Tumour diploidy and survival in breast cancer patients with BRCA2 mutations

Abstract

It is not well known to what extent carrying a BRCA2 mutation affects the survival of women with breast cancer and prognostic factors among BRCA2-positive women warrant investigation. Using a record linkage approach we compared the long-term survival in carriers and noncarriers of an inherited BRCA2 founder mutation (999del5), and sought to identify prognostic factors among the BRCA2 mutation-positive subset, including markers of genetic instability (aneuploidy) and mitotic activity (S-phase fraction). We established the genetic status of 2,967 Icelandic breast cancer patients (215 mutation carriers and 2,752 noncarriers) diagnosed from 1955 to 2004, representing 72 % of all cases diagnosed in the country during this period. Tumour ploidy and S-phase fraction were assessed on tumour cells by DNA flow cytometry. Prognostic factors were assessed blindly with respect to mutation status. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival by BRCA2 status, using Cox regression. After a median follow-up of 9.5 years, BRCA2 mutation carriers had a higher risk of death from breast cancer than noncarriers (HR 1.64, 95 % CI 1.24-2.16, p < 0.001). The risk increase was restricted to women with diploid tumours (HR 3.03, 95 % CI 1.91-4.79, p < 0.001). Among breast cancer patients with aneuploid tumours, survival of carriers was similar to that of noncarriers (HR 0.76, 95 % CI 0.41-1.41, p = 0.38). Increased tumour size and a positive nodal status predicted worse prognosis in all patients, whereas the highly correlated prognostic factors diploidy, low proliferative activity and a positive estrogen receptor status had reverse effects in mutation carriers and noncarriers. Breast cancer patients who carry the Icelandic founder BRCA2 mutation have inferior long-term survival than noncarriers, but the adverse prognosis is restricted to mutation carriers with diploid, slowly proliferating tumours.

Worse Breast Cancer Prognosis of BRCA1/BRCA2 Mutation Carriers: What's the Evidence? A Systematic Review with Meta-Analysis

“…The pooled, significant, unadjusted HR was 1.57 (95% CI 1.29–1.86) ( Table 3 and S6 Supporting Information, panel H). This survival difference seemed to be driven by one large study [ 62 ], and, when using the best-evidence synthesis, the evidence was still judged to be indecisive. For adjusted breast cancer-specific survival too few HQ studies were available ( Fig.…”

Effects of BRCA1- and BRCA2-Related Mutations on Ovarian and Breast Cancer Survival: A Meta-analysis

“…Meanwhile, a large scale study involving 2967 patients demonstrated adverse effect of BRCA2 mutations on breast cancer specific survival. (18) These inconsistencies in the research may be due to variations in sample size and the relative rarity of mutation carriers.…”

Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers

“…We recently published preliminary results that, in breast cancer patients carrying the Icelandic founder mutation 999del5, a positive oestrogen receptor (ER) status predicts an adverse outcome ( Tryggvadottir et al , 2013 ). It is important to verify those results in a larger study, and to find out whether the association between survival and ER status in this genetic subgroup might vary by treatment given.…”