Prognostic significance of phosphorylated P38 mitogen‐activated protein kinase and HER‐2 expression in lymph node‐positive breast carcinoma

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Abstract
BACKGROUND Chemotherapy‐induced p38 mitogen‐activated protein kinase (MAPK) phosphorylation reportedly leads to increased apoptosis in breast carcinoma cells. The goals of the current study were to assess the incidence of activated phosphorylated p38 MAPK (P‐p38) expression in invasive breast carcinoma, correlate expression of P‐p38 MAPK with HER‐2, and estimate the prognostic value of this marker in patients with lymph node‐positive breast carcinoma treated with adjuvant chemotherapy. METHODS P‐p38, HER‐2, and Ki‐67 were measured using immunohistochemistry (peroxidase method) in 96 patients with lymph node‐positive breast carcinoma treated with adjuvant fluorouracil, doxorubicin, and cyclophosphamide chemotherapy. All markers were measured in the primary tumors, before the initiation of adjuvant chemotherapy. The median follow‐up period was 11 years after initial cancer surgery. P‐p38 MAPK expression was scored visually and quantified using an image analyzer. RESULTS The rate of P‐p38 MAPK expression ranged from 19–24%, depending on the scoring system used. There was a trend toward shorter progression‐free survival (PFS) for patients whose tumors expressed high levels of P‐p38 MAPK, although the difference was not statistically significant (P = 0.39). PFS was shorter in patients whose tumors overexpressed P‐p38 MAPK and had a high level of Ki‐67 (P = 0.04). In HER‐2–negative patients, P‐p38 MAPK overexpression was associated with a shorter PFS (P = 0.05). CONCLUSIONS P38 MAPK phosphorylation occurred in 20% of primary breast carcinomas and may be associated with poor outcome in patients with lymph node‐positive breast carcinoma. Further studies are needed to define the interaction between P‐p38 MAPK and HER‐2 expression in breast carcinoma. Cancer 2004. © 2003 American Cancer Society.