Abstract
ObjectivesThe aim was to analyse the tumor expression of Notch1, Hes1, Ascl1, and DLL3 in Small-Cell Lung Cancer (SCLC) and each such biomarker’s potential association with clinical characteristics and prognosis after platinum-doublet chemotherapy (PDCT).Material and methodsThe protein expression of the biomarkers was evaluated using immunohistochemistry. Patients were categorized according to their sensitivity to first line PDCT: with a Progression-free survival (PFS) ≥ 3 months after completion of treatment considered “sensitive” and < 3 months after completion of treatment considered “refractory”. PFS and overall survival were computed using Kaplan-Meier curves with 95% confidence interval.Results and conclusionThe study included 46 patients, with 21 and 25 of the patients having “sensitive” and “refractory” disease, respectively. The majority of patients had a high DLL3 expression (n = 38), while a minority had Notch 1-high expression (n = 10). The chi-square test showed that there was a statistically significant negative association between Notch1 and Ascl1 expression (p = 0.013). The overall survival for patients with Notch1- high vs. low expression was 8.1 vs. 12.4 months, respectively (p = 0.036). Notch1 expression was an independent prognostic factor in the multivariate analysis (p = 0.02). No other biomarker showed any prognostic impact in this highly selected SCLC cohort. DLL3 is highly expressed in the majority of advanced staged SCLC cases, as expected. In the same patient population, Notch1 expression might have a potential prognostic implication, by driving a non-neuroendocrine differentiation process. Given the small number of cases with Notch1 high expression, the results of this study needs to be confirmed on a larger cohort.
Highlights
The aim of this study was to determine the protein expression levels of Notch1, Hes1, achaete-scute homolog 1 (Ascl1), Delta-like protein 3 (DLL3) in Small-Cell Lung Cancer (SCLC) tumor specimen and the potential association of these biomarkers to platinum chemotherapy sensitivity, prognosis as well as clinical factors in SCLC patients. This is to the best of our knowledge, the first study to analyze the expression of these four biomarkers in the same patient cohort. This is the first study, to our knowledge, which validates the use of specific Notch1, Hes1, and Ascl1 antibodies on human SCLC samples, and tries to find cut-offs for low vs high expression based on a biological and clinical rationale
The cohort was highly selected depending on sufficient biopsy material, received platinum chemotherapy and follow-up data, in order to evaluate the specific aims of this study
We found a negative association between Notch1 and Ascl1 expression in our SCLC cohort, which is supported by an earlier study which mechanistically reported that Ascl1 has the ability to reduce Notch1 at both transcription and post-translational level, the later by protein degradation [24]
Summary
Small-Cell Lung Cancer (SCLC) is sensitive to first line platinum-doublet chemotherapy (PDCT), with objective response in more than 50% of the patients [1]. SCLC is characterized by neuroendocrine differentiation and high proliferation [3]. Recent data is beginning to identify other subtypes of SCLC, one of which includes non-neuroendocrine features [1, 4]. A hypothesis is that the Notch signaling pathway is involved in regulating SCLC cells via neuroendocrine differentiation and epithelial to mesenchymal transition [5]. In vitro/in vivo studies have suggested that Notch expression can result in inhibition of cell growth and metastasis of SCLC, its role remains unclear [6, 7]. One gene that is regulated by the Notch protein is hairy/ enhancer of split (Hes1), a basic helix-loop-helix transcription factor, which has been described to prevent transcription of genes that regulate neuroendocrine differentiation [8,9,10]
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