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Updated: 1 hour 48 min ago

New 'iClusters' identify five subtypes of prostate cancer

Fri, 2015-07-31 06:00

"Scientists have identified five types of prostate cancer, each with a distinct genetic signature," BBC News reports. The hope is that recognising the genetic signature of a specific cancer could lead to targeted treatments, as is the case with some types of breast cancer.

By analysing the DNA of prostate cancer cells from 259 men, researchers identified five distinct prostate cancer subgroups. Called "iClusters", the subgroups described the genetic characteristics of the tumour and gave clues about how it might behave in the future.

In the future doctors might be able to use the iClusters to decide the best treatment for each man. However, they are not yet ready to be used in hospitals to influence treatment decisions.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge in collaboration with academic institutions in Sweden, Norway and Belfast.

It was funded by a large number of academic and charity medical research funders, including the National Institute for Health Research, Cancer Research UK, and the Swedish Cancer Society.

The study was published in the peer-reviewed medical journal EBioMedicine.

The BBC's article was balanced and accurate. It quoted researcher Dr Alastair Lamb, who said: "These findings could help doctors decide on the best course of treatment for each individual patient, based on the characteristics of their tumour."

He also cautioned there were still many questions to be ironed out, including whether the technique could be used routinely in hospitals. 

What kind of research was this?

This was a genetic study seeking to identify subgroups of prostate cancer. Prostate cancer is the most common cancer in men in the UK (not counting non-melanoma skin cancer), with more than 40,000 new cases diagnosed every year.

The cause remains unknown, and some cases of prostate cancer are more aggressive than others. Currently, treatment decisions and prognosis are based on the size and type of the tumour, whether it has spread, and the level of prostate-specific antigen (PSA) in the blood. PSA is a protein produced by the prostate.

In this study, the researchers wanted to see if the characteristics and behaviour of prostate cancers could be predicted by particular DNA errors.

Some countries use PSA to screen asymptomatic men for prostate cancer. But current opinion in the UK is this is not accurate enough. Inaccuracy could lead to many unnecessary operations in healthy men that can in turn lead to life-impacting complications, such as urinary incontinence and impotence.

Understanding the genetics and behaviour of cancer could be fundamental to improving the way we treat the disease in the future. 

What did the research involve?

DNA data from the prostate cancer cells of 259 men were number-crunched to produce five distinct subgroups, termed "iClusters". These not only described the tumour's DNA characteristics, but to some degree predicted their future clinical behaviour.

In total, the researchers studied 482 tumour samples from 259 men with primary prostate cancer. They produced the initial five subgroups using data from 156 men from a Cambridge database. To validate the findings, they repeated the exercise in a further 103 men from a Stockholm database.

The team also had data on tumour progression, including six-monthly PSA tests and cancer staging. The researchers didn't have survival information, so instead used "biochemical relapse" to predict future clinical behaviour. Biochemical relapse was defined as a PSA level above 0.2ng/ml.

The number-crunching involved integrating data on the number of copies of genes associated with prostate cancer (copy number alterations) and genetic points linked to changes in gene expression (known as array transcriptomics). This integrated approach is the origin of the "i" in iCluster. 

What were the basic results?

The study identified five separate patient subgroups with distinct genomic alterations and expression profiles, based on 100 discriminating genes. These subgroups consistently predicted biochemical relapse and were further validated in a third cohort with long-term follow-up.

The discriminating genes included six previously associated with prostate cancer (MAP3K7, MELK, RCBTB2, ELAC2, TPD52, ZBTB4), but also 94 not previously linked to the disease.

The study said the subset of the 100 genes outperformed established clinical predictors of poor prognosis (PSA, Gleason score), as well as previously published gene signatures.

How did the researchers interpret the results?

The researchers said the five profiles could be used for the early detection of aggressive cases of prostate cancer in a clinical setting, and inform treatment decisions.

They said: "Our findings are clinically significant because they will assist urologists in recommending different treatment approaches for those men who are classified as being in low, intermediate or high-risk categories according to conventional clinical criteria."

Conclusion

Using DNA analysis, this study identified five subgroups (iClusters) of prostate cancer. A large portion of the iCluster-discriminating genes were not previously known to be linked to prostate cancer – an interesting finding in itself. The hope is the iClusters might help doctors treat the disease better based on their specific genetic signature.

However, this study focused on developing reliable subgroups. It did not look at whether the groups improved treatment, disease progression or death rates from prostate cancer. This research is yet to be carried out.

One of the main limitations of the research is it used biochemical relapse to estimate survival. This may not be accurate and reduces the ability of the iClusters to predict future survival at this stage.

