Absence of HER4 expression predicts recurrence of ductal carcinoma in situ of the breast

The type 1 tyrosine kinase receptor HER2 (c-erbB2/neu) is associated with resistance to hormone therapy and poor survival in invasive breast cancer, whereas HER4 expression is associated with endocrine responsiveness. Patterns of tyrosine kinase receptor coexpression may aid prediction of recurrence risk after surgery for ductal carcinoma in situ (DCIS). Women who had undergone surgery for pure DCIS were studied. Out of 129 primary tumors, 39 had recurred and 90 had not recurred after 5 years of follow-up. Primary tumors were compared for HER2, HER3, and HER4, estrogen receptor, and Ki67 by immunohistochemistry. HER2 was expressed in 58%, HER3 in 49%, and HER4 in 63% of nonrecurrent DCIS, compared with HER2 expression in 82% (P = 0.008), HER3 expression in 71% (P = 0.04), and HER4 expression in 36% (P = 0.004) in DCIS that subsequently recurred. Dually expressing HER2/4 DCIS was more likely to be estrogen receptor positive than HER2-only-expressing DCIS (73% versus 53%; P = 0.05). HER2 expression was associated with a higher percentage and HER4 expression a significantly lower percentage of proliferating DCIS cells (median, 13.8% versus 8.4%; P = 0.001). Coexpression of HER2 with HER4 was associated with reduced recurrence compared with HER2-only positive DCIS (P = 0.003). This association remained significant when analyzing only high nuclear-grade DCIS (P = 0.015). Low nuclear grade, low proliferation rate and presence of HER4 expression were independent predictors of nonrecurrence. Potentially, HER4 expression may identify women who could avoid radiotherapy after breast-conserving surgery for DCIS.