Breast Cancer Prognosis Not Affected by BRCA Status

HAIFA, Israel, July 11 -- Breast cancer survival was similar among carriers and noncarriers of BRCA1 and BRCA2 mutations in an Israeli study in which 10% of Ashkenazi women had such a susceptibility mutation, researchers reported. Some features of breast cancer in women with a BRCA1 mutation suggest that it has a poor outcome, but little has been known about the influence of such mutations on the natural history of breast cancer or the response to treatment, wrote Gad Rennert, M.D., of Carmel Medical Center here, and colleagues in the July 12 issue of the New England Journal of Medicine.
To determine the influence, if any, of these mutations on breast-cancer prognosis, the researchers ran a retrospective population-based study of 2,514 Israeli women diagnosed in 1987 or 1988.
Deaths attributable to breast cancer, recorded in the Israel National Cancer Registry, were identified in the 10-year period after diagnosis.
A pathological sample from 1,794 women was obtained as well as medical records for 1,545 women. DNA extracted from tumor specimens was analyzed for the three founder mutations in BRCA1 and BRCA2.
A BRCA1 or BRCA2 mutation was identified in 131 of the 1,102 women who were of Ashkenazi Jewish ancestry. Of these 76 had BRCA1 mutations, 52 had BRCA2 mutations, and three had mutations in both genes and were excluded from analyses.
The adjusted hazard ratios for death from breast cancer were not significantly different among mutation carriers and noncarriers, the researchers reported.
The hazard ratio among BRCA1 carriers was 0.76 (95% confidence interval, 0.45 to 1.30; P=0.31).
The hazard ratio among BRCA2 carriers was 1.31(CI, 0.80 to 2.15; P=0.28).
Survival rates at 10 years were 67% for BRCA1 carriers and 56% for BRCA2 carriers, and 67% for noncarriers (P=0.25).
In this study, tumor size was not a predictor of death, and lymph node status was a predictor of only borderline significance, the investigators said.
Among women who did not receive chemotherapy after surgery, the 10-year survival rates were 76% for BRCA1 carriers, and 74% for noncarriers (P=0.86).
Among women who were treated with chemotherapy, the hazard ratio for death among BRCA1 carriers was 0.48 (CI, 0.19 to 1.21, P=0.12). Among all the women given chemotherapy, the 10-year survival rates were 71% for BRCA1 carriers and 46% for noncarriers (P=0.12).
However, the interaction between BRCA1 status and chemotherapy was significant only for overall survival (P=0.02), not for breast-cancer-specific survival, the researchers noted. The survival of BRCA2 carriers was similar to that of noncarriers, with or without chemotherapy.
Altogether, the researchers wrote, the influence of the BRCA mutations on the outcome of chemotherapy was not statistically significant.
Age did not seem to be a predictor of survival in either noncarriers or mutation carriers, the researchers said.
For 20 women younger than 50 at diagnosis, the adjusted hazard ratio for death among those with a BRCA1 mutation was 0.56 (P=0.15). For those 50 or older at diagnosis (mean age 61), survival times were similar for BRCA1 and noncarriers (HR 1.07, P=0.85).
Tumor size also did not predict the probability of death. Survival rates were similar for women with a tumor 2 cm or less and for those with larger tumors.
Study limitations included the lack of recording for tumor grade and estrogen-receptor status, and the possibility of misclassification of some hereditary cases. Since only 131 mutation carriers were identified, the subgroup analyses relied on a small number of subjects.
"Although we did not see any clear survival differences in association with the BRCA mutations we sought, potential important differences emerged when we analyzed the data according to tumor size and the use or nonuse of chemotherapy," the researchers concluded.
In an accompanying editorial, Patricia Hartge, Sc.D., of the National Cancer Institute in Bethesda, Md., wrote that from the perspective of counseling carriers of these mutations, the general conclusions offered by studies such as these are helpful overall but broad.
Once breast cancer has been diagnosed, the physician and patients might ask whether knowing the patient's BRCA status would affect prognosis or therapy. The answer to that question requires statistical adjustment for tumor state and grade and for other factors known at diagnosis.
In turn, such analyses of the marginal statistical contribution of the genetic test can affect the recommended practices in the population at large, she said. If the information that a woman is or is not a carrier adds to the prognostic model, then one would evaluate possible gains from screening more women who might be carriers.
Dr. Rennert and colleagues reported no relevant financial disclosures. The study was supported by a grant from the National Cancer Institute.
Dr. Hartge reported no financial conflicts relevant to this article. Primary source: New England Journal of MedicineSource reference: Rennert G, et al "Clinical Outcomes of Breast Cancer in Carriers of BRCA1 and BRCA2 Mutations" NEJM 2007;357:115-123. Additional source: New England Journal of MedicineSource reference: Hartge P "Genes, Cancer Risks, and Clinical Outcomes" NEJM 2007; 357:175-176.