ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 insertion Y772_A775dupYVMA was the most frequent alteration (58% vs 41.6% in the Chinese vs the US), followed by G776delinsVC/LC/VV/IC (10.7% vs 9.7%), and S310X (10.5% vs 15.4%). EGFR ex20 insertions were identified in the A767-V774 region, whereas ERBB2 ex20 insertions were observed in the Y772-P780 region. Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases.

BACKGROUND:Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung adenocarcinoma. More investigations about precision therapy in PEAC were required to improve the prognosis.METHODS:Twenty-four patients with PEAC were enrolled in this study. Tumor tissue samples were available from 17 patients for both DNA and RNA based next-generation sequencing, PD-L1 IHC staining and PCR-based microsatellite instability (MSI) analysis.RESULTS:TP53 (70.6%) and KRAS (47.1%) were the most frequently mutated genes in PEAC. For KRAS mutations, the prevalence of G12D (37.5%) and G12V (37.5%) was higher than G12A (12.5%) and G12C (12.5%). Actionable mutations in receptor tyrosine kinase (including one EGFR and two ALK mutations), PI3K/mTOR, RAS/RAF/MEK, homologous recombination repair (HRR) and cell cycle signaling pathways were identified in 94.1% of patients with PEAC. While PD-L1 expression was observed in 17.6% (3/17) patients, no MSI-H patients were identified. Transcriptomic data showed that two patients with positive PD-L1 expression had relatively high immune infiltration. In addition, prolonged survival was obtained with the treatment of osimertinib, ensartinib, and immunotherapy combined with chemotherapy in two EGFR-mutated, one ALK-rearranged, and one PD-L1 expressed patients, respectively.CONCLUSION:PEAC is a disease of genetic heterogeneity. The administration of EGFR and ALK inhibitors was effective in patients with PEAC. PD-L1 expression and KRAS mutation type may be used as predictive biomarkers for immunotherapy in PEAC. This study provided both theoretical basis and clinical evidence for PEAC.

Lung cancer is one of the most threatening diseases to human life and health because of its mortality. How to choose more efficient drugs and the appropriate timing of treatment for patients with advanced lung cancer is still a problem. As the urine proteome can sensitively reflect the pathological or physiological changes of the body, it has the potential to reflect the dynamic changes of the body after drug treatment. To investigate the changes in the urine proteome of patients with advanced lung cancer after different drug treatments, urine samples were collected and analyzed at different time points. The changes in the urine proteome from the pretreatment state were different in each patient, although some of them were treated with the same drugs. The changes in the biological processes reflected by the differential urinary proteins were consistent with the changes in the clinical manifestations of the patients. This study demonstrates that the pathophysiological changes of patients with advanced lung cancer can be reflected by changes in urinary protein after different drug treatments. In addition, the changes in urinary proteins can reflect the different biological processes in patients after the same drug treatment, and the patients’ clinical condition assessment results are consistent with these changes. These findings may provide additional information for clinical treatment.

Background: Necroptosis is associated with oncogenesis, tumor immunity and progression. This research aims to investigate the association of necroptosis-related genes with drug sensitivity and prognosis in hepatocellular carcinoma (HCC). Methods: Based on necroptosis-related signatures, HCC patients retrieved from the TCGA database were categorized. Survival outcomes, mutation profile, immune microenvironment, and drug sensitivity between HCC subtypes were further compared. Then, LASSO analysis was performed to construct a necroptosis-related prognostic signature, which was further evaluated using another independent cohort. Results: A total of 371 patients with HCC could be categorized into two necroptosis-related subtypes. About 36% of patients were allocated to subtype A, with worse survival, more mutant TP53, and a lower likelihood of immunotherapy response. In contrast, patients in subtype B had a favorable prognosis, with lower expression of immunosuppressive signatures but a lower abundance of B and CD8+ T-cell infiltration. The prognostic risk score calculated using the expression levels of nine genes involved in the necroptosis pathway (MLKL, FADD, XIAP, USP22, UHRF1, CASP8, RIPK3, ZBP1, and FAS) showed a significant association with tumor stage, histologic grade, and Child‒Pugh score. Additionally, the risk score model was proven to be accurate in both the training and independent external validation cohorts and performed better than the TNM staging system and three well-recognized risk score models. Conclusions: Based on necroptosis-related signatures, we identified two HCC subtypes with distinctive immune microenvironments, mutation profiles, drug sensitivities, and survival outcomes. A novel well-performing prognostic model was further constructed.

Abstract Background Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications. Methods Whole‐exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI). Results Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056–0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36. Conclusions TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.

PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

Background: Accumulating evidence has suggested that the extracellular matrix (ECM) plays a vital role in the development and progression of cancer, and could be recognized as a biomarker of the response to immunotherapy. However, the effect of the ECM signature in hepatocellular carcinoma (HCC) is not well understood. Methods: HCC patients derived from the TCGA-LIHC dataset were clustered according to the ECM signature. The differences in prognosis, functional enrichment, immune infiltration, and mutation characteristics between distinct molecular clusters were examined, and its predictive value on the sensitivities to chemotherapy and immunotherapy was further analyzed. Then, a prognostic model was built based on the ECM-related gene expression pattern. Results: HCC patients were assigned into two molecular subtypes. Approximately 80% of HCC patients were classified into cluster A with poor prognosis, more frequent TP53 mutation, and lower response rate to immunotherapy. In contrast, patients in cluster B had better survival outcomes and higher infiltration levels of dendritic cells, macrophages, and regulatory T cells. The prognostic risk score model based on the expression profiles of six ECM-related genes (SPP1, ADAMTS5, MMP1, BSG, LAMA2, and CDH1) demonstrated a significant association with higher histologic grade and advanced TNM stage. Moreover, the prognostic risk score showed good performance in both the training dataset and validation dataset, as well as improved prognostic capacity compared with TNM stage. Conclusions: We characterized two HCC subtypes with distinct clinical outcomes, immune infiltration, and mutation characteristics. A novel prognostic model based on the ECM signature was further developed, which may contribute to individualized prognostic prediction and aid in clinical decision-making.

e23519 Background: Both undifferentiated sarcoma of soft tissue and undifferentiated carcinomas can arise in multiple tissue and are with an aggressive clinical course. While undifferentiated sarcomas that remain a diagnosis of exclusion and show extreme genomic complexity, less is known about undifferentiated carcinoma. Methods: Sixty-two patients diagnosed as undifferentiated sarcoma (n = 36, 10 bone/limbs, 9 abdomen, 9 pelvis, and 8 chest/intrathoracic) or carcinoma (n = 26, excluding undifferentiated carcinoma of nasopharynx and thyroid, 15 chest/intrathoracic, 8 abdomen, and 3 pelvis) were recruited in the study. Mutational analysis was performed by next-generation sequencing of 1021 tumor related genes, which enabled analysis of TMB and MSI as well. PD-L1 expression data was available in 24 patients. Results: Fifty-eight patients (93.5%, 58/62) had at least 1 mutation identified and 542 SNV, 115 CNV and 5 fusions were identified in total in the 62 patients. The top 5 mutant genes were TP53 (56.5%, 35/62), TERT (11.3 %, 7/62), SMARCA4 (9.7%, 6/62), LRP1B (9.7%, 6/62), and MLL2 (9.7%, 6/62). Interestingly, mutation in TP53 was more common in undifferentiated carcinoma (73.08%, 19/26) than sarcoma (44.44%, 16/36, p = 0.0377). Two ERBB2 CNV and 1 KIF5B-RET fusion were identified in 2 gastric carcinoma and 1 lung large cell carcinoma. However, no carcinoma but 2 sarcoma (1 polymorphic undifferentiated sarcoma in the limb and 1 undifferentiated small round cell sarcoma in the lung) showed MSI-H, with TMB as high as 22.08 and 65.28 respectively, while the median TMB was 3.84 mutations/Mb. Among the 24 patients with PD-L1 data, 16 were > 1%, and 5 were > 50%, with no significant difference between undifferentiated carcinoma and sarcoma. Conclusions: In spite of the genome complexity in undifferentiated sarcoma of soft tissue and carcinoma, there was limited actionable mutations in these two aggressive tumors. However, immunotherapy should be considered since over half of these patients were PD-L1 positive and nearly a quarter of them had high PD-L1 expression.

Background:Lepidic adenocarcinoma (LPA) is an infrequent subtype of invasive pulmonary adenocarcinoma (ADC). However, the clinicopathological features and prognostic factors of LPA have not been elucidated. Methods:Data from the Surveillance, Epidemiology, and End Results (SEER) database of 4191 LPA patients were retrospectively analyzed and compared with non-LPA pulmonary ADC to explore the clinicopathological and prognosis features of LPA. Univariate and multivariate Cox proportional hazard models were performed to identify independent survival predictors for further nomogram development. The nomograms were validated using the concordance index, receiver operating characteristic curves, and calibration plots, as well as decision curve analysis, in both the training and validation cohorts. Results:Compared with non-LPA pulmonary ADC patients, those with LPA exhibited unique clinicopathological features, including more elderly and female patients, smaller tumor size, less pleural invasion, and lower histological grade and stage. Multivariate analyses showed that age, sex, race, tumor location, primary tumor size, pleural invasion, histological grade, stage, primary tumor surgery, and chemotherapy were independently associated with overall survival (OS) and cancer-specific survival (CSS) in patients with LPA. The nomograms showed good accuracy compared with the actual observed results and demonstrated improved prognostic capacity compared with the TNM stage. Conclusions:LPA is more frequently diagnosed in older people and women. LPA was inclined to be smaller in tumor size and lower in tumor grade and staging, which may indicate a favorable prognosis. The constructed nomograms accurately predict the long-term survival of LPA patients.

