Mutations in the BRCA1 gene that are either inherited (germline) or acquired (somatic) might not be key to the initiation of prostate cancer, as previously thought, suggests the first study of its kind, published online in the open access journal BMJ Oncology.
If confirmed in further studies, the findings suggest that it may be time to reassess current treatment with PARP (poly(ADP-ribose) polymerase) inhibitor drugs, which block the ability of cells, including cancer cells, to repair DNA damage, in men with BRCA1 genetic variants, say the researchers.
A linked editorial suggests that the findings pave the way for greater refinement of genetic testing and personalised treatment for men with prostate cancer.
Prostate cancer is the most common cancer in men, and genetic variants in DNA damage repair and response genes are known to have a role in disease progression.
For example, men with inherited or acquired mutations in BRCA2 or ATM genes are at heightened risk of aggressive disease and have worse outcomes than those who don't have these mutations, explain the researchers.
To try and quantify the contribution of inherited and acquired mutations in different DNA repair and response genes in men with prostate cancer, the researchers reviewed the genetic test results of 450 men with the disease in North West England between 2022 and 2024.
The men had either been tested for germline (166), somatic (280), or both types (4) of genetic variants of BRCA1, BRCA2, ATM, CDK12, and PALB2 genes, with a view to starting them on PARP inhibitor treatment.
In 340 cases, the men's cancer had spread elsewhere (metastasised). Their average age was 69, but ranged between 38 and 87.
Among those in this group who weren't tested, based on high risk—age or family history—at least 18 (just over 5%) had a germline BRCA2 variant, but only 1 had a germline BRCA1 (0.3%) variant. And of the 263 screened for germline ATM variants, 7(3%) tested positive.
Among the 124 undergoing germline testing based on high risk, their average age was 56 (range 34–77). Again, germline BRCA2 variation predominated, with 8 (8%) testing positive, but only one (less than 1%) testing positive for a germline BRCA1 variant.
Germline BRCA 1 and BRCA 2 test results were available for all 450 men. These revealed 27 germline BRCA2 variants (6%), but only 2 germline BRCA1 variants (0.5%), and one of these probably wasn't the driver as an ATM mutation was also present, note the researchers.
Six ATM germline variants were found among the 328 men tested for this genetic mutation. And among the 97 men tested for germline PALB2 variants just 1 was found in a man in his 70s with a strong family history of breast cancer.
Of those tested for CHEK2 (122), for Lynch (69), or for RAD51C/D (15) genetic mutations, none was found.
Somatic test results were available for 280 men whose cancer had spread elsewhere. Overall, 31 (11%) had an identifiable BRCA2 genetic variant. Of these, 16 (6%) were confirmed germline and 11 (4%) were confirmed somatic. Variant type was unclear in 4.
This indicates that BRCA2 variants, somatic and germline, have a major role in prostate cancer progression affecting at least 1 in 10 carriers with the disease, say the researchers.
BRCA1 variants, on the other hand, don't seem to be major contributors to disease initiation or progression, with only 1 somatic variant and 1 germline variant found in combination with a germline ATM variant in one case where the disease had spread elsewhere.
Both germline and somatic ATM mutations were also associated with disease spread as 16 out of the 263 (6%) tumour samples tested had an ATM genetic variant identified, 5 (2%) of which were germline, 7 (2.5%) of which were somatic, while 4 were indeterminate.
And the data suggest that somatic CDK12 and somatic and germline BRCA2 should no longer be considered mutually exclusive, as they have been previously.
The researchers acknowledge that only 217 tumour samples were tested for all genetic variants, and that they were unable to classify all those identified as either somatic or germline. And as the BRCA1 variant carriers were tested relatively recently, the longer term outcomes for these men aren't yet known, they point out.
"Even if there is a signal for non-metastatic prostate cancer in BRCA1, this may not justify PSA [prostate specific antigen] screening, given the high rates of overdiagnosis," say the researchers.
"It may be time, therefore, to question whether BRCA1 should be considered to be a prostate cancer predisposing gene, given its very low prevalence in the present study of somatic mutations," they suggest.
In a linked editorial, Drs Fumihiko Urabe and Kosuke Takemura, of, respectively, The Jikei University School of Medicine, Minato, Japan, and The Cancer Institute Hospital of JFCR, Tokyo, Japan agree that treatment options may need to be revised in light of the study findings.
"[They] reinforce the role of BRCA2 and ATM as key determinants of aggressive prostate cancer phenotypes. The limited involvement of BRCA1 suggests that tumours harbouring BRCA1 variants may not rely on homologous repair deficiency, potentially limiting their responsiveness to PARP [inhibitor]-based therapies," write the authors.
They add: "CDK12 mutations, previously considered mutually exclusive with BRCA2, were observed in conjunction with BRCA2 mutations, suggesting a potential for dual targeted therapies combining PARP [inhibitors] and immunotherapy."
And conferring the same potential for aggressive disease on both BRCA1 and BRCA2 is probably no longer appropriate, they suggest.
"Although many prior clinical studies have categorised BRCA1 and BRCA2 mutations together as a single group (BRCA1/2), this research leads to the conclusion that BRCA1 and BRCA2 should be analysed separately," they say.
"If post hoc analyses of previous clinical trials that grouped BRCA1/2 mutations reveal differing therapeutic effects, it may necessitate reevaluating the interpretation of BRCA1 and BRCA2 mutations in prostate cancer," they add.
Although further research in more diverse groups of patients is warranted, the study findings "pave the way for refining genetic testing strategies and personalised treatment approaches in prostate cancer," they conclude.
