outcomes. Novel therapeutic strategies are needed to enable treatment selection based on this genetic marker.

Circulating tumour cell increase as a biomarker of disease progression in metastatic castration-resistant prostate cancer patients with low baseline CTC counts.

Background: The development of treatment response and surrogate biomarkers for advanced prostate cancer care is an unmet clinical need. Patients with baseline circulating tumour cell (BLCTCs) counts <5/7.5 mL represent a good prognosis subgroup but are non-evaluable for response assessment (decrease in CTCs). The aim of the study is to determine the value of any increase in CTCs (CTC progression) as an indicator of progression in prostate cancer patients with low pre-treatment CTCs (<5). Patients and methods: We carried out a post hoc analysis of patients with BLCTCs < 5 treated in the COU-AA-301 (abiraterone or placebo + prednisone) and IMMC-38 (chemotherapy) trials. The association of CTC progression (increase in CTCs at 4, 8 or 12 weeks) with overall survival (OS) was evaluated in multi-variable Cox regression models. Performance of survival models with and without CTC progression was evaluated by calculating ROC curve area under the curves (AUCs) and weighted c-indices. Results: Overall, 511 patients with CTCs < 5 (421 in COU-AA-301 and 90 in IMMC-38) were selected; 212 (41.7%) had CTC progression at 4, 8 or 12 weeks after treatment initiation. CTC progression was associated with significantly worse OS [27.1 versus 15.1 m; hazard ratio (HR) 3.4 (95% confidence interval [CI] 2.5-4.5; P < 0.001)], independent of baseline CTCs and established clinical variables. Adding CTC progression to the OS model significantly improved ROC AUC (0.77 versus 0.66; P < 0.001). Models including CTC progression had superior ROC AUC (0.77 versus 0.69; P < 0.001) and weighted c-index [0.750 versus 0.705; delta c-index: 0.045 (95% CI 0.019-0.071)] values than those including CTC conversion (increase to CTCs ≥ 5). In COU-AA-301, the impact of CTC progression was independent of treatment arm. Conclusions: Increasing CTCs during the first 12 weeks of treatment are independently associated with worse OS from advanced prostate cancer in patients with baseline CTCs < 5 treated with abiraterone or chemotherapy and improve models with established prognostic variables. These findings must be prospectively validated.

Healthcare providers' knowledge of, attitudes to and practice of pre-exposure prophylaxis for HIV infection.

OBJECTIVES: Pre-exposure prophylaxis (PrEP) has proven biological efficacy in reducing the risk of sexual acquisition of HIV. Healthcare providers' (HCPs) knowledge of and attitudes to PrEP will be key to successful implementation. In England, PrEP is only available to men who have sex with men (MSM) through the open-label randomized PROUD pilot study of immediate or deferred use. METHODS: In September 2013, a cross-sectional survey of UK HCPs distributed through sexual health clinics (219) and professional societies' email lists (2599) and at a conference (80) asked about knowledge of, attitudes to and practice of PrEP. RESULTS: Overall, 328 of 2898 (11%) completed the survey, of whom 160 of 328 (49%) were doctors, 51 (16%) sexual health advisers (SHAs), 44 (14%) nurses and 73 (22%) unspecified. Over a quarter (83 of 311; 27%) were involved in PROUD. Most respondents (260 of 326; 80%) rated their knowledge of PrEP as medium or high. Over half of respondents (166 of 307; 54%) thought PrEP should be available outside of a clinical trial. The main barriers to supporting PrEP availability outside a clinical trial were concerns about current evidence (odds ratio [OR] 0.13), lack of UK-specific guidance (OR 0.35), concerns about adherence (OR 0.38) and risk of sexual or physical coercion for patients to have condomless or higher risk sex (OR 0.42 in multivariate regression). Just over half (147 of 277; 53%) had been asked about PrEP by patients in the past year, including almost half of those working in a clinic not involved in the PROUD study (86 of 202; 43%). CONCLUSIONS: There is support for PrEP availability outside a clinical trial, but HCPs have residual concerns about its effectiveness and negative consequences, and the absence of UK-specific implementation guidance.

Evaluating the extent of potential resistance to pre-exposure prophylaxis within the UK HIV-1-infectious population of men who have sex with men.

OBJECTIVES: Recent studies have shown that pre-exposure prophylaxis (PrEP) can substantially reduce the chance of acquiring HIV infection. However, PrEP efficacy has been found to be compromised in macaque studies if the challenge virus is antiretroviral therapy (ART)-resistant. Our objective was to evaluate the likelihood that a UK man who has sex with men (MSM) would be exposed to PrEP-resistant HIV in a homosexual encounter with an HIV-infectious partner. METHODS: Data from the UK Collaborative HIV Cohort (UK CHIC) study were linked to the UK HIV Drug Resistance Database for HIV-1-positive MSM patients seen between 2005 and 2008. Patients were categorized as undiagnosed; diagnosed but ART-naïve; ART-experienced and on treatment; and ART-experienced and on a treatment interruption. Considering current PrEP regimens, resistance to (a) tenofovir (TDF) alone, (b) TDF and emtricitabine (FTC), and (c) TDF or FTC was estimated. Patients without resistance tests had PrEP resistance imputed using bootstrapping and logistic regression models. RESULTS: The population-level prevalence of PrEP resistance in HIV-infectious individuals in 2008 was estimated to be 1.6, 0.9 and 4.1% for PrEP resistance definitions a, b and c, respectively. Prevalence in ART-experienced patients was highest, with negligible circulating resistance amongst ART-naïve individuals. The levels of resistance declined over the period of study. CONCLUSIONS: Our analysis indicates low levels of resistance to proposed PrEP drugs. The estimated PrEP resistance prevalence in UK HIV-infected MSM is towards the lower range of values used in simulation studies which have suggested that circulating PrEP drug resistance will have a negligible impact on PrEP efficacy at the population level.

[Scientific cooperation: limiting freedom of research by criminal law?]. / Wissenschaftliche Kooperation: Einschränkung der Freiheit der Forschung durch das Strafrecht?

Even after the strengthening by the law of 1997, the German criminal law regarding corruption is no obstacle for cooperation between medical research and industry. The injustice of corruption is an irregular exchange between performing one's duty and benefits. According to this, an enterprise may give funds to a scientist for research purposes if no counter performance exceeding the research is associated with this. However, it makes a difference if the scientist has to show his appreciation by influencing economic decisions of the clinic in favor of the enterprise. In case of such an injustice, it is, under the new law, no longer important if the benefit is destined for the scientist himself or for another person or organization. Thus, it is in the interest of both research and industry to avoid the suspicion of corruption in the first place. A prerequisite for this is the strict observance of the legal and administrative regulations concerning projects financed by third-party funds.