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Every month we collate a selection of the latest clinically-relevant research to help you keep up to date with the most important developments in the field of prostate cancer.

Articles have been selected based on impact factor of the journal, relevance to UK clinical practice and general interest. You may be able to access the full text from your Trust's library service or via ATHENS registration. Information from PubMed explains other ways to access full text articles. 

August 2015

Research round up from the clinic - top four articles from July 2015:

1. Docetaxel in combination with Hormone Therapy for men with advanced prostate cancer

Earlier this month results from a phase 3 clinical trial, the CHAARTED trial, were published in the New England Journal of Medicine. The study, by Sweeney et al., involved almost 800 men diagnosed with hormone-sensitive metastatic (advanced) prostate cancer. The trial assessed whether providing hormone therapy plus docetaxel chemotherapy would result in longer overall survival than with hormone-therapy alone. The authors reported men with advanced prostate cancer were found to live up to 13.6 months longer with docetaxel in addition to hormone therapy. The investigators also did additional sub-analysis of those with high-volume disease (where prostate cancer had spread to four or more locations in the body). In this subgroup, men who were given docetaxel in combination with hormone therapy had an even greater improvement in survival, living 17 months longer than those given hormone therapy alone. The authors concluded that six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. Prostate Cancer UK has some more information on the article here.

2. Neutrophil Count May Be Associated with Survival in Localized Prostate Cancer

Researchers in Montreal, Canada conducted a retrospective study of over 1,700 patients with localised prostate cancer treated with definitive external beam radiotherapy or brachytherapy. The study was designed to explore the influence of inflammatory markers on prostate cancer recurrence and survival after radiotherapy for patients with localised prostate cancer. The authors, Bahig et al., reported comorbidities other than cardiac history, and measurable peripheral plod markers, such as lymphocytes and neutrophil to lymphocyte ratio, were not associated with prostate cancer mortality. Conversely, neutrophil count, cardiac history, age, and Cancer of the Prostate Risk Assessment (CAPRA) score were associated with mortality. In addition, on multivariate analysis neutrophil count, age and Cancer of the Prostate Risk Assessment (CAPRA) score were also all independent predictors of overall survival. An association was not found for neutrophil count and biochemical recurrence free survival. In conclusion the authors stated neutrophil count, as a possible marker of systemic inflammation, appears to be an independent prognostic factor for overall mortality in localized prostate cancer. However, a validation cohort is needed to corroborate the results the group reported.

3. Lycopene intake and risk of prostate cancer – is there a relationship?

Chen et al., conducted a systematic review and meta-analysis looking at whether lycopene was inversely related to prostate cancer. They identified 26 studies (1999-2014), including over 17,000 cases of prostate cancer, which were analysed as part of the review. The review concluded lycopene could significantly reduce the incidence of prostate cancer with a linear dose-response effect for its intake, and nonlinear dose–response effect for circulating lycopene concentration. The authors also reported an inverse association between lycopene consumption and the risk of prostate cancer incidence for all studies, there was a trend for higher lycopene levels to reduce the incidence of prostate cancer. However, after removing one study in a sensitivity analysis and performing a sub-analysis from the remaining high-quality studies, higher lycopene consumption was shown to significantly lower prostate cancer risk. Limitations of the studies reviewed were also noted. Due to lycopene intake being assessed by food frequency questionnaires in different countries, and uses of different classifications of lycopene between studies, errors in measurement were inevitable.. In addition, the authors also noted not all studies adjusted for family history, which could impact the association between lycopene and prostate cancer risk. Furthermore, they also highlighted the need for further studies to determine the mechanism by which lycopene may act. Information from an analysis of global research on how diet, nutrition, physical activity and weight affect prostate cancer risk and survival from the World Cancer research Fund can be found here.

4. Adverse effects of common treatments for Benign Prostate Hyperplasia

A recent review by Traish et al., looked at data currently available and examined the potential role of 5α-reductase inhibitors (5α-RIs) therapy on the presence and persistence of adverse sexual side effects. Finasteride and Dutasteride are selective inhibitors of 5α-Rs, and are used as therapeutic agents for the treatment of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). They function by inhibiting the conversion of testosterone to 5α-dihydrotestosterone (5α-DHT) as well as several other critical steroid hormones. By reducing the concentration of 5α-DHT in the prostate, prostate volume decreases thus improving urinary flow. In this review the authors conclude that, in susceptible individuals, the use of finasteride and other 5α-R inhibitors is associated with a number of enduring sexual, mental and metabolic side effects, which can persist beyond the discontinuation of these therapies and profoundly compromise quality of life.

