P53 protein over-expression but not p53 gene mutation is a poor prognostic marker and a predictive marker for survival benefit from adjuvant chemotherapy in non-small cell lung cancer (NSCLC) in the JBR.10 Trial

7577 Background: JBR.10, a phase III inter-group trial randomized 482 patients with resected stage IB & II NSCLC to receive 4 cycles of adjuvant cisplatin + vinorelbine or observation alone. Chemotherapy patients had an overall survival (OS) benefit (Hazard Ratio [HR] 0.69, p=0.04). P53 has important regulatory roles in cell cycle progression, apoptosis, gene transcription and DNA repair. We evaluated the prognostic and predictive value of p53 in JBR.10. Methods: P53 protein expression was evaluated by immunohistochemistry (IHC) on tissue micro-arrays (282 available blocks). We used the DO7 antibody, and defined ≥15% nuclear staining as the cutoff for over- expression. Mutations in exons 5–9 were determined by denaturing high performance liquid chromatography (446 available samples), followed by sequencing of aberrant PCR products. Results: Successful assays: p53 mutation, 403/446 patients; p53 IHC, 254/282 patients. P53 gene mutations were found in 126/403 (31%) patients. In the observation arm, mutations were not prognostic of poorer survival (HR = 1.18, 95% CI 0.77–1.81; p= 0.45). Adjuvant chemotherapy effect was not significantly different in p53 mutated and wild type patients (interaction p = 0.66), the estimated HR was 0.68 (95% CI 0.46–1, p=0.047) for patients with wild type p53, and 0.79 (95% CI 0.47–1.33, p=0.37) for mutated patients. P53 protein over-expression was found in 133/254 (52%) patients. Patients with over-expression in the observation arm had a higher risk of death than patients with low expression (HR 1.89, 95% CI 1.07–3.34, p=0.03). However, the adjuvant chemotherapy effect was significantly better in p53 over-expressing patients (interaction p= 0.018), with an estimated HR of 0.53 (95% C.I. 0.31–0.90, p=0.03) for p53 over-expressing patients, and 1.40 (95% C.I. 0.78–2.52, p=0.26) for low expressing patients. Conclusions: P53 protein overexpression but not p53 gene mutation is both a significant prognostic marker of poorer survival in the JBR 10 population and a significant predictive marker for the benefit of adjuvant chemotherapy. [Table: see text]