Does hormone therapy make prostate cancer worse?

[Wendy_Winnall]

Recent news articles have reported that “Hormone therapy can make prostate cancer worse”. They refer to a new study that asked how hormone therapy can change prostate cancer, making it more aggressive and likely to spread. Is it time to throw away the hormone therapy drugs? No it’s not. But this new study sheds some light on how these changes occur and takes us closer to a test that will help determine who is at risk.

By reading the headlines of recent articles on the internet, you’d be forgiven for thinking that hormone therapy doesn’t work. Press release headlines have told us that “Hormone therapy can make prostate cancer worse” and “Treating prostate cancer with hormone therapy could be risky”. Reading past these headlines; the article they refer to has used experiments with mice to understand how hormone therapy can make prostate cancer more aggressive.

Does hormone therapy make prostate cancer worse? Hormone therapy slows the progression of advanced prostate cancer. But for some men, while it slows progression, these prostate tumours become more aggressive once they become resistant to the drugs.

Hormone therapy, also known as androgen deprivation therapy (ADT) is an effective treatment for advanced prostate cancer. In some cases, these cancers can change into a rarer type of prostate cancer called neuroendocrine. This more aggressive form of prostate cancer grow and spreads rapidly. It’s believed that, in some men, hormone therapy can contribute to the change into neuroendocrine prostate cancer. We don’t yet know what would be the fate of these men if they had not taken ADT. But we do know from trials with many different men, that ADT remains an effective treatment that halts progression of advanced prostate cancer. On average, ADT vastly extends to lives of men with prostate cancer.

Unfortunately, what happens on average, does not happen to all men. Some men won’t benefit as much from ADT as others. It’s important to understand why this is and how to identify who is at risk.

Hormone therapy (ADT) for advanced prostate cancer

For over 60 years, ADT has been used as a treatment for advanced prostate cancer. It was the first effective treatment for this disease. At the start of the 20^th century, there was no early detection of prostate cancer. Men were usually diagnosed once symptoms became apparent. So most of these men were diagnosed at a late stage, with prostate cancer that had spread outside of the prostate gland (advanced prostate cancer). Although prostate surgery was developed in the early 1900s, it was rarely used to treat prostate cancer. Early prostate surgery had very debilitating side effects and did nothing to stop men dying of this disease at the time. Surgery these days is a very effective treatment – because the cancer is usually diagnosed at an early stage, before it has spread.

In 1941, treatments that inhibited the actions of testosterone started to be used for prostate cancer. It was clear that inhibiting testosterone could slow the growth of advanced prostate cancer. This was the first treatment that could help improve survival times and temporarily relieve symptoms for men with prostate cancer. 60 years later, we have a range of different drugs that inhibit testosterone and other male hormones as treatments for prostate cancer. That’s the good news. The bad news is that although these drugs slow prostate cancer progression, they don’t cure metastatic prostate cancer. ADT drugs also have many difficult side effects.

Hormone therapy can drive a change into neuroendocrine prostate cancer

There are different types of prostate cancer. These cancers have different characteristics because they develop from different types of cells. The most common form of prostate cancer is called adenocarcinoma. Adenocarcinoma develops from two different types of glandular cells of the prostate, called basal cells and luminal cells. There are a number of other different types of prostate cancer that are less common. Neuroendocrine prostate cancer is an uncommon form of this cancer that is difficult to treat. Neuroendocrine cancer cells develop from normal (non-cancerous) neuroendocrine cells that are found in the prostate gland. The exact role of normal neuroendocrine cells the prostate is unknown, but they have features similar to nerve cells and cells that secrete hormones.

Prostate tumours sometimes consist entirely of neuroendocrine cancer cells, but these are quite rare. Pure neuroendocrine tumours are very aggressive and resistant to most conventional treatments for prostate cancer.

It’s more common to find prostate tumours that are a mix of adenocarcinoma cells and neuroendocrine cells. Tumours that were originally classed as adenocarcinomas can develop neuroendocrine features when they become resistant to ADT or other treatments. In other words, some metastatic prostate cancers start behaving more like neuroendocrine tumours than adenocarcinomas. It’s believed that in these cases, the ADT has contributed to the cancer changing its characteristics.

How does hormone therapy change prostate cancer?

A new study has asked what type of changes happen at the cellular level, during this transformation. The paper was published in one of the top journals, The Journal of Clinical Investigation. The researchers were a team from the Cedars-Sinai Medical Center in California, US. They were led by Prof Neil Bhowmick who specialises in research on the ways that advanced prostate cancer cells interact with the normal body cells around them.

Prof Bhowmick’s research group asked how the prostate cancer cells interacted with the non-cancerous cells near the tumour. They performed their experiments both in mice and cells grown in the laboratory, using samples of cells from human prostates. The researchers found that the tumour cells were affecting the normal prostate cells next to them. The prostate cancer cells caused excess production of glutamine in the cells next door. This biological molecule is one of the building blocks of proteins. Cells close to the prostate tumour were turned into "factories" that supplied glutamine as fuel for the cancer cells.

Glutamine was not just an energy source for some for prostate cancers. It could trigger a change to their cellular nature. Excess glutamine led to a “reprogramming event” that caused changes in the prostate cancer cells, driving them towards a neuroendocrine form. It also drove resistance of the tumours to ADT.

The researchers then examined the levels of glutamine in the blood of patients. Men with prostate cancer that responded to ADT had lower levels of glutamine than men whose tumours were resistant to ADT. This higher level of glutamine could be contributing to disease progression. This is very useful information and may help in designing future treatments.

It might be tempting to avoid glutamine to try to reduce the chances of advanced prostate cancer changing into a neuroendocrine type. However, glutamine is an essential part of every protein in every cell. So we can’t starve ourselves of glutamine. Glutamine can also be produced in the body if it’s levels run low. So eating a low-glutamine diet, if such a thing were possible, is very unlikely to help treat advanced prostate cancer. But this study has helped to determine what changes occur in the surrounding cells to make extra glutamine. This points ways to intervene in this damaging process. It’s possible that a drug could be designed that could interfere with glutamine production by the cells next to the tumour. It’s also possible that a blood test for glutamine levels could be used to identify men at risk of developing neuroendocrine prostate cancer when taking ADT.