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PSA testing for men with BRCA gene mutations

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Men who are carriers of BRCA2 gene mutations have a higher risk of being diagnosed with prostate cancer. This information provides an opportunity to catch prostate cancer early for these men. The IMPACT trial has tested whether PSA testing at a younger age is useful for men with BRCA gene mutations.

BRCA genes and DNA damage

BRCA genes were first discovered by breast cancer researchers. These two genes are called BRCA1 and BRCA2. Women with a family history of breast cancer can have blood tests to find out if they have BRCA gene mutations. Some women with these mutations choose to have surgical removal of their breasts to reduce their risk of breast cancer.

The two BRCA genes are used to make proteins involved in process called DNA repair. DNA repair helps to reverse DNA damage and protect from cancer. So when the genes involved in DNA repair have mutations that reduce their activity, the risk of cancer increases. People who carry mutations in BRCA genes are at higher risk of breast, ovary, prostate, colon and pancreatic cancer.

BRCA genes and prostate cancer risk

There is a well-established association between BRCA2 gene mutations and higher risk of prostate cancer. Depending on the study, the risk of getting prostate cancer by 65 years old is estimated to be 2.5 to 8.6 times higher for men with BRCA2 mutations compared to men without.

The story is not so straightforward for the BRCA1 gene. The association of BRCA1 mutations and prostate cancer is under debate. There seems to be a small increase in risk, but the clinical relevance of this is not well-defined.

The IMPACT study

A trial called IMPACT was designed to ask whether PSA testing for men with BRCA mutations will be useful for early detection of prostate cancer. IMPACT is a European study that has recruited men in multiple different countries. Men without a diagnosis of prostate cancer were recruited to this trial between 2005 and 2013. Results are now available for three years of screening for prostate cancer by these men.

The men joining the IMPACT trial were aged between 40 and 69 years old. They were invited into the trial through cancer genetics clinics from families with known BRCA1 or BRCA2 mutations. These mutations are passed down through families, but not everyone in the family will get the dangerous gene versions. A man who has one parent with a BRCA mutation has a 50% chance of inheriting this mutated gene. The IMPACT study recruitment strategy allowed inclusion of men with and without mutated BRCA genes.

919 men joining the study had BRCA1 mutations and 709 were non-carriers of BRCA1 mutations. 902 men had BRCA2 mutations, and 497 were BRCA2 non-carriers.

These men then underwent regular tests for prostate cancer. They had PSA tests at the start of the study, then each year for 3 years. The study is continuing and will report updated results after a further 5 years of screening. Men who had a PSA reading over 3.0 ng/ml went on to have a biopsy. Those with a negative result in the biopsy continued with PSA tests, whereas those with a prostate cancer diagnosis underwent treatment or active surveillance.

The first tests at the start of the study found that some of these men had prostate cancer. 7.7% of men had high PSA reading, with 2.4% found to have prostate cancer at the outset. It’s important to remember that this is a group of men with a family history of prostate cancer, therefore higher risk of getting prostate cancer than the average man.

After three years of screening, results from the IMPACT study showed:

  • Out of 3027 men, 527 had a high PSA test result, 357 had biopsies and 112 cancers were diagnosed (3.8% of the total).
  • BRCA2 group:2% of men with BRCA2 mutations were diagnosed with prostate cancer compared to 3.0% of non-carriers.
  • BRCA1 group:4% of men with BRCA1 mutations were diagnosed compare to 2.7 of men who didn’t carry BRCA1 mutations.

Men in the BRCA2 group had almost twice the risk of prostate cancer diagnosis from PSA testing compared to non-carriers. This was considered to be statistically and clinically significant. These men were diagnosed at a younger age. Their average age was 61, compared to 64 years old for non-carriers. Their prostate cancer was also more likely to be aggressive. 77% of men with BRCA2 mutations had intermediate or high-risk prostate cancer. These risks were higher than men without BRCA2 mutations; 40% of these men had intermediate or high-risk disease.

Men in the BRCA1 group had a slightly higher chance of being diagnosed, but this was not statistically significant in this study. This difference could have easily arisen by chance alone.

In summary, the IMPACT study has shown that annual PSA testing for men with BRCA2 gene mutations, but not BRCA1, is useful for detecting prostate cancer early. Men with BRCA2 mutations were diagnosed at an earlier age on average, and were more likely to have higher risk disease.

Limitations of the IMPACT study

One limitation of this study was that not all men with high PSA readings had the recommended biopsy. Men who had BRCA2 mutations were more likely to have a biopsy. It’s likely that a higher biopsy rate has been responsible for some of the increased diagnoses of prostate cancer for these men. However, this isn’t a major flaw, as it tells us how BRCA2 tests may affect men in reality. It’s rational to expect that men testing positive for BRCA2 mutations will be much more concerned about high PSA readings than other men. If we see more early diagnoses of aggressive cancer because of early testing, this will be a good outcome.

Another limitation of this study is that it started before having an MRI prior to biopsy became common. Since these scans have been subsidised in Australia last year, having an MRI after a high PSA score, prior to biopsy, has become a common approach to the diagnosis process. The IMPACT trial did not include MRI, as recruitment started before these tests became popular. Having an MRI before biopsy can rule out clinically significant prostate cancer. So the results of this study are not quite as relevant to the current situation in Australia as we’d like. In particular, we’d expect less men with high PSA finding that they don’t have prostate cancer after biopsy with the use of MRI. MRIs before biopsy help to reduce unnecessary biopsies in men without prostate cancer.

What does this mean for Australian men?

Men who have a family history of prostate cancer have a higher chance of getting this cancer. PCFA’s PSA testing guidelines recommend men with a family history of this disease consider starting PSA testing early. If you are aged 40 with a family history, talk to your GP about PSA testing for early detection of prostate cancer.

Men with a family history of prostate cancer may have gene alterations, such as BRCA2 mutations, that put them at higher risk of this cancer. If you have a family history of this disease and wish to know whether you have BRCA2 mutations, this can be determined using a simple test. However, there are many issues regarding genetic tests like these. 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 ethical and privacy issues that need to be considered. There are also health insurance issues that need to be considered. Men wishing to have genetic tests for genes such as BRCA2 are advised to discuss this at length with a genetic counsellor or a clinician who has specialist knowledge of genetic testing.

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