Roxanne Nelson

April 05, 2011

April 5, 2011 (Orlando, Florida) — Ovarian cancer patients with the BRCA2 gene mutation are more likely to survive their disease than those with the BRCA1 mutation and those without either mutation.

After adjustment for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest nonsignificant survival advantage (hazard ratio [HR], 0.84; P = .12). However, BRCA2 carriers showed a marked improvement in survival, compared with noncarriers (HR, 0.57; P = 6 ×10–4).

The data were presented here at the American Association for Cancer Research 102nd Annual Meeting.

Dr. Kelly Bolton

"This is the first solid evidence that BRCA2 carriers show a distinct clinical course from BRCA1 carriers," said lead author Kelly Bolton, MPhil, a predoctoral candidate at the National Cancer Institute.

"Our findings don't have any immediate impact on clinical practice, but they do have important implications for both clinical prediction and trial design — particularly for clinical trials," explained Ms. Bolton.

The next step is to try to understand the mechanism driving these survival differences. "There is some evidence from in vitro work and some retrospective clinical studies that suggest that response to chemotherapy may be different between carriers and noncarriers," she said. "There could also be biological differences that exist that we are not yet aware of between BRCA1 and BRCA2 carriers and noncarriers that are driving this association."

Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in about 10% to 15% of ovarian cancer patients, but are quite uncommon in the general population. Both genes play key roles in DNA damage repair, but appear to have distinct, although often complementary, functions, Ms. Bolton pointed out. Breast and ovarian cancer risks differ between the 2 carrier groups, and mutation-specific effects have been suggested for both.

Possible Treatment Implications

Survival among ovarian cancer patients is quite variable, noted Ellen Goode, PhD, associate professor of epidemiology at the Mayo Clinic in Rochester, Minnesota. "BRCA1 and BRCA2 are 2 genes that increase the risk of ovarian cancer."

"But what hasn't been definitively shown until now is that once you have ovarian cancer, if you are a carrier of one of these genes, that will affect your survival," she told Medscape Medical News. Dr. Goode was not involved in the study.

This study shows that there is a difference in outcome that could lead to variables in treatment. "It could be that we need more tailored chemotherapy, depending on BRCA status," she said.

It is still premature to consider testing all ovarian cancer patients for BRCA status, explained Dr. Goode, but it should be considered on an individual basis. "Testing for BRCA is very expensive, so it is not something that is feasible on a large scale," she said.

"If a woman has a family history of the disease and has already been tested, it is probably something that should be taken into account at this point," she added.

"In terms of chemotherapy regimens, a good next analysis would be to stratify women by carrier status," said Dr. Goode. "In the future, I think that this information will prove useful in terms of treatment."

Survival Advantage for BRCA2 Carriers

In this study, Ms. Bolton and colleagues conducted a large multicenter study to investigate the impact of germline BRCA1 and BRCA2 mutations on ovarian cancer survival.

The cohort consisted of 3531 women with invasive epithelial ovarian cancer, of whom 1178 were BRCA1 carriers, 367 were BRCA2 carriers, and 1986 were noncarriers. The team analyzed survival-time data obtained from 24 studies conducted in the United States, Europe, Israel, and Asia. The main analysis excluded patients who had not or who were likely to have not received platinum-based therapy.

BRCA1 and BRCA2 carriers were more likely than noncarriers to present with advanced-stage disease, high-grade tumors, and serous disease. The authors also observed that BRCA1 carriers tended to be younger than noncarriers at diagnosis (P = 2 × 10–9), and that BRCA2 carriers were slightly older at diagnosis (P = .002).

In terms of tumor stage, grade, and histology, there was no difference between BRCA1 and BRCA2 carriers, but there was a difference in age at diagnosis (P = 2 × 10–14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from noncarriers in overall survival (BRCA1 HR, 1.02; P = .77; BRCA2 HR, 0.89; P = .36). However, after adjustment for baseline characteristics, differences in the 3 groups emerged. For noncarriers, 5-year survival was 36%, for BRCA1 carriers it was 46%, and for BRCA2 carriers it was 61%.

The survival differences that were observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemosensitivity, the authors note.

American Association for Cancer Research (AACR) 102nd Annual Meeting: Abstract 2752. Presented April 4, 2011.


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