This study was conducted to evaluate the pathological characteristics of BRCA-associated invasive breast cancer in Hispanic women. The findings of this study are consistent with previous knowledge of the tumor characteristics of BRCA carriers. In particular, Hispanic BRCA1 carriers exhibited many of the same pathological characteristics that have been described in predominantly NHW BRCA1 carrier populations such as higher rates of steroid receptor negativity, low HER2 expression and high cellular proliferation as compared to Hispanic non-carriers. Likewise, as previously reported, the majority of Hispanic BRCA2-associated breast cancers in this study were high grade ductal carinomas and ER positive.
-associated breast cancers had significantly lower levels of PR expression than NHW BRCA
-associated breast cancers, irrespective of mutation status. Additional research on the possible clinical implications and molecular mechanisms involved in the loss of PR in this population is warranted as it could have important implications for the treatment and prevention of breast cancer in Hispanic women, particularly since PR has been found to be an independent predictor of endocrine therapy response [35
]. Studies have found that patients with ER-positive/PR-negative tumors who received adjuvant endocrine therapy have higher rates of recurrence and poorer survival compared to patients with ER-positive/PR-positive tumors.
The molecular mechanisms that have been hypothesized to explain the loss of PR in breast tumors include a nonfunctional ER, low circulating levels of estrogen, hypermethylation of the PR promoter, loss of heterozygosity at the PR gene locus, selective ER modulator or growth factor-induced membrane-initiated steroid signaling activity of ER, and altered ER coregulator levels or activity [38
]. In addition, recent data suggests that increased BMI (≥30kg/m2
) is associated with reduced ER and PR expression among younger women (under age 50) with breast cancer [39
]. The Hispanic women in this study had a slightly higher BMI compared to the NHW women. BMI was also slightly higher among the Hispanic women with PR-negative breast cancers. Additional studies with a larger sample are necessary to determine if there is a significant difference in BMI that may be contributing to the difference in PR expression identified in this study.
HER2 overexpression occurs in only 20-30% of sporadic breast cancers. Low levels of HER2 expression have been documented in studies of breast cancer in women of Hispanic descent [40
]. In this study, Hispanic and NHW breast cancers had similar HER2 expression within each of the three groups–BRCA1
carriers and non-carriers. Breast cancers from non-carriers had HER2 expression levels comparable to levels previously reported for sporadic breast cancers. Hispanic BRCA1
-associated breast cancers had low levels of HER2 expression, consistent with previous descriptions of the breast cancer immunophenotype in BRCA1
]. Although all of the Hispanic BRCA2
carriers also had low levels of HER2 expression, additional studies with a larger sample of Hispanic BRCA2
carriers are necessary to confirm this finding.
mutations are prevalent among women with triple-negative breast cancers (i.e., ER- and PR-negative and HER2 non-amplified) compared to women with non-triple-negative breast cancer. In addition, triple-negative breast cancers have been found to occur more frequently in non-Hispanic black and Hispanic women and are related to poorer overall survival [43
]. A higher proportion of Hispanic breast cancers in this study had a triple-negative immunophenotype compared to NHW breast cancers. The majority of the triple-negative breast cancers were identified among BRCA1
carriers of both ethnicities.
TP53 mutations usually result in p53 protein accumulation and prolonged half-life of the protein making immunohistochemistry a surrogate for mutational analysis. It has been hypothesized that loss of p53 function may be critical in the development of BRCA1-related tumors and therefore higher rates of p53 overexpression are observed among carriers. We observed p53 overexpression in a higher proportion of breast cancers in each group, except Hispanic BRCA2 carriers. This observation is consistent with findings from other studies in the literature for most of these groups, except for NHW women with breast cancer where p53 overexpression is approximately 20%. It is not clear if this discrepancy is due to the potentially non-representative nature of this small cohort, therefore a follow-up study is needed to further explore this issue.
The breast cancer tumors from Hispanic women in this study exhibited histological characteristics that have been previously reported in this ethnic population, including lower levels of lobular carcinoma (n=1) and higher levels of medullary carcinoma (n=7) [45
]. Although medullary histology is also known to be common among BRCA1
carriers, three of the seven with tumors of medullary histology were non-carriers.
Sample size may have contributed to a lack of statistical significance when stratifying the analyses by genes and ethnicity. As such, some of the comparisons might have been underpowered to detect a difference between the groups. In addition, due to administrative barriers at the respective hospital, tumor samples were not available for repeat testing for 20 Hispanic women. As a result, data from pathology reports was used to complete the data for analysis. As none of the pathology reports contained information on p53 expression, the lack of statistically significant results for p53 expression may have been due to missing data.
There was the potential for the introduction of bias related to year of diagnosis during the selection process due to matching for age at diagnosis. During the selection process, if a potential control tumor was not available for analysis, this individual was not selected for participation in the study. As a result, the majority of the tumors included in the study were those diagnosed within the last ten years as it is the practice of many hospital pathology laboratories to archive tumor tissue for less than ten years.
Likewise, for the metachronous bilateral breast cancer cases, the tumor more frequently available for study was the tumor most recently diagnosed. However this may not significantly affect the results of the study as no significant differences were detected when the tumors were compared. In addition, a study of bilateral breast cancer in BRCA
carriers revealed a high rate of concordance between independent primary tumors in these women [46
]. The majority of the bilateral breast cancer cases in this study were BRCA
carriers (23/30, 77%).
Differing fixation practices across institutions may have affected the immunohistochemical analysis of some tumor samples. Prolonged fixation may reduce the immunohistochemical reactivity of many paraffin section antibodies and as a consequence false negative immunohistochemical results may occur [47
This is the first report of a comparative study of the immunophenotype for a large set of BRCA-associated breast cancers in Hispanics and NHW. Our study suggests that Hispanic BRCA-associated breast cancer phenotypes are not substantially different from that of NHW BRCA-associated breast cancers; however there was a trend toward a difference in PR expression among BRCA1 and BRCA2 cases that could become significant in larger cohorts. This difference could impact the prevention, treatment, or outcome of breast cancer in Hispanic women and may reflect the effects of population-specific environmental or reproductive influences. Understanding the factors that impact PR expression and the influence of BRCA mutation status may provide insight into a potentially different mechanism of breast cancer development in Hispanic BRCA carriers.