Identification of an Adverse Biologic Profile in Cyclophosphamide/Metotrexate/5-Fluorouracil Treated Early Stage Breast Cancer Patients by Immunohistochemical Analysis of PI3K/p-Akt Pathway Alterations

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 24_Supplement; p. 6036
• Main Authors: Mottolese, M., Novelli, F., Di Benedetto, A., Melucci, E., Sperduti, I., Perracchio, L., Buglioni, S., Vici, P., Nisticò, C., Pinnarò, P., Fabi, A., Bria, E.
• Format: Journal Article
• Language: English
• Published: 15.12.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS-09-6036

Abstract Background: Akt activation through PI3K, leads to the phosphorylation of p27 protein thus avoiding nuclear entry and inducing mislocation to the cytoplasm of the protein with consequent inhibition of p27 cell cycle inhibitory function. The prognostic role of PI3K/Akt pathway alterations correlating phenotypic profiles with bio-pathologic variables of known clinical importance have been investigated in a retrospective series of early stage breast cancer patients (BC pts) treated with cyclophosphamide/metotrexate/5-fluorouracil based chemotherapy (CMF).Materials and methods: p-Akt, PI3K and p27 expression were evaluated by immunohistochemistry in a series of stage I/II BC pts who underwent conservative surgery and were candidates to receive CMF adjuvant therapy plus radiotherapy. Multiple Correspondence Analysis (MCA) was used to identify sub-groups of pts with different prognosis, while uni- and multivariate Cox regression analyses were applied to determine the impact of parameters identified by MCA on 10-yrs Disease Free Survival (DFS), together with clinico-pathological features. Receiver Operative Curve (ROC) analysis was adopted for optimal cut-off values.Results: In a series of 133 pts, with a median follow-up of 107 months (range 40 to 141), those pts characterized by high Ki67 index, p53+, p-Akt+, PI3K+ and HER2+ (Adverse Biologic Factors, ABF) were associated with tumor relapse at the MCA analysis. ROC analysis dicotomized between pts with a Favourable Biological Profile (FBP, <3 ABF) and Unfavorable Biologic Profile (UBP ≥ 3 ABF). UBP pts showed a significantly shorter 10- yrs DFS than FBP pts at Kaplan-Meier analysis (67.0% vs 91.3%, p=0.0006). According to the multivariate analysis, the biologic profile was the only significant prognostic indicator for longer DFS (p=0.002). Significant factors at uni- and multivariate analysis are shown in the table.Significant factors at uni- and multivariate analysisFactorsUnivariate (HR, 95% CI)p-valueMultivariate (HR, 95% CI)p-valueGrading3.32 (1.31-8.43)0.012--PgR2.37 (1.03-5.48)0.043--UBP4.24 (1.73-10.40)0.0024.24 (1.73-10.40)0.002 Discussion: These data suggest that the activation of Akt may contribute together with high Ki67 index, p53+, p-Akt+, PI3K+ and HER2+ in predicting recurrence in early stage BC pts homogeneously treated with CMF based therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6036.