GLASGOW — Men who carry the BRCA2 gene mutation, which is linked to breast and ovarian cancer, are at risk of developing aggressive prostate cancer and so should undergo regular prostate-specific antigen (PSA) testing, suggest findings from a major study.
The IMPACT Study involved almost 3000 men from 20 countries who were recruited from families known to harbor carriers of mutations of the BRCA1 and BRCA2 genes and who underwent annual PSA testing and biopsy. The study was presented at the National Cancer Research Institute (NCRI) 2019 Cancer Conference.
The results, which were published recently in European Urology, show that men who carried the BRCA2 mutations were almost twice as likely to develop prostate cancer than were noncarriers. They were also diagnosed with prostate cancer at a younger age and had more clinically significant disease.
“Our research shows very clearly that men with the BRCA2 gene fault are at increased risk of aggressive prostate cancer and that regular PSA testing could go some way to improving early diagnosis and treatment,” commented lead author Ros Eeles, MD, PhD, professor of oncogenetics at the Institute of Cancer Research, London, the United Kingdom.
“We’re now calling on regulatory bodies to update guidance so men with BRCA2 defects can get regular PSA screening,” she said in a statement.
“Every man over the age of 40 who carries a mutation in the BRCA2 gene should be offered an annual PSA test as a way of giving men more control over their own health by identifying prostate cancer which is more aggressive and needs treatment,” she added.
Eeles was speaking here at the National Cancer Research Institute (NCRI) 2019 Cancer Conference.
She told the audience that moves are already underway to introduce “systematic PSA screening” for men who carry BRCA2 mutations, “and the European Association of Urology guidelines committee is currently considering this.”
Hashim U. Ahmed, MD, PhD, professor of urology, Imperial College London, and chair of the NCRI Prostate Group, told Medscape Medical News that the study “clearly shows that men at higher risk have more to gain from PSA screening in terms of detecting clinically relevant cancers earlier.
“We don’t yet know whether this would translate into a cancer survival benefit, but one would assume it would,” he said. “Targeted screening in this manner” is one way to “confer the benefits of screening” to those at greatest risk, he added.
Common Cancer, but How to Screen?
Eeles pointed out that prostate cancer is the “commonest solid cancer in men in the United Kingdom.” One in eight men are diagnosed with the disease during their lifetime.
However, screening for prostate cancer in healthy men using the PSA test has been controversial ― and is not routinely performed in the United Kingdom ― because it finds disease that may never become clinically significant. It does not distinguish between aggressive cancer that needs treatment and indolent lesions that may never develop further.
Eeles noted that a single PSA testing can result in biopsies being performed “in 11%” of men, but the majority (81%) of the cancers “you find will be Gleason 6; ie, they’ll be indolent.”
The question is how to find the 19% of men with aggressive tumors but at the same time “leave the indolent ones alone, because of the potential side effects of treatment,” which include impotence and incontinence.
Eeles said that previous studies, including one published recently, have indicated that “male carriers of mutations in the breast cancer predisposition genes,” including BRCA2, have an increased risk for prostate cancer, “and we know from other data that this prostate cancer is more likely to metastasize.”
Details of the IMPACT Results
The IMPACT Study involved men aged 40 to 69 years from families with known pathogenic BRCA1 or BRCA2 mutations. The patients were recruited during a 2-year period at 65 centers in 20 countries.
In all, 2932 individuals took part, including 919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers.
The median age at enrollment was 54 years, and 97% were white. Urinary symptoms were reported by 24%, and 36% had previously undergone at least one PSA test. A family history of prostate cancer was reported by 31%.
In four PSA screenings conducted over 3 years, 527 (17.9%) individuals were found to have a PSA level >3.0 ng/mL, and 112 cancers (3.8%) were diagnosed from 357 biopsies.
In the BRCA2 cohort, prostate cancer was diagnosed in 5.2% of carriers and in 3.0% of noncarriers. In the BRCA1 cohort, the respective percentages were 3.4% and 2.7%.
Analysis showed that the prostate cancer incidence rate was higher in BRCA2 carriers than noncarriers, at 19.4 vs 12.0 per 1000 person-years (P = .03).
Eeles said that among BRCA2 carriers, biopsies had a positive predictive value of 31%, compared with only 18% among noncarriers (P = .025).
BRCA2 carriers were diagnosed at a younger age than noncarriers, at 61 years vs 64 years (P = .04), and they were more likely to have clinically significant intermediate- or high-risk disease, at 77% vs 40% (P = .01).
Carriers were also more likely than noncarriers to have disease of Gleason score >6, at 62% vs 27%.
There were no significant differences in any of these parameters between BRCA1 carriers and noncarriers.
Recommend Regular Screening
In the post-presentation discussion, Eeles said that she and her colleagues had recommended to the European Association of Urology guidelines committee that BRCA2 carriers begin PSA screening at age 40 years.
The committee questioned this, but Eeles explained that “we’re suggesting starting at 40 because we do have a smattering of cases at the very wide end of the confidence intervals in BRCA2 carriers, at 41 and 42.
“Interestingly, we don’t see very old cases with BRCA2 mutations,” she added, “so it may be that you see this increased risk as a sort of bubble between the ages of about 45 and 67.”
In his comments on the study, Ahmed said that one caveat was that the participants “did not seem to have had an MRI scan” after the PSA level was found to be increased.
“This might have improved the outcomes further and might have improved the compliance in the control arm, where more men refused an immediate biopsy,” he suggested.
During the discussion, Eeles said that they are looking over their MRI data, because other research has found that some individuals who have a family history of the disease or other genetic mutations have “apparently normal MRIs.
“The worry is that these people don’t have the same MRI profile as you see in the general population, where you’d use MRI for screening, so you might end up with an algorithm in the future where you identify people at higher risk from their genetics.”
She added: “They’d go down a pathway of potentially even biopsy primarily, but at the moment, we just don’t have the data.”
At the time the researchers’ article was published, Shirley Hodgson, MD, professor of cancer genetics, St. George’s, University of London, described the findings as “important.”
“Because there is a significantly increased prior risk of prostate cancer in men who carry [BRCA2] mutations, the predictive value of a positive screening test result is increased, making the test more specific than when it is done in the general population, where the prior risk of the disease is lower,” she said in a statement.
James Green, MD, consultant urological surgeon at Barts Health NHS Trust, added: “This is a very welcome study, as many people would like to see if screening is more useful in a subgroup of the population who are at a higher risk of cancer.
“Whilst some screening methods might be impractical in the overall population, they might be acceptable in people with genetic markers that predispose them to cancer or in those with a strong family of history of a specific cancer.”
Green concluded: “Obviously, it is important to see if the higher diagnosis rate found in this well-designed study at a younger age leads to more people being cured, but hopefully it will.”
The study was funded in the United Kingdom by Cancer Research UK and by a donation to the ICR from the Ronald and Rita McAulay Foundation. It was further supported by the NIHR Biomedical Research Center at the Royal Marsden and the Institute of Cancer Research. Eeles has received speaking honoraria, including support from Janssen.
National Cancer Research Institute (NCRI) 2019 Cancer Conference: Abstract 2530, presented November 5, 2019.
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