Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation.

Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

Excellent Prognosis of Patients With Invasive Lung Adenocarcinomas During Surgery Misdiagnosed as Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, or Minimally Invasive Adenocarcinoma by Frozen Section.

BACKGROUND: Our previous study revealed that intraoperative frozen section (FS) analysis could differentiate invasive lung adenocarcinoma (LUAD) accurately from preinvasive lesions. However, few articles have analyzed the clinical impact of FS errors such as underestimation of invasive adenocarcinomas (IACs), and whether complementary therapy is needed remains controversial. RESEARCH QUESTION: What is the prognosis of patients undergoing limited resection for invasive LUAD misdiagnosed as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive adenocarcinoma (MIA) by intraoperative FS analysis? STUDY DESIGN AND METHODS: From 2012 through 2018, data on 3031 patients undergoing sublobar resection of AAH, AIS, or MIA diagnosed by FS analysis were collected. The concordance rate between FS analysis and final pathologic results was evaluated. To assess the clinical significance of a discrepancy between FS and final pathologic results, patients with final pathologic results of IAC were identified for prognostic evaluation. RESULTS: When AAH, AIS, and MIA were classified together as a group, the overall concordance rate between FS and final pathologic results was 93.7%, and 192 patients (6.3%) received an upgraded diagnosis from the final pathologic results. Misdiagnosed IACs consisted of 94 patients (48.9%) with lepidic-predominant adenocarcinoma, 77 patients (40.1%) with acinar predominant adenocarcinoma, 19 patients (9.9%) with papillary predominant adenocarcinoma, one patient with solid predominant adenocarcinoma, and one patient with invasive mucinous adenocarcinoma. Among these patients, no positive N1 or N2 lymph node findings were observed. Moreover, the 5-year recurrence-free survival was still 100%, although the final pathologic results turned out to be IAC. INTERPRETATION: Patients undergoing limited resection of invasive LUAD misdiagnosed as AAH, AIS, or MIA by FS analysis showed excellent prognoses. Sublobar resection guided by FS diagnosis would be adequate for these underestimated cases of invasive LUAD.

Chinese perspectives on clinical efficacy and safety of alectinib in patients with ALK-positive advanced non-small cell lung cancer.

The incidence of lung cancer is increasing in China, in contrast to trends in Western countries, due to the increasing numbers of smokers and high levels of air pollution. Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85% of lung cancers. Better understanding of the pathogenesis of NSCLC has led to the identification of multiple genetic mutations and chromosomal translocations such as those in the anaplastic lymphoma kinase (ALK) gene. To facilitate the identification of treatment targets, multiple guidelines (European Society for Medical Oncology, National Comprehensive Cancer Network, and American Society of Clinical Oncology) now recommend screening for genetic factors to help guide treatment decisions. In recent years, multiple ALK inhibitors have been developed to treat NSCLC, including the first-generation tyrosine kinase inhibitor (TKI) crizotinib; second-generation TKIs such as ceritinib, ensartinib, brigatinib, and alectinib; the third-generation TKI lorlatinib; and the fourth-generation TKI repotrectinib. These agents differ in structure, potency, and activity, both systemically and their effects on central nervous system (CNS) metastases. Recently, alectinib was approved in China to treat patients with locally advanced or metastatic NSCLC that were ALK+. Alectinib has demonstrated activity against NSCLC, including metastases within the CNS, with better tolerability than crizotinib. These ALK inhibitors represent significant advances in the treatment of NSCLC and yet patients will likely still exhibit disease progression. Alectinib offers greater potency with greater specificity as well as a better toxicity profile than many other TKIs that are currently available. Here, we review the role of ALK as a therapeutic target in NSCLC, the testing methods for identifying ALK-rearranged NSCLC, and the various TKIs currently being used or explored for treatment in this setting, with a focus on alectinib from a Chinese perspective.

Appropriate lymphadenectomy significantly reduced recurrence after segmentectomy for patients with non-small cell lung cancer.