Dr Alastair Lamb, quoted by BBC Online, said: "The next step is to confirm these results in bigger studies and drill down into the molecular 'nuts and bolts' of each specific prostate cancer type."

Also on BBC Online, Dr Iain Frame, of Prostate Cancer UK, said: "For men to truly benefit from these findings, it is now vital that the research community comes together to confirm the most efficient methods for testing for different types of prostate cancer that can be brought to the clinic."

Links To The Headlines

Prostate cancer: Five types 'found'. BBC News, July 30 2015

Prostate cancer could actually be five different diseases, say scientists. The Independent, July 30 2015

'Five types' of prostate cancer identified. ITV News, July 30 2015

Scientists discover there are five kinds of prostate cancer: Treatment set to be transformed by findings that allow doctors to distinguish deadliest tumours. Mail Online, July 30 2015

Links To Science

Ross-Adams, Lamb AD, Dunning MJ, et al. Integration of copy number and transcriptomics provides risk stratification in prostate cancer: A discovery and validation cohort study. EBioMedicine. Published online July 30 2015

Categories: News

Can the so-called 'male menopause' be treated with HRT?

Thu, 2015-07-30 07:00

"New research suggests that testosterone deficiency in older men is much more prevalent than current screening methods suggest, and that more men would benefit from hormone treatment," The Daily Telegraph reports.

The male menopause, which remains controversial, is said to be a syndrome of associated symptoms linked to the fall of testosterone, which include:

The research behind the headlines involved more than 2,000 men given trials of testosterone therapy after attending private Men's Health clinics in the UK.

The men had an average age of 54, though some were aged 90. All the men reported symptoms associated with the so-called male menopause. Most (83%) had testosterone levels that would be considered to be in the normal range, but all were given trials of testosterone therapy.

The men reported a reduction in symptoms with treatment. However, there are risks associated with testosterone therapy, including an increased risk of prostate cancer and blood clots.

The study was an audit of men attending a clinic, so there was no control group. This and other factors mean the study's results are less reliable: a randomised controlled trial would have made the research more trustworthy.

It remains to be seen whether the benefits of testosterone therapy outweigh the risks for men currently considered to have testosterone levels within the normal range, and further studies are needed. 

Where did the story come from?

The study was carried out by researchers from the Centre for Men's Health and University College Hospital, both in London, and Edith Cowan University in Australia.

Funding was not reported, but one of the three authors works for a private Men's Health clinic. The clinic offers treatments for male menopause, erectile dysfunction and prostate health – this represents a potential financial conflict of interest.

The study was published in the peer-reviewed journal The Aging Male on an open-access basis. The research is available to read for free online.

Headlines such as "Academics find the male menopause is real" from the Daily Mail are simply not true. This study was an audit of men prescribed testosterone after reporting symptoms such as difficulty getting an erection. This type of study cannot prove whether the male menopause is real or not.

Reassuringly, all of the UK media outlets that covered the study made it clear the implications of this research have been disputed by other experts.

Most sources quoted Professor Frederick Wu of Manchester University, who disputed the claims made by this research. He said, "In my opinion, this publication is not only misleading, but potentially dangerous, particularly when the author calls for many more men to be treated, inappropriately, with testosterone." 

What kind of research was this?

This was a retrospective audit of men attending private Men's Health clinics in London, Edinburgh or Manchester since 1989 with symptoms of low testosterone.

This type of study can provide an insight into whether testosterone replacement provides symptom relief, but cannot prove cause and effect.

A prospective, double-blinded randomised controlled trial would be required to prove a causal relationship, as this eliminates potential biases and confounding factors

What did the research involve?

The researchers reviewed the medical notes of 2,693 men who had attended private Men's Health clinics since 1989. Their symptoms, reported to be present for around three to five years before attending the clinics, included:

  • loss of libido
  • low energy
  • difficulty achieving and maintaining an erection
  • loss of morning erections
  • night sweats
  • joint pains
  • depression
  • irritability
  • impaired memory

The clinics diagnosed the majority of the men (2,247) with inadequate testosterone levels based on their symptoms alone: diagnosis was not based on measured testosterone levels.

The researchers said many men had been denied treatment before because their testosterone levels were in the normal range. This study questions the reliability of these tests.

All of the men diagnosed with low testosterone levels based on symptoms alone were offered testosterone therapy in different forms. These included:

  • pellet implants
  • oral testosterone
  • testosterone scrotal cream
  • scrotal gel

A symptom checklist called the Andropause Checklist assessed changes in symptoms before and during treatment. It uses 20 questions to derive a score from 0 to 80. In this study, a score of less than 10 was considered normal and was the target for treatment. 

