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Testing for hereditary gene mutations in men with metastatic prostate cancer

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International guidelines recommend genetic tests for men with metastatic prostate cancer. The aim of these tests is to look for mutations in genes that may have contributed to the cancer. Unfortunately, these tests are expensive. They are not systematically performed in Australia. Would Australian men with metastatic prostate cancer benefit from genetic tests?

Changes to DNA are the underlying problem in cells that lead to cancer

Each cell in the human body carries a copy of that person’s DNA code. DNA is a long molecule that makes up most of the 46 chromosomes in each cell. It is a chain of repeated units. The sequence of these units holds the information used to make all the proteins and some other biological molecules in our body. A gene is a segment of DNA that holds the information for one biological molecule, such as one protein. So a mutation of the DNA in a gene could affect the protein produced from that gene’s information.

The entire DNA sequence in each cell of one person’s body is essentially identical. However, small changes (mutations) arise over time, as we get older. Some of these DNA mutations are dangerous. The underlying problem in all cancers is dangerous DNA mutations that cause some cells to grow in an uncontrolled manner. Usually, a number of these dangerous mutations need to build up in the one cell before it grows out of control. The human body fights back in more than one way. The DNA repair process involves a group of proteins that fix DNA mistakes. The immune system is also able to fight back, killing cells that are behaving abnormally. But sometimes cells with enough dangerous mutations escape these controls, becoming cancerous. A tumour forms from these uncontrolled cancer cells. Metastatic tumours form if some of these tumour cells detach and move to different areas. They move through the blood or lymph to other organs, where new versions of the original tumour start to grow.

Inherited risk from faulty genes

Each person has very similar DNA to other people. It’s what makes us different to other animals and life forms. But our DNA is not identical (except for identical twins). Some people inherit problems in their DNA from their ancestors. We know of some specific gene mutations, passed down through families, that put people at greater risk of getting cancer. These are different to the mutations that build up over time. Inherited mutations are already present from birth. They can also be passed on to children, putting them at greater risk as well.

DNA repair genes

Mutations in a person’s DNA can occur due to:

  1. Intrinsic factors Every time a cell divides into two cells, there is a chance a mistake will be introduced into the DNA. Over time, these can build up in the cell, causing problems. This is why age is such a strong risk factor for cancer.
  2. External factors causing DNA damage. Examples are radiation, alcohol, cigarette smoke, sunburn caused by UV light and asbestos.

To reduce the number of these DNA mistakes, the body has a DNA repair process. This is a group of proteins that recognise and repair these mistakes. The DNA segments that hold the information to make these proteins are called DNA repair genes.

Unfortunately, some people’s DNA repair machinery doesn’t work as well as it should. Inefficient DNA repair can increase a person’s risk of some cancers. Ironically, mutations in DNA repair genes themselves can become the inherited genes that put people at greater risk.

People with Lynch Syndrome have an increased risk of some cancers. These people have mutations in specific genes involved in a DNA repair process called mismatch repair. Mutations in Lynch Syndrome genes are sometimes found in men with prostate cancer.

Inherited gene mutations increase the risk of prostate cancer

Men with a family history of prostate cancer have an increased risk of getting this cancer. This is particularly so if the family member was diagnosed at a young age or had aggressive prostate cancer. A man with a close male relative with prostate cancer has over double the risk compared to other men. It’s believed that mutations in specific genes are passed down through these families, putting these men at risk. These mutations could be in DNA repair genes, or other genes that contribute to prostate cancer.

The gene most commonly associated with increased prostate cancer risk is BRCA2, a DNA repair gene. Mutations in this gene are estimated to occur in 5% to 9% of men with metastatic prostate cancer. A number of other hereditary gene mutations are found in men with metastatic prostate cancer. These are inherited mutations that are present from birth, not ones that have arisen in the prostate cells gradually over a lifetime.

Genetic tests for prostate cancer

Tests for gene mutations could benefit men with prostate cancer, or those at risk of prostate cancer. There are two main types of genetics tests:

1. Hereditary gene mutations: These tests look for gene variants that have been inherited from ancestors. They are present from birth, and exist in all cells in the body. Not every man who has a hereditary gene mutation will get prostate cancer. Similarly, prostate cancer occurs in many men for whom no known hereditary gene mutations can be found. But having mutations in these genes can put a man at greater risk.

Testing for hereditary gene mutations is relatively easy. A blood sample or similar sample of tissue is taken. This is sent to a laboratory to have the DNA sequence of hereditary genes analysed. Unfortunately, these tests are expensive.

These tests can be done for men who don’t have prostate cancer, to ask if they are at greater risk. Alternatively, the results can also be useful for men who have prostate cancer, to help guide treatment choices. The main subject of this blog is genetic testing for men with metastatic prostate cancer.

