Newswise — WASHINGTON, D.C. — Patients with breast cancer who had a BRCA1 mutation had significantly worse overall and recurrence-free survival rates compared with patients without BRCA mutations, but no evidence for a difference in survival was found between patients with BRCA2 mutations and those without a BRCA mutation, according to data from a large Dutch study presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.
Previous studies investigating survival differences between women with BRCA1 or BRCA2 mutations and those without a BRCA mutation, or noncarriers, have been inconsistent, according to Marjanka M. K. Schmidt, Ph.D., a group leader in the Experimental Therapy Division of the Netherlands Cancer Institute in Amsterdam. “We have analyzed data from one of the largest, least biased, BRCA1/2-genotyped breast cancer cohorts,” she said.
Schmidt and colleagues evaluated BRCA status and survival in 5,518 patients who had been diagnosed with breast cancer before the age of 50 and had been treated at any one of 10 cancer clinics in the Netherlands. They found that 3.6 percent of the patients had a BRCA1 mutation and 1.2 percent had a BRCA2 mutation.
Researchers tested patients’ samples for 78 different inherited BRCA1 or BRCA2 mutations and linked these to long-term outcome during a mean follow-up of 11.3 years. The proportion of ER-positive tumors was similar between noncarriers’ tumors (86 percent) and tumors from patients with a BRCA2 mutation (81 percent) but was low among tumors from patients with BRCA1 mutations (29 percent).
The data revealed that women with a BRCA1 mutation were 1.5 times more likely to have a breast cancer recurrence and were 1.2 times more likely to die from breast cancer compared with noncarriers. There was no evidence for worse survival among patients with BRCA2 mutations compared with noncarriers.
In preliminary analyses, the effect of BRCA1 on survival remained after the researchers adjusted for tumor characteristics. “However, in our review, we also found that the effects were attenuated when tumor characteristics were adjusted for,” Schmidt said. “So part of the worse survival in BRCA1 mutation carriers is likely explained by tumor characteristics and part by the mutation itself.”
The differences in survival between BRCA1 mutation carriers and noncarriers might indicate that treatment should depend, in part, on which mutation a woman has, according to Schmidt.
“Currently, patients are treated on the basis of their tumor characteristics, not on their BRCA status, aside from prophylactic measures and, for example, PARP inhibitors in clinical trials,” she said. “If we could show that BRCA status, independent of tumor characteristics, is predictive of prognosis, this could be taken into account in prediction models and could facilitate treatment decisions.”
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Abstract Number: 1338
Presenter: Marjanka M. K. Schmidt, Ph.D.
Title: Breast cancer survival of BRCA1/2 carriers compared to non-BRCA1/2 carriers in a large breast cancer cohort
Authors: Marjanka MK Schmidt1, Alexandra J. van den Broek1, Rob AEM Tollenaar2, Flora E. van Leeuwen1, Laura J. Van 't Veer1, on behalf of collaborators of 10 centers in the Netherlands. 1Netherlands Cancer Institute, Amsterdam, Netherlands; 2Leiden University Medical Center, Leiden, Netherlands
The biological background and different pathological aspects of BRCA1-associated tumors support the hypothesis that patients carrying a BRCA1 and/or BRCA2 mutation might have a worse breast cancer prognosis compared to non-carriers. However, studies showed inconsistent results, possibly due to differences in study design, study size, study populations and methodological quality. We recently performed a systematic review taking into account the quality of all relevant studies published so far on BRCA1/2 mutation carriership and survival (n=63). Using a best-evidence synthesis, we found that there is only moderate evidence for a worse unadjusted recurrence-free survival for BRCA1 mutation carriers compared to non-carriers (pooled absolute survival difference of 10%) (to be submitted). The aim of the current study was to evaluate breast cancer outcome in a multicenter cohort of breast cancer patients with long-term follow-up, unselected for family history.
We included invasive pathologically-confirmed breast cancers, diagnosed before <50 years of age, in the period 1970-2002, in ten Dutch centers, in patients with no previous malignancies. DNA for BRCA1/2 analyses was isolated from formalin-fixed, paraffin-embedded tissue blocks containing normal (non-tumor) tissue. A selection of most frequently occurring BRCA1/2 mutations was analyzed using Taqman PCR and fragment length analyses confirmed by direct sequencing, capturing ~70% of all Dutch pathogenic mutations. Clinico-pathological data and follow-up, including recurrences and second tumors, were retrieved from tumor registries, medical records and the Dutch municipal registry. Part of the tumor characteristics (grade, ER, PR, HER2) was obtained by revision. Cox proportional hazard models were run using STATA; multivariate models were adjusted for grade, size, nodal status and age.
Among 5518 breast cancer patients with a BRCA1/2 result we found 3.6% BRCA1 and 1.2% BRCA2 mutation carriers. The proportions of ER-positive breast cancers in non-BRCA, BRCA1 and BRCA2 mutation carriers were 86%, 29% and 81% respectively. Mean follow-up of the cohort was 11.3 years. Overall survival was worse for BRCA1 mutation carriers compared to non-carriers (HR-unadjusted 1.4 (95%CI: 1.1-1.7), p=0.003; HR-adjusted 1.2 (1-1.6), p=0.07); recurrence-free survival was also worse for BRCA1 mutation carriers (HR-adjusted 1.5 (1.1-1.9), p=0.004). We did not find evidence for a different survival of BRCA2 mutation carriers, except for a suggestion of a worse overall survival. These results are preliminary and further analyses including stratifications by tumor subtype and treatment will be presented at the AACR meeting. In one of the largest, unbiased, BRCA1/2 genotyped breast cancer cohort study, we found evidence for a significant worse overall and recurrence-free survival adjusted for clinico-pathological factors of BRCA1 mutation carriers
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