BRCA1 Contribution to Prostate Cancer Called Into Question

Mutations in BRCA1 do not appear to contribute significantly to the risk of prostate cancer progression, according to DNA test results from 450 prostate cancer specimens.

Test results for all of the specimens (localized and metastatic disease) revealed germline BRCA1 pathogenic variants in two (0.44%) cases as compared with 6% for germline BRCA2 variants and 1.8% for germline ATM variants. One of the BRCA variants occurred along with an ATM mutation. In a subset of 280 patients with metastatic disease, one patient had a somatic BRCA1 pathogenic variant, as compared with somatic BRCA2 variants in 4% and somatic ATM variants in 2.7%. Additionally, 6% of the 280 patients had germline BRCA2 variants.

The findings suggest that tumors associated with a germline BRCA1 variant may not be driven by homologous repair deficiency and therefore may not respond to treatment with PARP inhibitors, reported D. Gareth Evans, MD, of the Manchester Academic Health Science Centre in England, and co-authors in BMJ Oncology.

“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,” the authors wrote. “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.”

In an accompanying editorial, Fumihiko Urabe, MD, PhD, of the Jikei University School of Medicine in Minato, Japan, and Kosuke Takemura, MD, PhD, of the Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, suggested that current treatment guidelines for prostate cancer might need to be revisited in light of the findings, noting that they “reinforce the role of BRCA2 and ATM as key determinants of aggressive prostate cancer phenotypes.”

“The limited involvement of BRCA1 suggests that tumors harboring BRCA1 variants may not rely on homologous repair deficiency, potentially limiting their responsiveness to PARP-based therapies,” they added.

Emmanuel Antonarakis, MD, of the University of Minnesota in Minneapolis, told MedPage Today that the findings are consistent with accumulating data that show that the impact of BRCA1 mutations on prognosis and PARP inhibitor sensitivity in prostate cancer is very different from the impact of BRCA2 mutations.

“This is distinct from other BRCA-associated cancers where BRCA1 and BRCA2 defects have similar risk profiles and also result in comparable sensitivity to PARP inhibitors,” Antonarakis said.

“Five years ago, our group was the first to propose that BRCA1 and BRCA2 mutations should be considered distinctly in prostate cancer patients, especially with respect to PARP inhibitor sensitivity,” he continued. “While BRCA2-mutated advanced prostate cancers are associated with a 50-60% response rate and a progression-free survival of 9-10 months with PARP inhibitor treatment, BRCA1-mutated prostate cancers only obtain a 20-30% response rate with a progression-free survival of only 3-4 months.”

Thus, mutations in BRCA1 and BRCA2 should not be lumped together in this disease as is commonly done for patients with breast/ovarian and pancreatic cancers, Antonarakis added.

Germline BRCA2 pathogenic variants cause about 4% of prostate cancers, and other homologous repair genes — BRCA1, ATM, PALB2, and Lynch syndrome genes — also have a role, but their relative contributions to risk are less established, Evans and co-authors noted in their introduction.

To take a closer look at homologous repair genes’ contribution to prostate cancer, the investigators reviewed results of germline and somatic DNA testing from 450 patients with localized or metastatic prostate cancer during 2022 to 2024, primarily in Northwest England. The study population comprised 166 patients who had germline testing, 280 who had somatic testing, and four patients who had both.

Overall, test results for the 450 patients revealed 27 germline BRCA2 pathogenic variants, two germline BRCA1 variants, and six (of 328 evaluable patients) with germline ATM variants. Additionally, one patient had a germline PALB2 variant, and CHEK2, Lynch syndrome, and RAD51C/D appeared in none of the tested specimens.

In the 280 patients with metastatic disease, somatic testing showed that 31 (11.1%) had BRCA2 variants, of which 16 (5.7%) were confirmed germline and 11 (4%) were confirmed somatic. Of 263 evaluable tumor samples, 16 (6.1%) had an ATM variant, five of which were germline, seven somatic, and four unconfirmed. Test results also showed somatic CDK12 variants in nine of 220 evaluable specimens, including two with BRCA2 variants.

The authors acknowledged several limitations to the study, including an inability to classify all variants as somatic or germline, as well as a high failure rate for somatic testing (45.4% of samples). In addition, the study was not a systematic screening of all men with prostate cancer, which limited the ability to calculate case indices for de novo hormone-sensitive metastatic disease or localized prostate cancer.

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