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The Mesenchymal State Predicts Poor Disease-Free Survival in Resectable Non-Small Cell Lung Cancer.

ABSTRACT: The epithelial-mesenchymal transition (EMT) is thought to contribute to the overall invasiveness of malignant cells. Expression of cluster of differentiation (CD) 44 and CD90 mark the mesenchymal state in multiple epithelial malignancies. Their role in lung cancer remains unclear, however. This study evaluated the prognostic significance of CD44 and CD90 coexpression in patients with resectable primary non-small cell lung cancer (NSCLC).This was a nonconcurrent cohort study of patients with resectable NSCLC, stratified by the degree of expression of CD44/CD90 double-positive cells in their primary tumor. Flow cytometry was used for immunophenotyping of freshly isolated disaggregated tumor. We analyzed the relationship between expression of CD44/CD90 and relapse-free survival.We evaluated 37 patients (18 men; median age, 70 years) with NSCLC. For this group, the geometric mean proportion of cells coexpressing CD44/CD90 was 0.52%. Expression of CD44/CD90 was significantly elevated (24.4%, geometric mean) in 6 patients. The median relapse-free survival for patients with high CD44/CD90 coexpression was 7.7 months (95% confidence interval, 4.2 to 11.7) compared with 40 months (95% confidence interval, 18.2 to 77.8) for the group with low CD44/CD90 coexpression (p = 0.00006 by Mantel log-rank test). The assessment of risk based upon CD44/CD90 expression status was not correlated with pathologic staging (p = 0.073 by ?2).High expression of CD44 and CD90 was associated with significantly reduced relapse-free survival in NSCLC patients. These results suggest that CD44 and CD90 may be important markers of tumor progression in NSCLC.

SUBMITTER: Mehta K

PROVIDER: S-EPMC5894479 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The Mesenchymal State Predicts Poor Disease-Free Survival in Resectable Non-Small Cell Lung Cancer.

Mehta Kunal K Moravcikova Erika E McFall David D Luketich James D JD Pennathur Arjun A Donnenberg Albert D AD Donnenberg Vera S VS

The Annals of thoracic surgery 20170509 1

<h4>Background</h4>The epithelial-mesenchymal transition (EMT) is thought to contribute to the overall invasiveness of malignant cells. Expression of cluster of differentiation (CD) 44 and CD90 mark the mesenchymal state in multiple epithelial malignancies. Their role in lung cancer remains unclear, however. This study evaluated the prognostic significance of CD44 and CD90 coexpression in patients with resectable primary non-small cell lung cancer (NSCLC).<h4>Methods</h4>This was a nonconcurrent ...[more]

PMID: 28499650

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Project description:BackgroundImmunotherapy has emerged as a promising treatment strategy in malignant tumors. Inhibitors and neutralizing antibodies targeted PD-1 or PD-L1 show improved clinical outcomes in advanced non-small cell lung cancers (NSCLCs). Previous studies concluded that PD-1 was mainly expressed on activated T cells, B cells and other immune cells. Recently, two studies suggested that PD-1 could be detected in the tumor cells of melanoma and hepatocellular carcinoma. Tumor-endogenous PD-1 in NSCLCs has not been reported at present. Thus, we intended to explore the expression and prognostic relevance of tumor-endogenous PD-1 in NSCLCs.MethodsWe detected the PD-1 expression in fresh tumor samples and tumor slices by flow cytometer and immunohistochemical analysis respectively. Overall survival (OS) and dis-ease-free survival (DFS) were analyzed with Kaplan-Meier survival curve. We explored the PD-1 expression in lung cancer cell lines and investigated its effect on cell proliferation.ResultsFlow cytometry showed that tumor cells with endogenous PD-1 constituted 2.08%, 2.42%, 1.79%, and 1.21% in 4 clinical NSCLC samples respectively. Thirty-four patients (34%) in the cohort were positive for tumor-endogenous PD-1 in IHC analysis. Patients with tumor-endogenous PD-1 had significantly worse 5-year overall survival (OS) and disease-free survival (DFS). Multivariate analysis identified tumor-endogenous PD-1 as an independent risk factor (HR =3.807, 95% CI: 2.031-7.135, P<0.05). PD-1 could be observed in 4 kinds of lung cancer cell lines (A549, H1975, H1299 and HCC827). PD-1 overexpression could enhance proliferation and clone formation of these cell lines.ConclusionsPD-1 was endogenously expressed on the tumor cells of NSCLCs, and it could serve as an independent prognostic risk factor. The molecular mechanism of inferior survival of tumor-endogenous PD-1 may attribute to its role in promoting cell proliferation and clone formation. Our results demonstrated the non-immune role of PD-1 in tumor microenvironment and may provide new thinking for the therapy of NSCLCs.

Project description:BackgroundThere is currently a lack of effective biomarkers to evaluate efficacy of neoadjuvant therapy (NAT) for resectable non-small cell lung cancer (NSCLC) patients. Circulating tumor DNA (ctDNA) has been investigated as a non-invasive tool for the assessment of tumor burden and minimal residual disease (MRD). The utility of ctDNA profiling in reflecting NAT efficacy, however, has not been confirmed. This study explored the association of ctDNA change with treatment response to NAT and recurrence-free survival (RFS) after surgery.MethodsEligible patients with stage IB-IIIA NSCLC were retrospectively included if they had received neoadjuvant immunotherapy combined with chemotherapy (IO+Chemo), dual immunotherapy (IO+IO), or chemotherapy alone (Chemo). We conducted ctDNA profiling before and after NAT, after surgery, and during follow-ups using an ultra-deep lung cancer-specific MRD (LC-MRD) sequencing panel.ResultsA total of 22 patients who received NAT followed by surgery between August 2018 and July 2019 were included in this study. The major pathological response (MPR) rates were 58.33% (7/12) in the IO+Chemo group, 25.00% (1/4) in the IO+IO group, and 16.67% (1/6) in the Chemo group. The ctDNA dynamics during NAT were highly concordant with pathologic response, demonstrating 100% sensitivity and 83.33% specificity, for an overall accuracy of 91.67%. Pre-surgery detectable ctDNA (after NAT) trended to correlate with inferior RFS [hazard ratio (HR), 7.41; 95% confidence interval (CI): 0.91-60.22, log-rank P=0.03]. At 3-8 days after surgery, ctDNA was detectable in 31.8% of patients and was an independent risk factor for recurrence (HR, 5.37; 95% CI: 1.27-22.67; log-rank P=0.01). The presence of ctDNA at 3 months after surgery showed 83% sensitivity and 90% specificity for predicting relapse (C-index, 0.79; 95% CI: 0.62-0.95). During disease monitoring after surgery, molecular recurrence by means of ctDNA preceded radiographic relapse, with a median time of 6.83 months.ConclusionsThis study investigated the potential of ctDNA in evaluating NAT efficacy in NSCLC, implying the high concordance between ctDNA and pathological response. We also set out the prognostic value of perioperative ctDNA in predicting recurrence.

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The Mesenchymal State Predicts Poor Disease-Free Survival in Resectable Non-Small Cell Lung Cancer.

Publications

The Mesenchymal State Predicts Poor Disease-Free Survival in Resectable Non-Small Cell Lung Cancer.

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