Membrane Carbonic Anhydrase IX Expression and Relapse Risk in Resected Stage I-II Non-Small-Cell Lung Cancer

Background: Adjuvant chemotherapy reduces recurrences of non-small-cell lung cancer (NSCLC). To determine which patients need adjuvant chemotherapy, we assessed factors associated with time to relapse (TTR). Methods: In 230 resected stage I-II NSCLCs, we correlated immunohistochemistry scores for factors associated with cell growth rate, growth regulation, hypoxia, cell survival, and cell death with TTR. Results: With a median follow-up of 82 months (1-158) for those alive and relapse free at last follow-up, median time to recurrence was not reached. The 2- and 5-year probabilities of maintaining freedom from recurrence were 80.7% (95% confidence interval, 75.3%, 86.4%) and 74.6% (95% confidence interval, 68.6%, 81.2%), respectively. TTR curves flattened at an apparent cure rate of 70%. In multicovariate Cox models, factors correlating with shorter TTR were membranous carbonic anhydrase IX (mCAIX) staining (any versus none, hazard ratio = 2.083, p = 0.023) and node stage (N1 versus N0, hazard ratio = 2.591, p = 0.002). mCAIX scores correlated positively with tumor size, grade, squamous histology, necrosis, mitoses, Ki67, p53, nuclear DNA methyltransferase 1, and cytoplasmic enhancer-of-split-and-hairy-related protein, and they correlated inversely with papillary histology, epidermal growth factor receptor mutation (trend), copper transporter-1, and cytoplasmic hypoxia-inducible factor-1 alpha, vascular endothelial growth factor, DNA methyltransferase 1, and excision repair cross-complementing rodent repair deficiency, complementation group 1. Conclusion: Nodal stage and mCAIX immunohistochemistry were the strongest independent predictors of shorter TTR in resected NSCLCs. mCAIX correlated with tumor size, markers of tumor proliferation and necrosis, and tumor genetic characteristics, and it paradoxically correlated inversely with the hypoxia markers, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor. Presence of mCAIX could help determine patients with high risk of recurrence who might require adjuvant chemotherapy.