July 2015

Research round up from the clinic - top four articles from July 2015:

1. Could targeting the protein DNA-PKcs prevent the spread of prostate cancer?

In this study, Goodwin et al. aimed to determine the molecular basis of DNA-PKcs function and the contribution of DNA-PKcs-mediated transcriptional regulation on tumour phenotypes. The DNA-dependent protein kinase (DNA-PK) is composed of two units, including a catalytic subunit (DNA-PKcs) that plays an important role in the DNA damage response and maintenance of genomic stability. This research, which was carried out in the United States, involved mouse models and clinical analysis of tumour samples from 232 patients. Samples were obtained using a case-cohort study design to randomly sample 20% of patients for analysis, in addition to all in whom metastases developed, from a cohort of 1,010 high-risk men who underwent radical prostatectomy between 2000 and 2006.

The authors identified DNA-PKcs as a key contributor to metastatic progression, and the findings support a model wherein the transcriptional regulatory functions of DNA-PKcs induce a signalling program that drives tumour metastases and lethal disease. Dr Iain Frame, director of research at Prostate Cancer UK said “Getting to grips with how and why cancer cells spread around the body is one of the biggest challenges we face today. The answer to this question will allow us to not only predict which early stage prostate cancers may go on to spread and become dangerous, but also develop new treatments to stop the cells spreading in the first place. Although this research could provide us with some of the answers we desperately need, it's still early days. We look forward to further results of this trial and hope they lead to better ways to prevent and treat advanced prostate cancer.”

2. Are surveillance strategies effective for men with low-risk prostate cancer?

Many men diagnosed with localised, low-risk prostate cancer, which may not be lethal, undergo primary treatment with surgery or radiation. These treatments can affect health-related quality of life (HRQOL), including longstanding side effects such as erectile dysfunction and impaired urinary function. This review, by Filson and colleagues from UCLA in the United States, describes the current surveillance protocols (e.g. active surveillance and watchful waiting), and reviews the outcomes for each of these strategies in terms of cancer survival and quality of life. Additionally the review addresses the novel technologies such as prostate MRI and fusion biopsies that may prove beneficial for surveillance patients.

The authors concluded active surveillance and expectant management strategies can produce excellent long-term disease-specific survival and minimal morbidity for men with prostate cancer. Questions remain regarding both the identification of optimal candidates for surveillance, as well as understanding the ideal monitoring strategy. Despite increased adoption of expectant management, active surveillance still remains broadly underused and more data will be needed to clarify the factors contributing to the findings of the review at a population level.

3. Novel Biomarker Signature may predict aggressive prostate cancer in African-Americans

Researchers from the United States and Canada evaluated whether genetic factors could affect ethnic disparities in prostate cancer development and disease progression. The study looked at the ethnicity-specific expression of 20 prostate cancer-associated biomarkers in 154 African Americans and 243 European American patients. The researchers analysed these samples to find out which of the 20 validated genes—some of which initiate and some which drive cancer - were expressed in high or low quantities in the two populations of men. The authors identified a subtype which they called "triple negative prostate cancer," and defined as the absence or low levels of three genes called ERG, ETS, and SPINK1.

They reported African American men with high disease severity and risk of recurrence (this was calculated using a validated scoring system known as CAPRA-S) and more advanced Gleason grade disease at diagnosis were more likely to be triple negative when compared to European American men with a similar disease scores at diagnosis. In addition, the researchers also found other genes that were expressed at different levels in African American versus European American men. Further studies are already underway to validate the significance of this trend. The authors concluded that the subset of prostate cancer biomarkers they identified may explain in part the biologic contribution to ethnic disparity in prostate cancer outcomes between African American and European American men. In a clinical setting, it may suggest that some African American men with prostate cancer might have a better shot at survival if they are treated with a different approach than standard of care, however more research and investigation is required to refine the biomarkers that will capture these differences and develop approaches that help reduce the disparities in outcomes.

4. Black men are twice as likely to die from prostate cancer as white men

A study recently published in BMC Medicine, by researchers at Prostate Cancer UK and Public Health England, looked at the absolute risk figures to help men of different ethnicities better understand their risk of being diagnosed with, and dying from, prostate cancer. Previous research has estimated that a UK man’s lifetime risk of being diagnosed with prostate cancer is 1 in 8, and prostate cancer incidence rate data in England shows that Black men are significantly more likely, and Asian men significantly less likely, to be diagnosed with the disease compared to White men. The authors of this current study analysed prostate cancer incidence and mortality data of over 100,000 men, along with population and ethnicity figures from a combination of sources, to calculate the lifetime risk of being diagnosed with, and dying from, prostate cancer by ethnic group.