What were the basic results?

The average age of the men was 54, with a range from 24 to 90. The average length of follow-up to assess symptoms and testosterone levels was one to two years after treatment. Treatment lasted from 3 to 12 years depending on the testosterone delivery (implant, gel, pill or cream).

Symptomatic relief – defined as a symptom score of less than 10 on a 0 to 80 scale – was achieved for all testosterone therapies two years into treatment.

Some treatments led to symptomatic relief within a year. Men with more severe symptoms were less likely to respond well to the testosterone therapy.

None of the men were reported to have an increased prostate after testosterone treatment, but the average follow-up was just one year.

An unreported proportion of the men had an increased number of red blood cells (polycythaemia) – a known side effect of testosterone treatment that increases the risk of blood clots. These men had to be treated for this by having blood taken regularly to reduce the number back to safe levels.  

How did the researchers interpret the results?

The researchers concluded that, "With appropriate and necessary monitoring of safety parameters, testosterone treatment appears safe and economic.

"Many men who could benefit in terms of symptom relief, with improvement in related clinical conditions and prevention of the long-term effects of testosterone deficiency, may remain untreated because of excessive reliance on laboratory measures of androgens for diagnosis and treatment alongside unwarranted safety concerns." 

Conclusion

This study found that offering men testosterone when they reported symptoms usually described by men with low testosterone caused a reduction in their symptoms. This was despite 83% of the men having testosterone levels considered to be in the normal range, above 10nmol/l.

The authors say that treating people according to symptoms should be more important than basing it on testosterone blood levels alone. They say these blood levels may be inaccurate, and some individuals may naturally need higher levels of testosterone than others. This is an interesting concept worthy of further robust study.

However, there are potentially serious side effects reported with testosterone therapy, and this study does not address these risks or provide evidence that more people should be treated.

This study's findings have many limitations:

  • Because of the nature of the study, there was no placebo group to act as a control.
  • The study was retrospective, which is a less reliable type of study than prospective trials.
  • The men did not have a laboratory-confirmed diagnosis of low testosterone, and the research relied on self-reported symptoms. The authors say the men's blood results may have been in the normal range for their age, but this may be lower than their individual level used to be. While this is a plausible conclusion, it is not backed by the evidence – the study did not measure each man's testosterone levels when they had no symptoms. Additionally, guidelines recommend that men are only treated if their testosterone level is below 10nmol/l, which was only the case for 17% of these men. Some had four times this cut-off, with levels of up to 40nmol/l.
  • All men were advised to make lifestyle changes, including reducing their stress levels, alcohol intake and weight if necessary, and increasing how much exercise they did, which could have influenced the results.
  • Other interventions were also started where necessary, including treatment for high blood pressure, high cholesterol and diabetes, which may also have affected the results.
  • The authors concluded that testosterone is a safe treatment, saying they have treated men in this way over the course of 25 years and have not seen known problems such as increased prostate size or blood clots. However, the average length of follow-up in this study was just one year.

The US Food and Drug Administration (FDA) issued a warning in 2014 about the increased risk of blood clots with the use of testosterone replacement. They only recommend that testosterone is prescribed for men who do not produce testosterone or who have low levels as a result of a medical condition that requires treatment, such as chemotherapy.

In the UK there are no official NHS guidelines, but the Society for Endocrinology recommends that male patients are treated on a case-by-case basis, depending on their symptoms.

If you suffer from the symptoms described above, it may be worth seeing your GP – testosterone replacement therapy is effective for men who are found to have low testosterone levels.

It remains to be seen whether the benefits of testosterone therapy would outweigh the risks for men currently considered to have testosterone levels within the normal range.

Many problems with issues such as erectile dysfunction and loss of libido are often the result of psychological, rather than physical, issues. It may be unwise to seek out hormonal treatments without first speaking to a sex therapist or a similar type of counsellor. The College of Sexual and Relationship Therapists has contact details for accredited therapists.  

Links To The Headlines

Is the 'manopause' more widespread than we thought? The Daily Telegraph, July 30 2015

Male menopause is real, claims controversial new study. The Independent, July 30 2015

Could testosterone HRT help treat the male menopause: Therapy should be provided as men also suffer hot flushes and low libido once they pass 50. Mail Online, July 30 2015

Links To Science

Carruthers M, Cathcart P, Feneley MR. Evolution of testosterone treatment over 25 years: symptom responses, endocrine profiles and cardiovascular changes. The Aging Male. Published online July 28 2015

Categories: News