Abstract 4648: High membrane carbonic anhydrase IX (CAIX) expression predicts relapse of resected stage I-II non-small cell lung cancer (NSCLC)
Authors: Stewart David J. , Nunez Maria I. , Behrens Carmen , Lin Heather , Lee J. Jack , Roth Jack , Heymach John Victor , Liu Diane D. , Wistuba Ivan Ignacio 
Published: February 2011

Background: Stage predicts outcome in NSCLC but some stage I-II patients relapse. Additional prognostic factors are needed.

Methods: From our NSCLC tumor bank we selected tissues of 230 stage I-II patients who had not received adjuvant chemotherapy. We assessed by immunohistochemistry (IHC) selected factors related to cell growth rate and regulation, hypoxia, transporters and DNA repair. IHC scores (0-300) were calculated by multiplying stain intensity (0-3) by % tumor cells stained. We assessed nuclear (N) p53, p21WAF1/CIP1, Ki67; cytoplasmic (C) COX2, DcR2; N and C CTR1, DNMT1, HIF1a, Rb, pRb, SHARP2, Survivin, VEGF, p14ARF, p16INK4, ERCC1; C and membrane (M) CAIX, TGF-beta. Definitions were: Time to Relapse (TTR): time from surgery to relapse or last follow up (LFU), with censoring at LFU or death or diagnosis of a metastatic 2nd primary, if clinically relapse-free from initial NSCLC; Overall Survival (OS): time from surgery to death, with censoring at LFU if alive at that time.

Results: Exponential decay nonlinear regression analysis [EDNRA] of TTR curves suggested that 70% of patients were cured, with a TTR half-life = 20 months for those relapsing. By EDNRA, OS was uniphasic with half-life = 89 months and no indication of a survival inflection point differentiating those dying from NSCLC vs other causes. In multivariate Cox models, factors correlating with high recurrence risk were M CAIX (any vs none, hazard ratio [HR] 2.08, p=0.02) and node stage (N1 vs N0, HR 2.59, p=0.002). M CAIX (HR 1.92, p=0.05) and node stage (HR 2.54, p=0.003) remain in the model if tumor diameter (TD) is forced into the model (TD HR=1.068, p=0.36). M CAIX correlated (p&lt;0.05) directly with TD, squamous vs adenocarcinoma, C CAIX, C SHARP2, N DNMT1, N pRb and N Ki67 and inversely with C and N CTR1, C and N p16INK4, C DNMT1, C HIF1a, C VEGF, C Rb and N p14ARF. In multivariate Cox models, short OS correlated with age (HR 1.05, p&lt;0.0001), smoking history (HR 2.56, p=0.01), node stage (HR 1.67, p&lt;0.05), TD (HR 1.16, p&lt;0.03), high C CAIX (HR 1.004, p=0.009), low C Rb (HR 0.993, p&lt;0.0001) and high C pRB (HR 1.005, p=0.03). In univariate analyses, factors correlating (p&lt;0.05) with high node stage were high TD and N Rb, and low C DNMT1 and C Rb, with trends (p&lt;0.10) to correlations with high M CAIX, N Survivin, N p53 and N pRb and with low C CTR1, C HIF1a and N p16INK4. Factors correlating (p&lt;0.05) with high TD included high node stage and M CAIX, low C VEGF and other factors.

Conclusion: CAIX deserves further attention as a prognostic factor and therapy target, and correlated more strongly with TTR than did TD or other markers, including the hypoxia markers VEGF and HIF1a. The lack of inflection points on OS EDNRA curves suggests that some of the factors may predict comorbidity and not tumor biology. Hence, TTR as defined here may be the preferred endpoint to assess tumor biology. Support: DoD grant # W81XWH-07-1-0306 and UT-Lung SPORE P50CA070907.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4648.