BACKGROUND: Segmentectomy has been widely used for small-sized non-small cell lung cancer (NSCLC). The objective of this study is to determine the impact of number of harvested lymph nodes (LNs) on survival for patients undergoing segmentectomy. METHODS: The clinicopathologic data of patients undergoing segmentectomy for NSCLC from July 2011 to December 2014 were retrospectively analyzed. Survival analysis was performed by Kaplan-Meier method and Cox regression analysis. RESULTS: A total of 259 patients with NSCLC were eligible for analysis. Patients with harvested LN ≥6 had higher frequency of nodal metastasis in pathologic examination (9.4% vs. 1.5%, P=0.005). The 3-year recurrence-free survival (RFS) of patients with harvested LN ≥6 (90.2%) was significantly higher than that of patients with harvested LN <6 (73.7%, log-rank P=0.038). Multivariable Cox analysis identified harvested LN ≥6 as an independent predictor for improved RFS [hazard ratio (HR) =0.35; 95% confidence interval (CI): 0.14-0.90; P=0.029]. There was no significant difference in RFS between patients with harvested LN station ≥3 and <3 (log-rank P=0.34). CONCLUSIONS: The number of harvest LN ≥6 was independently associated with improved RFS for NSCLC patients undergoing segmentectomy, supporting the National Comprehensive Cancer Network (NCCN) guidelines of appropriate LN sampling.

Disease-free survival improved by use of adjuvant EGFR tyrosine kinase inhibitors in resectable non-small cell lung cancer: an updated meta-analysis.

BACKGROUND: A previous meta-analysis of our research team suggested survival advantage from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) after surgery in patients with EGFR-mutant non-small cell lung cancer (NSCLC). This study aims to follow up on the findings of the previous one and presents our latest updates through the past few years. METHODS: The study advanced the previous meta-analysis and included a comprehensive range of relevant studies in PubMed. Disease-free survival (DFS) with hazard ratios (HRs) was calculated using random and/or fixed-effects models. Subgroup analysis and meta-regression analysis were also performed. RESULTS: A total of 2,223 patients in seven studies were eligible for the analysis. Adjuvant EGFR-TKIs administration was significantly associated with superior DFS [HR, 0.60; 95% confidence interval (CI), 0.42-0.87], corresponding to an absolute benefit of 3.4% at 3 years, yet with significant heterogeneity (I2=80.0%, P <0.001). EGFR mutation rate of included patients was found to be a source of heterogeneity by meta-regression analysis (P=0.005). In the EGFR-mutant sub-population, HR for DFS was 0.51 (95% CI, 0.39-0.65), corresponding to an absolute benefit of 7.1% at 3 years. The rate of overall grade 3 or greater adverse events (AEs) was 38.9% (95% CI, 35.9-41.9%). CONCLUSIONS: The updated meta-analysis provided strengthened evidence of significant DFS advantage of adjuvant EGFR-TKI treatment for patients with EGFR-mutant NSCLC after complete resection.

Efficacy of EGFR Tyrosine Kinase Inhibitors in the Adjuvant Treatment for Operable Non-small Cell Lung Cancer by a Meta-Analysis.

BACKGROUND: The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the adjuvant treatment of non-small cell lung cancer (NSCLC) has not been well-established. Our meta-analysis aimed to determine whether the administration of EGFR-TKIs could improve the outcomes of patients with NSCLC undergoing complete resection. METHODS: We comprehensively searched databases and extracted data from eligible studies. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) as well as disease relapse with odds ratios (OR) were calculated using random and/or fixed-effects models. Meta-regression analysis and test for interaction between subgroups were also carried out. RESULTS: A total of 1,960 patients in five studies were included. Adjuvant EGFR-TKI treatment was associated with a significant benefit on DFS (HR, 0.63; 95% CI, 0.41-0.99), corresponding to an absolute benefit of 3.1% at 3 years, yet with significant heterogeneity (I(2) = 83.4%, P < .001). The survival benefit was superior (Pinteraction = .03) in studies with more than an 18-month median treatment duration. EGFR mutation rate was also identified as a source of heterogeneity (P = .017). In the population with EGFR mutations, HR for DFS was 0.48 (95% CI, 0.36-0.65), corresponding to an absolute benefit of 9.5% at 3 years, with a reduced risk of distant metastasis (OR, 0.71; 95% CI, 0.56-0.92). Adjuvant EGFR-TKI treatment resulted in a marginally statistically significant benefit on OS (HR, 0.72; 95% CI, 0.49-1.06). The rate of overall grade 3 or greater adverse events was 42.3% (95% CI, 39.1-45.6). CONCLUSIONS: Adjuvant EGFR-TKI treatment may enhance disease-free survival and reduce the risk of distant metastasis in patients with EGFR-mutant NSCLC undergoing complete resection.