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Breast Tumor Immunophenotype of BRCA1-Mutation Carriers Is Influenced by Age at Diagnosis

Departments of Cancer Biology [S. A. J. V., L. M. K., G. C.], Biostatistics [P. E.], Hematology and Oncology [G. T. B.], and Anatomic Pathology [J. M., R. R. T.], Cleveland Clinic Foundation, Cleveland, Ohio 44195; and Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada N1G-2W1 [G. D.]

Purpose: Breast tumors of BRCA1 mutation carriers and those of early onset breast cancer cases share similar histological features, being generally high-grade, highly proliferative, aneuploid tumors that are predominantly estrogen- and progesterone-receptor negative. Because histological features of tumors of premenopausal women differ from those of tumors of older women, we sought to determine whether the immunophenotype of breast tumors of BRCA1 mutation carriers was influenced by age at diagnosis.

Experimental Design: We examined 31 breast tumors from BRCA1 mutation carriers and compared them with 81 tumors of age-matched (plus or minus 5 years) breast cancer patients unselected for family history. Tumors were further matched for histology, grade, and size. Paraffin-embedded tumor tissues were examined for protein expression of estrogen receptor (ER), PR, Ki-67, cyclin D1, TP53, HER2, ß-catenin, and cyclin E using immunohistochemical approaches.

Results: ER (P = 0.01), PR (P = 0.06), and cyclin D1 (P = 0.002) were less frequently expressed and Ki-67 (P = 0.01) and ß-catenin (P = 0.04) were more frequently expressed in tumors of BRCA1 mutation carriers than controls. After age stratification, we found a significant difference in the frequency of tumors of BRCA1 mutation carriers diagnosed before 50 years of age compared with age-matched controls that stained positive for ER (P = 0.01), PR (P = 0.03), Ki-67 (P = 0.008), cyclin D1 (P < 0.001), HER2 (P = 0.04), and ß-catenin (P = 0.05). However, no significant differences were observed in tumors of BRCA1 mutation carriers diagnosed at age 50 or older compared with age-matched controls.

Conclusions: These data suggest that age at diagnosis, possibly related to menopausal status, may be an important factor in the expression of specific proteins in breast tumors of BRCA1 mutation carriers.

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