BRCA mutations, molecular markers, and clinical variables in early-onset breast cancer: A population-based study

Summary

Early age at onset is generally considered an indicator of genetic susceptibility to breast cancer. To address both the proportion of early-onset breast cancer associated with BRCA-1 or BRCA-2 germline mutation and the contribution of germline mutations to the clinical features and outcome of these tumors, we analyzed molecular status and clinical variables of a population-based sample of 66 Italian women diagnosed with breast cancer before the age of 40 who were unselected for family history. BRCA mutations were screened by automated sequencing of the entire BRCA-1 and BRCA-2 coding regions and splice junctions. Twenty-eight late-onset (over 45 years), sporadic, breast cancers were designated as “control group” for comparisons with early-onset cases. BRCA mutations (10 BRCA-1 and 6 BRCA-2) were detected in 15 (22.7%) out of 66 tested patients. The combination of ER, PR, HER-2/neu negativity and p53 positivity was significantly more frequent in BRCA-1 positive tumors than in BRCA-2 positive and non-BRCA tumors (P=0.03). Taken collectively, BRCA-positive tumors correlated with high histologic grade and ER negativity compared with non-BRCA and sporadic tumors (P=0.05 and 0.003, respectively). There were no significant differences between BRCA-associated breast cancers (BABC) and non-BABC in relapse-free, event-free, and overall survival. Our data confirm that the combination of age at onset and tumor phenotype can provide an efficient model for identifying individuals with a high probability of carrying BRCA mutations and support the hypothesis that breast cancer in BRCA carriers is qualitatively distinct from other early-onset breast cancers and from late-onset, sporadic, breast carcinomas. Further studies on incident cases are necessary to define the independent prognostic significance of germline BRCA mutations.

Introduction

Breast cancer is considered a multifactorial disorder caused by both non-genetic and genetic factors. The clustering of breast cancer in families has been recognized for many years, suggesting that there may be an inherited component, and it has been estimated that 5–10% of all breast cancers arise in individuals carrying a germline mutation.¹

A substantial proportion of hereditary breast cancers can be attributed to mutations in 1 of 2 genes, BRCA-1 or BRCA-2. Early studies of families with multiple cases of breast and ovarian cancer suggested that BRCA-1 mutation carriers may have a lifetime breast cancer risk of up to 84% and an ovarian cancer risk of up to 44%.² However, other studies of less selected families have suggested that the risks may be somewhat lower than these initial estimates.³ BRCA-1 and BRCA-2 mutations are thought to confer a similar susceptibility to breast cancer, but BRCA-2 mutations may pose a lower risk of ovarian cancer. Moreover, BRCA-2 has been determined to contribute to fewer cases of early-onset breast cancer than BRCA-1.⁴

Typically, breast cancers occurring in BRCA-1 mutation carriers are high-grade and have a high proliferation rate, with medullary or atypical medullary cancers being over-represented. In contrast, lobular cancers and extensive intraductal cancers are more frequent in women with germline BRCA-2 mutations.⁵ Despite a higher prevalence of adverse histopathological features in BRCA-1-associated breast cancers, some investigators have proposed that women with germline BRCA-1 mutations who develop breast cancer may have a better prognosis than their counterparts with sporadic disease.⁶ The prognosis of breast cancer in women with BRCA-2 mutation is undefined.

The majority of studies on the correlation of BRCA-1 and BRCA-2 with molecular markers have involved participants from families with multiple individuals affected by breast and/or ovarian cancer, or from Jewish or Icelandic women, who are known to have a high prevalence (because of founder effects within their populations) of a germline mutation at specific sites within these 2 genes. While a unique molecular phenotype has not emerged for BRCA-2-associated breast cancers,⁷ these studies have indicated that breast cancers in BRCA-1 mutation carriers are typically estrogen receptor (ER)-, progesterone receptor (PR)-, and HER-2/neu-negative (so-called “triple negatives”), and 80–90% of triple negative breast cancers are “basal-like” according to DNA microarray and immunohistochemical analysis.⁸ It is possible that the pathogenesis of breast cancers occurring in these defined groups is influenced not only by the specific site of the germline BRCA-1 or BRCA-2 mutation, but also by other modifying genetic or environmental factors specific to these groups of women. It is therefore not known whether the somatic molecular alterations described in the cancers of these selected population subgroups resemble those seen in the general population.

In contrast to the numerous studies involving BRCA in cancer families and large founder effect populations, there have been very few population-based studies looking at BRCA mutations and correlations with molecular markers. Early age at onset is generally considered an indicator of genetic susceptibility to breast cancer and it has been demonstrated to be associated with a higher risk in relatives.⁹ Several studies have shown that early-onset breast cancer displays histological features suggestive of an aggressive cancer phenotype that have also been reported in cancers arising in BRCA-1 mutation carriers. Hence, it is not clear if the association of a significant proportion of early-onset breast cancers with BRCA-1 mutations is responsible for the high frequency of histologically aggressive tumors in young women and there is uncertainty as to the extent to which breast cancers occurring in women with germline BRCA-1 mutations can be distinguished from early-onset cancers arising in women without germline mutations in this gene.

To help address the questions of the proportion of early-onset breast cancer associated with BRCA-1 or BRCA-2 germline mutation and of the contribution of germline mutations to the clinical features and outcome of these tumors, we analyzed molecular profile and clinical variables of a population-based sample of Italian breast cancer patients who were selected on the basis of having had early-onset breast cancer.