Correlation of MDM2, p53 and MIB-1 Expression with Response to Neoadjuvant Chemotherapy in High-Grade Extremity Osteosarcomas and Clinical Outcome
Shalaka N Shirke-Satpute, Bharat Rekhi, Saral S Desai, Ajay Puri, Manish Agarwal, Nirmala A Jambhekar. Tata Memorial Hospital, Mumbai, India
Background: There is a need for identifying predictive markers in high-grade osteosarcomas which would help predict response to neoadjuvant chemotherapy (NACT), so that the treatment can be individualised. This study was carried out to correlate immunohistochemical expression of MDM2 (murine double minute 2), p53 and MIB-1 in pre-treatment biopsies of high-grade extremity osteosarcomas with percentage of tumor necrosis (chemotherapy response) on resected specimens and also with clinical outcome, with an objective to find predictors of NACT response.
Design: Immunohistochemistry for MDM2, p53 and MIB-1 was performed on 100 pre-treatment biopsies of high-grade extremity osteosarcomas. MDM2 and p53 of ≥10% and MIB-1 of >10% tumor cell nuclear staining were considered as positive staining. Chemotherapy response was graded according to Huvos grading system, wherein good responders (GR) had >90% tumor necrosis and poor responders (PR) had ≤90% tumor necrosis. P values were calculated by Log Rank test, using SPSS version 16 (P<0.05 was significant) and survival outcomes by Kaplan-Meier curves.
Results: The mean Disease Free Survival (DFS) for GR (47 months) was significantly higher than for PR (28 months) (P=0.02). Similarly, mean Overall Survival (OAS) for GR (61 months) was significantly higher than for PR (36 months) (P=0.03). More GR (54.3%) had MDM2 negative tumors than PR (33.3%) (P=0.05). However the mean DFS for MDM2 negative tumors was 41 months in contrast to 42 for MDM2 positive cases (P=0.7). Mean OAS for MDM2 negative cases was 49 months in contrast to 64 for MDM2 positive cases (P=0.37). There was no significant correlation between overexpression of p53 and MIB-1 with NACT response. Mean DFS for p53 positive cases was 42 months and for p53 negative cases was 45 (P=0.97). Mean OAS for p53 positive cases was 54 months and for p53 negative cases was 61 (P=0.8). There was no significant correlation between high MIB-1 expression and DFS (P=0.89). Mean OAS for cases with high MIB-1 was 52 months and with low MIB-1 was 58 (P=0.73).
Conclusions: This study reinforces significant association of grade of tumor necrosis in NACT treated high-grade osteosarcoma cases and clinical outcome. However within the studied markers, although MDM2 negativity significantly correlated with good NACT response, p53 negativity correlated with improved survival and MIB-1 over expression came forth as a marker of biologic aggressiveness, none of these markers revealed any statistically significant results vis a vis clinical outcome implying lack of role as predictive markers.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 3, Tuesday Afternoon