Immune checkpoint inhibitors (ICIs) have shown significant efficacy in clinical trials and applications of various malignant tumors, and have been approved for clinical application in China. ICIs can cause immune-related adverse events (irAEs), which may affect any organs. Early identification and appropriate treatment can improve patient outcome. 18F-FDG PET/CT is capable of early detection of irAEs and provides effective clinical guidance. This article reviews the clinical application of 18F-FDG PET/CT in detecting irAEs, including typical imaging findings and research progress.

Osimertinib-induced interstitial lung disease (ILD) is an uncommon, but fatal pulmonary toxicity in some patients. We report a case of a 64-year-old male with stage IV adeno-non-small cell lung cancer (NSCLC) harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) treated with osimertinib 80 mg/d for first-line targeted therapy. On day 60 after initiating treatment of osimertinib, the patient developed ILD. Osimertinib was discontinued immediately and oral prednisone 60 mg/d was initiated, ILD improved within 13 d. After balancing the risk and benefit, osimertinib was restarted concurrently with prednisone. The patient showed neither disease progression nor a recurrence of ILD for more than 16 months. Based on our case and literature review, retreatment with osimertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant NSCLC.
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Lung adenocarcinoma (LUAD) is the most common histological subtype in non-small cell lung cancer, which is the malignant tumor with the highest mortality and morbidity in the world. Herein, ZNF280A, a member of the zinc finger protein family carrying two consecutive Cys2His2 zinc finger domains, was shown by us to act as a tumor driver in LUAD. The immunohistochemical analysis of ZNF280A in LUAD indicated its positive correlation with tumor grade, pathological stage and lymphatic metastasis, and negative relationship with patients’ survival. A loss-of-function study revealed the inhibition of LUAD development by ZNF280A in vitro and in vivo, whereas ZNF280A overexpression induced opposite effects. Statistical analysis of gene expression profiling in LUAD cells with or without ZNF280A knockdown identified EIF3C as a potential downstream of ZNF280A, which possesses similar regulatory effects on phenotypes of LUAD cells with ZNF280A. Moreover, downregulation of EIF3C in ZNF280A-overexpressed cells could attenuate neutralize the ZNF280A-induced promotion of LUAD. In summary, our study demonstrated that ZNF280A may promote the development of LUAD by regulating cell proliferation, apoptosis, cell cycle, and cell migration and probably via interacting EIF3C.

Recent studies have reported the crucial role of stanniocalcin-2 (STC2) in hepatocellular carcinoma; however, its role in head and neck squamous cell carcinoma (HNSCC) remains elusive. In this study, microRNA-206 (miR-206) was predicted to target STC2 gene. The study herein aimed to elucidate the effect of miR-206 on HNSCC by targeting STC2. STC2 was highly expressed in HNSCC tissues and cells. By targeting STC2, miR-206 decreased mRNA and protein expression of STC2. Importantly, our study showed that miR-206 blocked the Akt signaling pathway by inhibiting STC2. Intriguingly, our data from in vitro and in vivo experiments suggested that miR-206 overexpression led to decreased cell proliferation and increased cell apoptosis and autophagy, as well as suppressed tumor growth; whereas, STC2 silencing reversed the effects of miR-206 inhibitor on those biological behaviors. In this study, we investigated the antioncogenic effect of miR-206 on HNSCC by targeting STC2, and highlighted miR-206/STC2 aixs as potential therapeutic targets for HNSCC.

