How to evaluate the risk/benefit of trimodality therapy in locally advanced non-small-cell lung cancer

The trimodality approach represented by concurrent chemoradiotherapy followed by surgical resection is a highly effective, but potentially toxic therapy for locally advanced non-small-cell lung cancer (NSCLC). In this review, we discuss the current status of this therapy in patients with mediastinal node-positive (N2) stage III NSCLC or superior sulcus tumor, and present an overview of the principles for optimisation of the risk/benefit. Numerous clinical questions remain, and enrolment of patients into well-designed clinical trials should be encouraged.     

MNK/eIF4E inhibition overcomes anlotinib resistance in non-small cell lung cancer

Anlotinib is approved for refractory cases in advanced non-small-cell lung cancer (NSCLC). This is a novel oral multitarget tyrosine kinase inhibitor, but patients inevitably face prospects of drug resistance during the treatment process. Using anlotinib-resistant NSCLC models, this work investigated the underlying molecular mechanism and systematically addressed the issue of anlotinib resistance. We demonstrated that expression and activity of eukaryotic translation initiation factor 4E (eIF4E) were upregulated in NSCLC cells due to prolonged exposure to anlotinib. eIF4E depletion resulted in significant effects to anlotinib-resistant cells, showing proliferation inhibition and apoptosis inducement. We further showed that MAP kinase interacting serine/threonine kinase (MNK)-dependent eIF4E inhibition by cercosporamide was active against anlotinib-resistant cells and significantly augmented anlotinib's efficacy in parental NSCLC cells. Importantly, observations from in-vitro experiments are consistent in in vivo anlotinib-resistant and anlotinib-sensitive NSCLC cancer xenograft mouse models. Our work is the first to reveal that eIF4E is involved intimately in anlotinib resistance development in NSCLC, and this eIF4E activation can be reversed by cercosporamide or other MNK inhibitors.     

Comparative analysis of methodologies for predicting overall survival in patients with non-small cell lung cancer based on the number and rate of resected positive lymph nodes: A study based on the SEER database for 2010 through 2019

Background

Lymph node (LN) metastasis is crucial in non-small cell lung cancer (NSCLC) prognosis and treatment, but the TNM system lacks LN quantity consideration. Our goal is to investigate the role of positive LNs (nPLN) and positive LN rate (LNR) in overall survival (OS) and assess whether they offer higher value in prognostic assessment of NSCLC than N-stage.

Methods

Patients were stratified into four subgroups using X-Tile software. Statistical analysis was conducted using the Kaplan–Meier method, univariate analysis, and multivariate Cox regression analysis. Model performance was evaluated using the Harrell consistency index (C-index), Akaike information criterion (AIC), and Bayesian information criterion (BIC). The prognostic performance of the nodal classification was validated using overall survival as the endpoint.

Results

The survival curves demonstrate distinct disparities between each nPLN and LNR category. A pronounced trend toward deteriorating overall survival from N-PLN 1 to N-PLN 2+ was observed across all tumor size categories. However, the differences between each LNR category were only significant for tumors ≤3 cm and 5–7 cm. Notably, both nPLN and LNR classifications displayed a higher C-index, lower AIC, and lower BIC compared with the N staging. Furthermore, the LNR classification provided superior prognostic stratification when compared with the nPLN classification.

Conclusions

Our results demonstrate that nPLN and LNR classifications may offer improved prognostic performance compared with the current N classification for LN-positive NSCLC patients. Nonetheless, more studies are needed to assess the feasibility of incorporating these classifications into the next TNM staging system.     

Frizzled-7-targeting antibody (SHH002-hu1) potently suppresses non–small-cell lung cancer via Wnt/β-catenin signaling

Non–small-cell lung cancer (NSCLC) is one of the deadliest cancers worldwide, and metastasis is considered one of the leading causes of treatment failure in NSCLC. Wnt/β-catenin signaling is crucially involved in epithelial–mesenchymal transition (EMT), a crucial factor in promoting metastasis, and also contributes to resistance developed by NSCLC to targeted agents. Frizzled-7 (Fzd7), a critical receptor of Wnt/β-catenin signaling, is aberrantly expressed in NSCLC and has been confirmed to be positively correlated with poor clinical outcomes. SHH002-hu1, a humanized antibody targeting Fzd7, was previously successfully generated by our group. Here, we studied the anti-tumor effects of SHH002-hu1 against NSCLC and revealed the underlying mechanism. First, immunofluorescence (IF) and near-infrared (NIR) imaging assays showed that SHH002-hu1 specifically binds Fzd7⁺ NSCLC cells and targets NSCLC tissues. Wound healing and transwell invasion assays indicated that SHH002-hu1 significantly inhibits the migration and invasion of NSCLC cells. Subsequently, TOP-FLASH/FOP-FLASH luciferase reporter, IF, and western blot assays validated that SHH002-hu1 effectively suppresses the activation of Wnt/β-catenin signaling, and further attenuates the EMT of NSCLC cells. Finally, the subcutaneous xenotransplanted tumor model of A549/H1975, as well as the popliteal lymph node (LN) metastasis model, was established, and SHH002-hu1 was demonstrated to inhibit the growth of NSCLC xenografts and suppress LN metastasis of NSCLC. Above all, SHH002-hu1 with selectivity toward Fzd7⁺ NSCLC and the potential of inhibiting invasion and metastasis of NSCLC via disrupting Wnt/β-catenin signaling, is indicated as a good candidate for the targeted therapy of NSCLC.     

Clinical management of stage III non-small cell lung cancer in India: An expert consensus statement

Non-small cell lung cancer (NSCLC) is considered the most common type of lung cancer (>80% of all lung cancers); patients are often diagnosed at advanced stages of the disease. The management of NSCLC is considered challenging owing to variations in size, an extension of the tumors, involvement patterns, and classification. Although adequate literature and guidelines are available on the management of NSCLC in several countries, an Indian perspective on stage III NSCLC management is lacking. We used the modified Delphi approach to form consensus statements. A thorough literature search was done. The authors then convened and deliberated over published literature, available guidelines, and clinical judgment. Recommendation statements were formed for different clinical scenarios. These statements were sent as a form of survey to other oncologists, and their responses were recorded and mentioned. Evidence-based statements were formed for diagnosing and managing stage III NSCLC. These recommendation statements cover various aspects—surgical, radiation, and medical treatment in various clinical scenarios including adjuvant, neoadjuvant, and consolidation therapies.     

Update on histologic classification of non-small cell lung cancer

Given the recent advances in personalized medicine in lung cancer that are mostly observed in adenocarcinomas, an international multidisciplinary group of lung cancer specialists has recommended a new sub-classification of resected adenocarcinomas, and a histologic classification in small biopsies and cytologic material that constitutes the majority of specimens. Whereas the classification of adenocarcinomas has been shown to have better correlation with prognosis than the current WHO classification, it has brought many questions that need to be addressed. In order to further classify poorly-differentiated NSCLC while preserving tissue for molecular testing in small samples, a minimal 2-marker panel of immunohistochemistry (TTF-1 and 63/p40) has been recommended. In the current WHO classification, squamous cell carcinoma and large cell carcinoma categories include several variants, some of which are based solely on cytomorphologic features and do not appear to have biologic significance. Thus, a new, biology-based sub-classification is also warranted in those categories.