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

Abstract

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 stages I-II NSCLCs we correlated immunohistochemistry (IHC) 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 (1-158) months 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 [CI]:(75.3%, 86.4%)) and 74.6% (95% CI:(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 vs none, hazard ratio [HR]=2.083, p=0.023) and node stage (N1 vs N0, HR=2.591, p=0.002). mCAIX scores correlated positively with tumor size, grade, squamous histology, necrosis, mitoses, Ki67, p53, nuclear DNMT1 and cytoplasmic SHARP2, and correlated inversely with papillary histology, EGFR mutation (trend), CTR1, and cytoplasmic HIF-1α, VEGF, DNMT1, and ERCC1. Conclusion Nodal stage and mCAIX IHC 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 paradoxically correlated inversely with the hypoxia markers HIF-1α and VEGF. Presence of mCAIX could help determine patients with high-risk of recurrence who might require adjuvant chemotherapy.

Prognostic Significance of Carbonic Anhydrase IX Expression in Cancer Patients: A Meta-Analysis

“…The overall HR with 95%CI is visualized with the diamond shape. Dashed line indicates no association between CAIX and prognosis ( 29 , 33 , 34 , 48 , 57 , 59 , 68 , 73 , 74 , 82 , 84 , 85 , 87 , 89 , 90 , 97 , 98 , 112 , 117 , 119 , 121 , 125 , 131 – 143 ).…”

Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms

“…By its catalytical as well as PG-domain related action, carbonic anhydrase IX is involved in various processes leading to tumor cell survival and dissemination. Clinical data show that strong CA IX expression often correlates with high tumor grade, advanced stage, necrosis or poor prognosis in various types of tumors [including glioblastoma ( 74 ), breast carcinoma ( 75 – 77 ), lung carcinoma ( 78 ), head and neck cancer ( 79 ), brain tumors ( 80 ), gastric cancer ( 81 ), and non-small cell lung cancer ( 82 )]. CA IX expression seems to relate to resistance to antitumor therapy, including chemotherapy, radiotherapy and anti-angiogenic treatment.…”

“…At present, the association between CA IX level in tumor tissue and worse response to therapy has been proved also in patients suffering from various types of carcinoma [e.g. head and neck ( 85 ), rectal ( 85 , 86 ), breast ( 87 , 88 ) and non-small cell lung cancer ( 82 , 89 )]. Synthetic glucocorticoid dexamethasone is often prescribed in cancer-related clinical settings.…”

PI3‐kinase pathway biomarkers in oral cancer and tumor immune cells

“…[13][14][15] Expression of each biomarker was jointly quantified by 2 pathologists (MN and IW) in 3 cores per sample and the average was used for downstream statistical analysis. Immunohistochemical staining was performed on deparaffinized and hydrated sections.…”

“…These antibodies had been shown to be specific by Western blot analysis using nonsmall cell lung cancer cell lines and human bronchial epithelial cell line models and had been optimized for immunohistochemistry using cell line pellets fixed in formalin and embedded in paraffin, as previously reported by our group. [13][14][15] Expression of each biomarker was jointly quantified by 2 pathologists (MN and IW) in 3 cores per sample and the average was used for downstream statistical analysis. Scoring of 3 cores allowed us to account for and potentially minimize (but not completely eliminate) interpretation bias resulting from tumor heterogeneity that certainly exists when assessing protein expression levels in different regions of the tumor.…”