Immunohistochemical analysis of C/EBPalpha in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: a correlative study of E3590

Abstract

Purpose: We sought to determine the association of C/EBPalpha expression status with clinical, pathologic and molecular characteristics, as well as outcomes, in non-small-cell lung cancer (NSCLC). This is the first comprehensive study of this transcription factor in patients with NSCLC.

Patients and methods: Our cohort originated from ECOG 3590 (randomized trial of postoperative adjuvant therapy with thoracic radiation or cisplatin and etoposide plus thoracic radiation in patients with completely resected stages II and IIIA NSCLC; and its laboratory correlate, ECOG 4592). One hundred and sixty four tumor samples contained sufficient material for immunohistochemical (IHC) analysis. C/EBPalpha tumor staining was compared to that of basal bronchial cells (3+). 0 or 1+ (weak) suggested lack of, while 2 or 3+ (strong) suggested C/EBPalpha expression.

Results: Ninety tumors (55%) had 0 or 1+ C/EBPalpha staining, and the remaining 74 (45%) 2 or 3+. Patients with squamous cell carcinomas had a higher percentage of weak C/EBPalpha IHC staining compared to other histologies (p=0.048) and there was a trend for loss of C/EBPalpha in poorly differentiated compared to well differentiated tumors (p=0.07). There was no association between C/EBPalpha IHC and mutations in p53 or K-ras. The median disease-free survival for patients with weak and strong C/EBPalpha IHC expression was 29.6 and 30.6 months, respectively (p=0.94). The median overall survival between the weak and strong groups was 43.5 and 38.5 months, respectively (p=0.83).

Conclusions: Loss of expression of C/EBPalpha is seen in over half of stage II and IIIA NSCLC, specifically in squamous cell carcinomas and poorly differentiated tumors. Since down-regulation of C/EBPalpha is a common event in NSCLC, further elucidation of the involvement of C/EBPalpha in the pathogenesis and progression of lung cancer may identify novel therapeutic targets.

Figures

Figure 1

Immunohistochemical patterns for C/EBPα expression in E3590. Representative images: A) Normal bronchial mucosa with strong C/EBPa staining of bronchial epithelium (3+). B) Lack of C/EBPα staining (0) within tumor cells, C) Faint C/EBPα staining (1+), D) Moderate staining (2+), E) Strong C/EBPα staining within tumor cells (3+, which is comparable to that of the normal bronchial epithelium). (A, 100X; B, C, D and E, 400X).

Figure 2

Survival curves in the weak and strong C/EBPα immunohistochemistry (IHC) groups. A) Disease-free survival and B) Overall survival. The solid line represents the strong IHC (2+ or 3+) group and the dashed line represents the weak IHC group (0 or 1+).

Figure 3

Survival curves in the weak and strong C/EBPα immunohistochemistry (IHC) groups by treatment arm of E3590. A) Overall survival in arm A: radiotherapy; and B) Overall survival in arm B: chemoradiation. The solid line represents the strong IHC (2+ or 3+) group and the dashed line represents the weak IHC group (0 or 1+).