A large Dutch study of BRCA1/2 status among younger women diagnosed with breast cancer found that those with a BRCA1 mutation were 1.2 times more likely to die from breast cancer than patients without a BRCA1 mutation. No statistically significant survival difference was found for those with BRCA2 mutations.

In a study of 5,518 women diagnosed with breast cancer before age 50, Dutch researchers found that those who carry BRCA1 germline mutations have a poorer prognosis than noncarriers. The patients had been treated at one of 10 cancer clinics in the Netherlands between 1970 and 2002.

Several smaller studies conducted in the late 1990s, shortly after the BRCA1/2 mutations were discovered, showed worse overall breast cancer survival for carriers. Because the BRCA genes are involved in DNA repair and known to be associated with breast cancer development, “this link to prognosis makes sense biologically,” says lead investigator Marjanka Schmidt, PhD, an epidemiologist at the Netherlands Cancer Institute in Amsterdam.

However, those earlier studies focused on Ashkenazi Jews, who typically exhibit only 3 BRCA1/2 mutations out of hundreds of possible variants. “We wanted to see if those findings would be validated in the Dutch population, where the spectrum of variants is wider,” says Schmidt.

Among the 3.6% of patients found to be BRCA1 mutation carriers, overall survival rates were 1.2 times worse than in noncarriers, and recurrence-free survival was 1.5 times worse during an average follow-up time of 11.3 years. Among the 1.2% of patients found to be BRCA2 mutation carriers, data suggested worse overall survival, but this result did not reach statistical significance.

Also notable: The proportion of estrogen receptor (ER)–positive tumors was similar between patients without BRCA mutations and those with a BRCA2 mutation (86% vs. 81%) but was low among patients with a BRCA1 mutation (29%).

Although these findings do not suggest a change in clinical decision making today, they could influence treatment in the future. “If ongoing clinical trials relevant to BRCA1/2 carriers, such as PARP inhibitors, pan out, it will become more important to know up front whether someone is a carrier or not,” says Schmidt, who presented the findings at the American Association for Cancer Research Annual Meeting 2013, held April 6–10 in Washington, DC.

A more fine-grained analysis of the data is under way. “We are working toward building a more specific prediction model that includes BRCA1/2 carrier status as well as other tumor characteristics,” such as tumor grade, tumor type (ER-positive, HER2-enriched, or triple-negative), and other immunohistologic markers, says Schmidt.

In 2011, Schmidt's group presented early, still unpublished data proposing a prediction model that uses age, tumor characteristics, and BRCA1/2 mutation carrier status to stratify the risk of contralateral breast cancer, a risk known to be elevated in those carriers. “We now want to figure out how much of the worse survival observed in our current study is due to the high risk of contralateral breast cancer among BRCA1/2 carriers,” says Schmidt.

©2013 American Association for Cancer Research.
2013