The study reported the lifetime risk of being diagnosed with prostate cancer is approximately 1 in 4 for Black men, 1 in 8 for white men and 1 in 13 for Asian men. In addition, the article reports the lifetime risk of dying from prostate cancer – approximately 1 in 12 for Black men, 1 in 24 for White men and 1 in 44 for Asian men. The authors conclude the findings should be used for targeted awareness-raising, but raise the fact that other risk factors can also affect an individual man’s risk of prostate cancer (including family history, weight and age). In addition, they recommend that further work is needed to understand the mechanisms behind the higher than average risk in Black men.

5. Prostate cancer is five different diseases

Cancer Research UK scientists have identified five distinct types of prostate cancer and found a way to distinguish between them. The study published at the end of July analysed 482 tumours and carried out integrated genomic profiling of 259 men with prostate cancer to identify gene sets that differentiated five subgroups of prostate cancer. The study then used these subgroups to help stratify risk and predict disease relapse. The authors highlighted that the study demonstrates the importance of integrated genomic analyses incorporating both benign and tumour tissue data in identifying molecular alterations, which may have a predictive of clinical outcome in independent patient cohorts. The study findings need to be confirmed in clinical trials with larger groups of men, but the authors concluded they could have important implications for how doctors treat prostate cancer in the future, by identifying tumours that are more likely to grow and spread aggressively through the body.

Dr Iain Frame, director of research at the Prostate Cancer UK said: "Developing the ability to tell a man which type of prostate cancer he has and which treatments it will respond to is hugely important if we are going to beat this disease. This research confirms just how crucial this approach is, while revealing that the disease and how we categorise its variations will be more complex than originally thought." Check out the science blog the five faces of prostate cancer? on the Cancer Research UK website for more information on what the research was about and what it means for men.

June 2015

Research round up from the clinic - top four articles from June 2015:

1. Cigarette smoking is associated with increased risk of biochemical recurrence following prostatectomy

For the first time, an international study led by MedUni Vienna and Basle University Hospital has provided evidence of a link between smoking and biochemical recurrence (BCR) of prostate cancer after prostatectomy. In a study of 6,538 patients, Rieken and colleagues showed a significant 63% and 80% increased risk of BCR in ex-smokers and current smokers, respectively, compared to ‘never smokers’. The research also showed that the negative impact of smoking on the risk of BCR is reduced to that of ‘never smokers’ after 10 years of not smoking.

2. Phase III trial shows adding docetaxel and estramustine to ADT improves relapse-free survival for high-risk localised prostate cancer patients

The GETUG-12 trial published results of the addition of docetaxel and estramustine to ADT, compared to ADT alone, in patients with non-metastatic high-risk localised disease. (Last month, we reported on the STAMPEDE trial results from ASCO 2015 which looked at metastatic patients – see here). In GETUG-12, Fizazi et al used the primary end point of ‘relapse-free survival’ which, after 8 years, was 62% in the men on ADT + docetaxel and estramustine, compared to 50% in the men on ADT alone. However, since this trial's inception in 2002, estramustine has fallen out of favour as a treatment for prostate cancer because of a lack of additive effects with docetaxel and its gastrointestinal toxic effects, and prostate-specific antigen endpoints are accorded less importance, limiting the generalisability of the results. At present, docetaxel should be reserved for metastatic disease either in the castration-sensitive setting, such as was assessed in CHAARTED and STAMPEDE, or for castration-resistant disease.

3. Scientists unveil the ‘Rosetta Stone’ of prostate cancer

An international team of scientists, led by the ICR in London, analysed the genetic codes of metastatic tumours from the bone, soft tissues, lymph nodes and liver of 150 patients with advanced prostate cancer. This enabled Robinson et al to produce a comprehensive genetic map of the mutations in prostate cancers that have spread round the body. The mutations found included some already known (e.g. in the BRCA1/2 genes) as well as previously undetected mutations in prostate cancer (eg in the PI3K and RAF gene families). They discovered that almost 90% of men with advanced prostate cancer carry genetic mutations in their tumours that could be targeted by either existing or new cancer drugs.

4. Increased prevalence of metabolic syndrome associated with ADT

Morote and colleagues conducted an observational prospective study involving 539 prostate cancer patients scheduled to receive three-month depot LHRH analogs for longer than 12 months. The authors examined the prevalence of full metabolic syndrome, assessed according to different definitions, and its components and found that at six and 12 months after ADT initiation there were significant increases in waist circumference, BMI, fasting glucose, triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterol. At 12 months there were significant increases in metabolic syndrome prevalence. The authors concluded that counselling patients on the prevention, early detection, and treatment of specific metabolic alterations is recommended.