Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features

Abstract

IntroductionMost breast cancers that occur in women with germline BRCA1 mutations are estrogen receptor-negative (ER-) and also typically lack expression of progesterone receptor (PR) and HER2 overexpression. We undertook a study to assess the clinical factors that predict for an estrogen receptor positive (ER+) breast cancer in BRCA1 mutation carriers and to characterize the pathologic features of these tumors.MethodsClinical characteristics of BRCA1 carriers with 58 ER+ and 114 ER- first invasive breast cancers were compared. Pathologic features of BRCA1 ER+ cancers were compared to those of BRCA1 ER- cancers and to age-matched ER+ sporadic cancers.ResultsBRCA1 carriers aged ≥ 50 at diagnosis of first invasive breast cancer were more likely to have an ER+ cancer compared to those aged < 50 (57% vs 29%, P = 0.005). ER+ BRCA1 cancers were less likely than ER- BRCA1 cancers to have "BRCA-associated" features such as high mitotic activity, geographic necrosis/fibrotic focus, and pushing margins (RR 0.06, 0.22, 0.24; P < 0.001, 0.02, 0.03 respectively). When compared to sporadic ER+ cancers, ER+ BRCA1 cancers were more often of invasive ductal type (RR 2.4, P = 0.03), with a high mitotic rate (RR 5.0, P = 0.006) and absent or mild lymphocytic infiltrate (RR 10.2, P = 0.04).ConclusionsBRCA1 carriers who are older at first breast cancer diagnosis are more likely to have ER+ tumors than younger BRCA1 carriers. These ER+ cancers appear pathologically "intermediate" between ER- BRCA1 cancers and ER+ sporadic breast cancers raising the possibility that either some ER+ BRCA1 cancers are incidental or that there is a unique mechanism by which these cancers develop.

RareBRCA1haplotypes including 3’UTR SNPs associated with breast cancer risk

“…Our finding that the rare haplotypes are primarily in TN and ER + breast cancer is consistent with the published literature showing that BRCA1 coding sequence mutations are most frequently associated with TN (57%), 7 and ER + breast cancers (34%), 8 and are rarely found in HER2 + breast cancers (about 3%). 9 We hypothesize that the significant association of the rare haplotypes with TN and ER + breast cancer indicates that these haplotypes (and/or functional SNPs within the haplotypes) are associated with true BRCA1 dysfunction and studies to better prove this are ongoing.…”

“…6 Overall, breast tumors resulting from BRCA1 mutations are most frequently TN (57%), 7 or ER + breast cancers (34%), 8 and are rarely HER2 + breast cancers (about 3%). 9 While TN tumors are often characterized by low expression of BRCA1, 10 because BRCA1 mutations are quite rare, they only account for approximately 10-20% of the TN tumors.…”

Oncogenes and Tumor Suppressor Genes

“…These mice develop mammary tumors with full penetrancy and a median tumor latency of 6.3 months (Shafee et al 2008). In line with recent reports (Atchley et al 2008;Tung et al 2010), both ERa-positive and ERa-negative tumors were identified and p63 expression was up-regulated. These findings raise the possibility that the cells of origin in BRCA1-mediated breast carcinogenesis may be heterogeneous.…”

“…Earlier studies indicated that the majority of BRCA1-associated cancers are triple (ERa, PR, and HER-2) negative, basal-type breast cancers (reviewed in Lynch et al 2008). However, recent reports show that BRCA1-associated breast cancers can be ERa-and PR-positive, especially in aged patients (Atchley et al 2008;Tung et al 2010). The BRCA1 gene encodes a protein of 1863 amino acids with a predicted molecular weight of 220 kDa (Miki et al 1994).…”

Time to Think Outside the (Genetic) Box

“…3) with triple-negativity testing and other potential molecular markers (11,12) to explore the relationship of BRCA1 methylation in peripheral blood to BRCA1-associated breast cancer.…”