Background: Neoantigens are newly formed antigens that have not been previously recognized by the immune system. They may arise from altered tumor proteins that form as a result of mutations. Although neoantigens have recently been linked to antitumor immunity in long-term survivors of cancers, such as melanoma and colorectal cancer, their prognostic and immune-modulatory role in many cancer types remains undefined. Objective: The purpose of this study is to identify prognostic markers for long-term extrahepatic cholangiocarcinoma (EHCC) survival. Methods: We investigated neoantigens in EHCC, a rare, aggressive cancer with a 5-year overall survival rate lower than 10%, using a combination of whole-exome sequencing (WES), RNA sequencing (RNA-seq), computational biophysics, and immunohistochemistry. Results: Our analysis revealed a decreased neutrophil infiltration-related trend of high-quality neoantigen load with IC50 <500 nM (r=-0.445, P=0.043). Among 24 EHCC patients examined, we identified four long-term survivors with WDFY3 neoantigens and none with WDFY3 neoantigens in the short-term survivors. The WDFY3 neoantigens are associated with a lower infiltration of neutrophils (p=0.013), lower expression of CCL5 (p=0.025), CXCL9 (p=0.036) and TIGIT (p=0.016), and less favorable prognosis (p=0.030). In contrast, the prognosis was not significantly associated with tumor mutation burden, neoantigen load, or immune cell infiltration. Conclusion: We suggest that the WDFY3 neoantigens may affect prognosis by regulating antitumor immunity and that the WDFY3 neoantigens may be harnessed as potential targets for immunotherapy of EHCC.

Purpose: We aimed to develop a nomogram for predicting the prognosis of patients with distal cholangiocarcinoma (DCC) and to compare its performance with that of the American Joint Committee on Cancer (AJCC) TNM system. Patients and Methods: To develop a nomogram, we collected the clinical data of 147 patients diagnosed with DCC who underwent pancreatoduodenectomy. Predictive accuracy and discriminative ability were determined using a concordance index and a calibration curve. Predictive performance was compared with that of a current staging systems for DCC. Results: Multivariate analysis revealed that jaundice, alcohol consumption, high fibrinogen, poorly differentiated tumor cells, positive lymph nodes, and positive margins were significantly associated with overall survival. These variables were incorporated into the nomogram. The concordance index of the nomogram for predicting overall survival was 0.737 (P<0.001), which is significantly higher than the concordance index values (concordance index = 0.586) acquired using the AJCC TNM system (eighth edition). The calibration curve agreed well with predicted prediction and observed overall survival. Conclusion: We developed a nomogram for predicting the prognoses of patients with distal cholangiocarcinoma, which had superior practical clinical value compared with that of the AJCC TNM system.

1例以无症状性甲胎蛋白升高为表现的61岁女性患者，经消化内科、基本外科、病理科、肿瘤科等多学科协作诊治，确诊为较罕见的胃肝样腺癌，在接受手术、术后化学和放射治疗，以及为期3年的随访后，实现病情缓解和长期生存。

Introduction Cholangiocarcinoma is a common malignant tumor, with an incidence that has continued to rise over the past 40 years. China has a high incidence of cholangiocarcinoma, which is far higher than that in Europe and the United States. Cholangiocarcinoma is divided into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma (ECC). Surgical resection is the first consideration for the treatment of both types of cholangiocarcinoma. The surgical procedure for ECC can be grouped based on the location, as follows: the different conditions of the patients, radiotherapy, chemotherapy, target therapy, and immunotherapy for treatment. Correspondence: Shunda Du Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Shuai-Fu-Yuan, Wang-Fu-Jing, Beijing 100730, People’s Republic of China Tel +86-139 1183 2900 Fax +86-10-69156043 Email dushd@pumch.cn Cancer Management and Research Dovepress

Introduction: Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCTO 3607539). Methods: A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee. Results: As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group. Conclusions: In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

人身体每天都在产生癌细胞,但并不是所有人都会得癌症,是因为有的人身体里的免疫细胞打败了这些癌细胞.那么,如何让免疫细胞可以持续战胜癌细胞呢? 在预防癌症的过程中,控制体重、健康饮食和运动是3个非常重要的因素. 有20％的癌症是肥胖引起的,超重和肥胖可以使多种癌症风险升高,包括食管癌、胃癌、甲状腺癌、结肠直肠癌等.每天至少进行30～60分钟的中高强度体育锻炼,可以有效降低乳腺癌和结肠癌的风险.此外,前列腺癌、肺癌和子宫内膜癌的发病率也会有所下降.与此同时,运动本身会影响人体的褪黑素水平,改善免疫系统功能,是对抗癌细胞的有力武器.

目前免疫治疗成为肿瘤治疗的热点,临床应用较为成熟的免疫治疗主要为程序性死亡受体(PD-1)及其配体1(PD-L1)抑制剂.PD-1是一种免疫检验点,与其位于抗原呈递细胞表面的配体(PD-L1、PD-L2)结合后,可抑制T细胞的激活,起到免疫“刹车”的作用.PD-1抑制剂纳武单抗、派姆单抗和PD-L1抑制剂阿特珠单抗等均有较好的治疗效果和安全性.将PD-1/PD-L1抑制剂与传统化疗相结合,可显著提高肿瘤患者的总存活期和无进展生存期.