2. Tumour gene mutations: It’s also possible to test for gene mutations that have arisen in the tumours. These would be mutations in the tumour cells that are not present in the rest of the body. This type of test needs a sample of the tumour. These samples can be taken after prostate surgery, or even during a biopsy. The Oncotype Dx test is used by some Australian men with prostate cancer. It tests 17 genes from prostate biopsies. The results are turned into an overall score that predicts the “risk of a favourable outcome”. This test is useful for men with localised prostate cancer to help predict the chances that it could spread. This may help patients and doctors to decide between treatment or active surveillance. The Oncotype Dx test is available in Australia, but there is no rebate, so expect a cost of approximately $4,500.

Hereditary gene tests for men with metastatic prostate cancer

When a man is diagnosed with metastatic prostate cancer, having tests to look for mutations in hereditary genes associated with prostate cancer can be useful. There are two reasons for this. Firstly, the results of the test may help guide treatment decisions. Secondly, if mutations are found, this information can be valuable to other family members who may wish to learn about their own risks.

If the test finds a mutation in a hereditary gene associated with prostate cancer, this could help guide treatment decisions. But this will only happen if a known mutation is found. For instance, if a man has a mutation in a BRCA gene, there is evidence that they would benefit from receiving platinum chemotherapy (such as carboplatin).

Men with metastatic prostate cancer who have BRCA mutations might also benefit from drugs that target DNA repair problems, called PARP inhibitors. Olaparib (Lynparza) is an example of a PARP inhibitor that is used by women with ovarian cancer, or people with breast cancer. It’s prescribed to people who have a known BRCA mutation. Unfortunately, there are no PARP inhibitors approved for prostate cancer, as phase 3 trials showing their benefit are not yet published. However, it’s possible to join clinical trials testing PARP inhibitors. Some Australian men with metastatic prostate cancer who have BRCA mutations join these trials.

Another possible outcome of genetic tests for men with metastatic prostate cancer is to find mutations in Lynch Syndrome genes. These men might benefit from treatment with immunotherapies, such as the drug Keytruda.

Hereditary genetic testing in Australia

International guidelines recommend the use of tests for hereditary genes by men with metastatic prostate cancer. The National Comprehensive Cancer Network (NCCN) in the US makes recommendations for testing genes such as BRCA2 and ATM. They recommend these tests for all men with prostate cancer if they have high-risk or very high-risk disease, metastatic disease, positive lymph nodes, or a family history of prostate cancer. There are no such guidelines in Australia.

Unfortunately, only a subset of Australian men with metastatic prostate cancer have these tests. The cost of these tests is not reimbursed for men with prostate cancer, so they can be quite expensive. Australian laboratories charge roughly $750 per test. Fortunately, they can be done more cheaply if samples are sent overseas.

Would Australian men with metastatic prostate cancer benefit from hereditary gene testing?

As a first step to answering this question, a team from St Vincent’s Hospital in Sydney has asked how often these tests are used and what impact the results have. The results of this study have now been published in the Asia Pacific Journal of Clinical Oncology.

The St Vincent’s team reviewed the results of genetic testing for 100 men at their clinic. These men had metastatic prostate cancer and received testing between 2016 and 2018. They were tested for mutations in a minimum of 14 genes associated with prostate cancer. Some had additional testing for other genes, such as genes associated with Lynch Syndrome.

The results of genetic tests are not always straightforward. There are hundreds of possible mutations for each gene. Some are known to contribute to cancer. Some are suspected to contribute to cancer. For others, the consequences are unknown.

Of the 100 patients in this study, 9% had mutations that are known to contribute to prostate cancer. Two had mutations that are suspected to contribute to prostate cancer. 15% of the men had gene mutations of unknown consequences. These proportions are similar to results from international studies. The researchers also observed that most of the dangerous mutations were present in men who were 60 years old or under.

Did the genetic tests help these men? A much larger study is necessary to ask whether these genetics tests can change outcomes. But we do know that 2 of these men were subsequently enrolled into clinical trials testing PARP inhibitor drugs.

One of the drawbacks of this study was that the 100 men were mostly Caucasian. Different ethnic groups often have considerable differences in the genes they carry. Therefore, the results of this study are mostly applicable to Caucasian men in Australia. A more comprehensive study is needed to examine genetic testing for the wide range of different people living in Australia. 

 

If genetic testing by men with metastatic prostate cancer was widespread, this would create a wonderful resource for researchers (assuming that access to the data is possible). If precision medicine is to become a reality, we need to know how to select the most appropriate treatment for each patient. This will only come from research involving lots of men. Data that link treatments outcomes to genetics and other clinical markers would be useful in guiding treatment choices, making precision medicine possible.

 

Australian men with metastatic prostate cancer wishing to have genetic testing should discuss this with their specialists. Any genetic testing would ideally be accompanied by specialist genetic counselling to discuss the consequences of knowing this information. For example, knowing that you have a mutation that can cause cancer means that you know your children have a high chance of also having this mutation. There are many ethical and privacy issues that need to be considered. There are also health insurance issues that need to be considered. Counselling is available from genetic counsellors, as well as medical specialists with additional genetics training (called genetics specialists).

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