BackgroundSelection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer.MethodsA retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8.ResultsThe expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same.ConclusionIntegrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.

With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non-small cell lung cancer. Methods: Patients were evaluated using an imaging protocol including CT, 18 F-FDG PET, H 2 15 O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS). Results: Forty-four patients were included, and 40 underwent CT and 18 F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P 5 0.01, and 12.5 vs. 2.9 mo, P 5 0.009, respectively). Whole-tumor K trans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor K trans values-that is, an increase in regions with low or high K trans values-after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P 5 0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P 5 0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and K trans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point. Conclusion: PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.

First-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG-PET is the best predictive test for PFS.

Approximately 30–40% of the patients with early stage non-small cell lung cancer (NSCLC) will present with recurrent disease within two years of resection. Here, we performed extensive galectin expression profiling in a retrospective study using frozen and paraffin embedded tumor tissues from 87 stage I/II NSCLC patients. Our data show that galectin mRNA expression in NSCLC is confined to galectin-1, -3, -4, -7, -8, and -9. Next to stage, univariable Cox regression analysis identified galectin-1, galectin-9FL and galectin-9Δ5 as possible prognostic markers. Kaplan-Meier survival estimates revealed that overall survival was significantly shorter in patients that express galectin-1 above median levels, i.e., 23.0 (2.9–43.1) vs. 59.9 (47.7–72.1) months (p = 0.020) as well as in patients that express galectin-9Δ5 or galectin-9FL below the median, resp. 59.9 (41.9–75.9) vs. 32.8 (8.7–56.9) months (p = 0.014) or 23.2 (−0.4–46.8) vs. 58.9 (42.9–74.9) months (p = 0.042). All three galectins were also prognostic for disease free survival. Multivariable Cox regression analysis showed that for OS, the most significant prognostic model included stage, age, gal-1 and gal-9Δ5 while the model for DFS included stage, age and gal-9Δ5. In conclusion, the current study confirms the prognostic value of galectin-1 and identifies galectin-9Δ5 as novel potential prognostic markers in early stage NSCLC. These findings could help to identify early stage NSCLC patients that might benefit most from adjuvant chemotherapy.

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Background: Galectins are proteins with a conserved carbohydrate recognition domain and a high affinity for beta-galactosides on glycoconjugates. They are differentially expressed in many pathologies, including cancer. Recent findings suggest a prognostic potential of galectin-1 and -3 in lung cancer as increased expression is frequently associated with enhanced malignancy and poor patient survival. However, prognostic values of the other 13 members of the galectin family in lung cancer remain elusive. We performed extensive galectin expression profiling and determined the prognostic value of all known human galectins in early stage non-small cell lung cancer (NSCLC) patients. Methods: A retrospective study was performed on primary tumors from 93 early stage NSCLC patients with a follow-up of at least 5 years. The mRNA expression levels of all human galectins in NSCLC tumor tissue were determined by qPCR and correlated with overall survival. Additionally, tissue microarrays (TMAs) comprising of both normal and tumor lung tissue were stained for galectin-9 and staining frequency was scored in epithelial cells and endothelial cells (EC). Results: Galectin mRNA expression in NSCLC was shown to be confined to galectin-1, -3, -4, -7, -8, and -9. Patients with galectin-1 expression levels above median showed significant shorter overall survival (43.5 (95% CI 32.4-54.6) vs. 72.2 (59.3-89.0) months; p=0.039, HR=1.5). The expression of galectin-3 was not prognostic in our patient group. Only one other galectin was found to be of prognostic value, i.e. a splice variant of galectin-9 lacking exon 5 (galectin-9D5). Patients with galectin-9D5 expression levels below median have shorter overall survival (49.2 (34.1-64.2) vs. 67.3 (55.0-79.6) months; p=0.007, HR=2.2). Overall patient survival was even worse when patients with high galectin-1 and low galectin-9D5 levels were compared to all other patients (30.0 (16.2-43.9) vs. 70.8 (58.6-83.0) months; p=0.002, HR=4.6). Immunohistochemical staining of TMAs for total galectin-9 revealed no differences between epithelial cells of normal and tumor tissue. However, galectin-9 protein levels were significantly increased in tumor EC compared to normal EC. Conclusion: Comprehensive galectin expression profiling identified a spice variant of galectin-9, i.e. galectin-9D5, as a novel prognostic marker in early stage NSCLC. Interestingly, whereas low galectin-9D5 mRNA expression levels predict poor patient survival, we observed an increased galectin-9 protein expression in tumor EC compared to normal EC. Further research is warranted to unravel role of galectin-9 in angiogenesis and immune regulation in NSCLC. Since it has been shown that adjuvant chemotherapy can improve the survival of patients with resected stage II-IIIa NSCLC, determining the galectin expression profile might serve as a tool in predicting prognosis and treatment selection for individual patients. Citation Format: Victor L. Thijssen, Iris A. Schulkens, Roy Heusschen, Vivian van den Boogaart, Robert-Jan van Suylen, Thang V. Pham, Anne-Marie C. Dingemans, Arjan W. Griffioen. Galectin-9D5 is a prognostic marker in early stage non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 38. doi:10.1158/1538-7445.AM2013-38