Study Uncovers Why BRCA2-mutant Prostate Tumors Are So Aggressive

Study Uncovers Why BRCA2-mutant Prostate Tumors Are So Aggressive

Men who carry mutations of the tumor-suppressor gene BRCA2 are at higher risk of developing prostate cancer, and chances are they will have a more aggressive form of the disease, but researchers have only now understood why this happens.

A recent study has shown that BRCA2 mutations trigger genetic changes in prostate tumors that resemble those seen in metastasis — or cancer spreading to other organs. The mutations lead to more aggressive disease and poorer prognosis.

The research emphasizes the importance of genetic testing in prostate cancer, which can improve personalized treatment and lead to better outcomes.

The study, “Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories,” was published in Nature Communications.

Prostate tumors in men with BRCA2 mutations are very aggressive, associated with younger age of onset, affect the lymph nodes more often than non-BRCA2-mutant tumors, and lead to higher patient mortality rates.

In these patients, localized prostate cancer rapidly progresses to metastatic castrate-resistant prostate cancer. This form of the disease no longer responds to standard hormone therapy, and one result is a five-year survival rate of only 50-60 percent.

To understand why BRCA2-mutant prostate cancers are so aggressive, an international team of scientists, led by Australia’s Monash University Biomedicine Discovery Institute (BDI), sought to characterize the genomic alterations seen in men with localized prostate cancers who inherited BRCA2 mutations.

After extensive analysis of localized prostate tumor specimens from 14 men with BRCA2 mutations — collected during surgical removal of tumors — the team compared their data with that in a companion study.

The other study, led by collaborators in the Monash-led study, looked at prostate cancer samples from more than 320 patients without BRCA2 mutations. The research was published in Nature at the same time as the Monash study.

Surprisingly, the team found that localized prostate tumors of patients with faulty BRCA2 were genetically similar to the metastasis seen in men with metastatic prostate cancer. This genetic profile, which was associated with the activation of signaling pathways that rendered the cancer more aggressive, was rarely observed in localized prostate cancer of men lacking BRCA2 mutations.

Together, the findings explained why men with BRCA2 mutations have more aggressive disease, and suggest they should be managed with aggressive treatment at the time of their diagnosis to improve their outcomes.

“As the tumors in men with the BRCA2 gene fault are so different from the ‘get-go,’ our findings raise the question about whether these patients should be managed differently at diagnosis,” Dr. Renea Taylor, a fellow at Monash who led the study, said in a press release.

“[T]hese new findings detailing the genomic instability of BRCA2 prostate cancer are important as we may be able to target this with new therapies,” said Declan Murphy,director of Genitourinary Oncology at the Peter MacCallum Cancer Center and study author.

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