Basal Cytokeratin and Epidermal Growth Factor Receptor Expression Are Not Predictive of BRCA1 Mutation Status in Women With Triple-negative Breast Cancers

Abstract

Over 80% of breast cancers in women with germline BRCA1 mutations are estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative ("triple negative") and most of these have a basal-like phenotype by expression profiling and immunophenotypic analysis. However, whether or not expression of biomarkers characteristic of basal-like breast cancers helps to define a subset of women with triple-negative breast cancers who are likely to harbor BRCA1 mutations is an unresolved issue. We randomly identified 165 women from the Dana-Farber/Harvard Cancer Center SPORE annotated specimen bank with primary invasive, triple-negative breast cancers. Tissue microarrays were constructed by obtaining triplicate 0.6 mm cores from available paraffin blocks from 130 cases: only unstained slides were available for immunostaining from 35 cases. Slides cut from the tissue microarrays and the unstained slides were immunostained for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (to confirm triple-negative status) and for several markers that have been reported to be useful in defining the basal-like phenotype, including basal cytokeratins CK5/6, CK14, and CK17 and epidermal growth factor receptor (EGFR). Full sequencing analysis for BRCA1 germline mutations was performed on blood specimens from all cases. The final study population consisted of 144 cases in which (1) triple-negative status was confirmed; (2) there was sufficient material for analysis of basal cytokeratins and EGFR; and (3) germline BRCA1 mutation status was known. Among these triple-negative breast cancer cases, 97 (67%) expressed one or more basal cytokeratins and 102 (71%) showed EGFR expression. Basal cytokeratin expression was detected in 65% of the tumor from the 20 BRCA1 mutation carriers and in 68% of the cancers from women without mutations (P=NS). EGFR expression was identified in a similar proportion of tumors from women with and without BRCA1 mutations (75% vs. 72%, P=NS). Basal cytokeratin and EGFR expression are both highly prevalent among triple-negative breast cancers. The frequency of expression of basal cytokeratins and EGFR was similar in women with and without BRCA1 mutations. Therefore, although the expression of basal cytokeratins and/or EGFR can be used to identify triple-negative breast cancers that have a basal-like phenotype, expression of these markers alone is not sufficient to distinguish which women with triple-negative breast cancers are likely to harbor BRCA1 germline mutations.