Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Introduction: Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first-line treatment of NSCLC; however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. Methods: Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 out of 22). Operation was performed between day 29 and 43. Positron emission tomographycomputed tomography scans were obtained at baseline and before the operation. The primary end point was safety. Efficacy end points included rate of major pathologic response (MPR) and objective response rate. Expression of programmed cell death ligand 1 was also evaluated (registration number: ChiCTR-OIC-17013726). Results: A total of 40 patients enrolled, all of whom received two doses of sintilimab and 37 underwent radical resection. A total of 21 patients (52.5%) experienced neoadjuvant treatment-related adverse events (TRAEs). Four patients (10.0%) experienced grade 3 or higher neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an objective response rate of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including six (16.2%) with a pathologic complete response in primary tumor and three (8.1%) in lymph nodes as well. Squamous cell NSCLC exhibited superior response compared with adenocarcinoma (MPR: 48.4% versus 0%). Decrease of maximum standardized uptake values after sintilimab treatment correlated with pathologic remission (p < 0.00001). Baseline programmed cell death ligand 1 expression of stromal cells instead of tumor cells was correlated with pathologic regression (p ¼ 0.0471).

Accurately evaluating minimal residual disease (MRD) could facilitate early intervention and personalized adjuvant therapies. Here, using ultradeep targeted next-generation sequencing (NGS), we evaluate the clinical utility of circulating tumor DNA (ctDNA) for dynamic recurrence risk and adjuvant chemotherapy (ACT) benefit prediction in resected non-small cell lung cancer (NSCLC). Both postsurgical and post-ACT ctDNA positivity are significantly associated with worse recurrence-free survival. In stage II-III patients, the postsurgical ctDNA positive group benefit from ACT, while ctDNA negative patients have a low risk of relapse regardless of whether or not ACT is administered. During disease surveillance, ctDNA positivity precedes radiological recurrence by a median of 88 days. Using joint modeling of longitudinal ctDNA analysis and time-to-recurrence, we accurately predict patients’ postsurgical 12-month and 15-month recurrence status. Our findings reveal longitudinal ctDNA analysis as a promising tool to detect MRD in NSCLC, and we show pioneering work of using postsurgical ctDNA status to guide ACT and applying joint modeling to dynamically predict recurrence risk, although the results need to be further confirmed in future studies.

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Background Lung adenocarcinomas (LUAD) is the most common histological subtype of lung cancers. Tumor immune microenvironment (TIME) is involved in tumorigeneses, progressions, and metastases. This study is aimed to develop a robust immune‐related signature of LUAD. Methods A total of 1774 LUAD cases sourced from public databases were included in this study. Immune scores were calculated through ESTIMATE algorithm and weighted gene co‐expression network analysis (WGCNA) was applied to identify immune‐related genes. Stability selections and Lasso COX regressions were implemented to construct prognostic signatures. Validations and comparisons with other immune‐related signatures were conducted in independent Gene Expression Omnibus (GEO) cohorts. Abundant infiltrated immune cells and pathway enrichment analyses were carried out, respectively, through ImmuCellAI and gene set enrichment analysis (GSEA). Results In Cancer Genome Atlas (TCGA) LUAD cohorts, immune scores of higher levels were significantly associated with better prognoses ( P < .05). Yellow (n = 270) and Blue (n = 764) colored genes were selected as immune‐related genes, and after univariate Cox regression analysis ( P < .005), a total of 133 genes were screened out for subsequent model constructions. A four‐gene signature (ARNTL2, ECT2, PPIA, and TUBA4A) named IPSLUAD was developed through stability selection and Lasso COX regression. It was suggested by multivariate and subgroup analyses that IPSLUAD was an independent prognostic factor. It was suggested by Kaplan‐Meier survival analysis that eight out of nine patients in high‐risk groups had significantly worse prognoses in validation data sets ( P < .05). IPSLUAD outperformed other signatures in two independent cohorts. Conclusions A robust immune‐related prognostic signature with great performances in multiple LUAD cohorts was developed in this study.

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Background : The systemic immune-inflammation index (SII) has been reported to be associated with patient survival in various kinds of solid tumors. However, just few studies have focused on its prognostic value in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Materials and Methods : This study was a single-institution, retrospective analysis of 468 ESCC patients who underwent curative esophagectomy at the Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between 2005 and 2008. The receiver operating curve (ROC) was plotted to compare the discrimination ability of the SII and other inflammatory factors for overall survival (OS) and disease-free survival (DFS). Univariate and multivariate analyses were performed based on the Cox proportional hazards regression model. Results : The SII, neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were all associated with OS in ESCC patients. The SII, NLR, and PLR were independent prognostic factors for OS (hazard ratio (HR) = 1.604, 95% confidence interval (CI) 1.247-2.063, P < 0.001; HR = 1.396, 95% CI 1.074-1.815, P = 0.013; HR = 1.370, 95% CI 1.067-1.758, P = 0.013, respectively) and DFS (HR = 1.681, 95% CI 1.307-2.162, P < 0.001; HR = 1.376, 95% CI 1.059-1.788, P = 0.017; HR = 1.398, 95% CI 1.089-1.794, P = 0.009, respectively). The area under the curve (AUC) for SII was bigger than NLR, PLR, and MLR (0.553, 0.540, 0.532, and 0.521, respectively). Conclusion : The SII is a simple and promising prognostic predictor for patients with surgically resected ESCC. The prognostic value of SII is superior to those of the NLR, PLR and MLR. Moreover, the SII retained prognostic significance in stage I-II ESCC subgroup (OS, DFS) and stage III ESCC subgroup (DFS).