BRCA2 Mutation May Speed Prostate Cancer Progression

REYKJAVIK, Iceland, June 15 -- There's more evidence that mutations in the BRCA2 cancer susceptibility gene can contribute to prostate neoplasia as well as to breast and ovarian malignancies.

In an Icelandic registry study, one such mutation appears to promote aggressive disease progression as well, researchers found. The rare BRCA2 999del5 founder mutation was associated with diagnosis at a younger age (P=0.002), more advanced tumor stage (P<0.001), and higher tumor grade (P=0.007).

Carriers also had substantially shorter median survival after diagnosis than noncarriers (2.1 years versus 12.4 years), reported Laufey Tryggvadttir, M.Sc., of the University of Iceland here and the Icelandic Cancer Registry in Skgarhl, and colleagues.

Further study is needed to determine whether other BRCA2 mutations accelerate disease progression, they reported online in the Journal of the National Cancer Institute.

Previous research at the Memorial Sloan-Kettering Cancer Center in New York determined that men in families carrying BRCA2 genetic mutations have a three- to five-fold increased risk of prostate cancer.

Although the Islandic findings are not of immediate clinical use, they may add a piece to the puzzle in determining genetic prognostic markers, commented Sholom Wacholder, Ph.D., of the National Cancer Institute in Bethesda, Md., and colleagues, in an accompanying editorial.

"This work may clarify when and how BRCA2 mutations alter carcinogenesis," they wrote. "More generally, it offers an avenue for improving the accuracy of information available to patients when they are diagnosed with cancer."

The prevalence of the BRCA2 999del5 mutation is likely only 1% to 2% among prostate cancer patients in Iceland, the researchers said. Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risk of breast, ovarian, prostate and other cancers.

So to find the highest concentration of men with prostate cancer associated with the mutation, the researchers examined the population-based Icelandic Cancer Registry for prostate cancer patients among relatives of women with breast cancer.

The registry included 994 women with breast cancer dating back to 1911 and 29,603 of their male relatives. Among them, 596 men had been diagnosed with prostate cancer from 1955 to 2004, excluding those first diagnosed at autopsy.

Tissue or blood samples from 88% of these patients were analyzed for the genetic mutation.

Thirty men (5.7%) carried the BRCA2 mutation. These carriers were matched for year of diagnosis and birth with 59 noncarrier controls.

Disease characteristics at diagnosis for mutation carriers compared with controls were:

• Younger age at diagnosis (69.0 versus 74.0 years, P=0.002).
• More commonly metastatic (55.2% versus 24.6%).
• More commonly diagnosed at advanced stages (stage three or four 79.3% versus 38.6%, P<0.001).
• More commonly diagnosed with high grade tumors (grade three to four 84.0% versus 52.7%, P=0.007).

The outlook for survival was also poorer overall for carriers compared with noncarriers (P<0.001).

Mortality at five years after diagnosis was 79% versus 29% among controls. At 10 years, 90% versus 45% had died.

Median survival was substantially lower at 2.1 years for carriers (95% confidence interval 1.4 to 3.6) compared with 12.4 years for controls (95% CI 9.9 to 19.7).

The risk of dying from prostate cancer was significantly elevated for mutation carriers compared with noncarriers. The hazard ratios were:

• 3.64 in unadjusted analyses (95% CI 2.29 to 5.78).
• 3.42 after adjustment for year of birth and diagnosis (95% CI 2.12 to 5.51).
• 2.35 after adjusting for tumor stage and grade (95% CI 1.08 to 5.11).

Interestingly, the survival rate improved over the nearly 50-year study period for noncarrriers but not for mutation carriers. The survival rate was not significantly improved for mutation carriers diagnosed after versus before 1985 (HR 1.16, 95% CI 0.48 to 2.82) but was for noncarriers 0.52 (95% CI 0.38 to 0.72).

"This difference indicates that, among mutation carriers, the course of the disease has been unaffected by changes in treatment and diagnostic activity that occurred with time," the investigators wrote.

However, "It is not clear whether the lack of improvement in survival reflects chance, is due to the small numbers, or signals a real difference," Dr. Wacholder and colleagues cautioned.

Cancer risk from BRCA2 mutations differs depending on the location of a mutation within the gene, so extrapolation of the aggressive characteristics associated with 999del5 to other mutation locations is unknown.

Studies in other populations with different common mutations will be necessary to answer that question, the researchers said.

"Small numbers combined with the multitude of different founder mutations seen in distinct ethnic groups force researchers and clinicians and patients to draw scientific conclusions and develop treatment plans with only pieces of the puzzle," Dr. Wacholder and colleagues wrote.

Meanwhile, men with newly diagnosed prostate cancer may not gain much from learning they do not carry BRCA2 mutations, they said. Prognosis and survival are not much different for noncarriers than for patients overall because carriers are rare, they added.

Discovering a man with prostate cancer carries a BRCA2 mutation, though, may affect treatment considerations, they said.