Specific genomic alterations and prognostic analysis of perihilar cholangiocarcinoma and distal cholangiocarcinoma

BackgroundCholangiocarcinoma (CCA), which consists of intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), is an aggressive malignancy worldwide. PCCA and dCCA are often classified as extrahepatic CCA (exCCA). However, the differences in mutational characteristics between pCCA and dCCA remain unclear.MethodsDeep sequencing targeting of 450 cancer genes was performed for genomic alteration detection. The tumor mutational burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was conducted using Fisher’s exact test.ResultsFGFR2 and ERBB2 mutations mainly occurred in iCCA and exCCA, respectively. In exCCA, the frequencies of PIK3CA, FAT4, KDM6A, MDM2, and TCF7L2 mutations were significantly higher in pCCA compared to dCCA, while the frequencies of TP53 and KRAS mutations were markedly lower in pCCA than those in dCCA. The prognosis-related mutations were different among the CCA subtypes. NF1 mutation was associated with short disease-free survival (DFS) and overall survival (OS), and ERBB2 mutation was associated with short DFS in dCCA patients. Meanwhile, MAP2K4 mutation was associated with long DFS and OS, and TERT mutation was associated with short DFS in pCCA. A series of mutations in genes, including ARID1A, ARID2, SMAD4, TERT, TP53, and KRAS, were found to be associated with the TMB.ConclusionsIn this study, we investigated the comprehensive genomic characterizations of CCA patients, identified the significant alterations in each subtype, and identified potential biomarkers for prognosis prediction. These results provide molecular evidence for the heterogeneity of CCA subtypes and evidence for further precision targeted therapy of CCA patients.     

Next-generation sequencing of prostate cancer: genomic and pathway alterations,potential actionability patterns,and relative rate of use of clinical-grade testing

Despite being one of the most common cancers, treatment options for prostate cancer are limited. Novel approaches for advanced disease are needed. We evaluated the relative rate of use of clinical-grade next generation sequencing (NGS) in prostate cancer, as well as genomic alterations identified and their potential actionability. Of 4864 patients from multiple institutions for whom NGS was ordered by physicians, only 67 (1.4%) had prostate cancer, representing 1/10 the ordering rate for lung cancer. Prostate cancers harbored 148 unique alterations affecting 63 distinct genes. No two patients had an identical molecular portfolio. The median number of characterized genomic alterations per patient was 3 (range, 1 to 9). Fifty-six of 67 patients (84%) had ≥ 1 potentially actionable alteration. TMPRSS2 fusions affected 28.4% of patients. Genomic aberrations were most frequently detected in TP53 (55.2% of patients), PTEN (29.9%), MYC (17.9%), PIK3CA (13.4%), APC (9.0%), BRCA2 (9.0%), CCND1 (9.0%), and RB1 genes (9.0%). The PI3K (52.2% of patients), WNT (13.5%), DNA repair (17.9%), cell cycle (19.4%), and MAPK (14.9%) machinery were commonly impacted. A minority of patients harbored BRAF, NTRK, ERBB2, or mismatch repair gene abnormalities, which are highly druggable in some cancers. Only ~ 10% of prostate cancer trials (clinicaltrials.gov, year 2017) applied a (non-hormone) biomarker before intervention. In conclusion, though use of clinical-grade NGS is relatively low and only a minority of trials deploy DNA-based biomarkers, many prostate cancer-associated molecular alterations may be pharmacologically tractable with genomcially targeted therapy or, in the case of mismatch repair anomalies, with checkpoint inhibitor immunotherapy.     

Safety and effectiveness of apatinib in elderly patients with metastatic gastric cancer: a sub-analysis from the large-scale,prospective observational study of apatinib for gastric cancer treatment in a real-world clinical setting (AHEAD-G202)

BackgroundApatinib was shown to improve the survival of Chinese patients with refractory metastatic gastric cancer (mGC). As an orally administered drug, it has been widely used in elderly patients because the dosing schedule can be adjusted flexibly. However, data on the efficacy and safety of apatinib in elderly patients is scarce. The aim of this study was to evaluate the toxicity and effectiveness of apatinib for elderly patients with mGC in a real-world setting.MethodsData from the sub-population of patients who were ≥65 years enrolled in the AHEAD-G202 trial were analyzed. Patients with mGC were prospectively registered and initially received ≤850 mg oral apatinib daily combined or not combined with chemotherapy, at the investigator’s discretion. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS).ResultsA total of 117 patients were included. There were 51 (43.59%) patients in the low-dose (250 mg) group, 60 (51.28%) patients in the mid-dose (425 to 500 mg) group, and 6 (5.13%) patients in the high-dose (850 mg) group according to the initial daily doses. Hypertension (6.84%) was the only grade 3–4 adverse event (AE) with a prevalence of more than 5% and across the low-dose (11.76%), mid-dose (3.33%) and high-dose group (0%). The median OS and PFS were 7.13 months (95% CI: 5.04 to 9.22 months) and 4.27 months (95% CI: 3.24 to 5.29 months), respectively. The OS and PFS were similar among the 65–74 and ≥75 years groups (χ²=1.406, P=0.306; χ²=0.378, P=0.066, respectively). The OS and PFS were also comparable among the 3 dose groups.ConclusionsElderly patients with mGC can tolerate and benefit from apatinib therapy. A lower initial daily dosing strategy may be a suitable choice for elderly patients in clinical practice.     

TCGA database analysis of the tumor mutation burden and its clinical significance in colon cancer

BackgroundColon cancer is one of the most common malignant tumors, with high rates of incidence and death. The tumor mutational burden (TMB), which is characterized by microsatellite instability, has been becoming a powerful predictor which can show tumor behavior and response to immunotherapy.MethodsIn this study, we analyzed 437 mutation data of colon cancer samples obtained from The Cancer Genome Atlas (TCGA) and divided patients into low- and high-TMB groups according to the TMB value. Then we identified differentially-expressed genes (DEGs), conducted immune cell infiltration and survival analyses between groups.ResultsThe higher TMB of the patients with colon cancer predicts a poorer prognosis. Functional analysis was performed to assess the prognostic value of the top 30 core genes. The CIBER-SORT algorithm was used to investigate the correlation between the immune cells and TMB subtypes. An immune prognosis model was constructed to screen out immune genes related to prognosis, and the tumor immunity assessment resource (TIMER) was then used to determine the correlation between gene expression and the abundance of tumor-infiltrating immune cell subsets in colon cancer. We observed that APC, TP53, TTN, KRAS, MUC16, SYNE1, PIK3CA have higher somatic mutations. DEGs enrichment analysis showed that they are involved in the regulation of neuroactive ligand-receptor interaction, the Cyclic adenosine monophosphate (cAMP) signaling pathway, the calcium signaling pathway, and pantothenate and Coenzyme A (CoA) biosynthesis. The difference in the abundance of various white blood cell subtypes showed that Cluster of Differentiation 8 (CD8) T cells (P=0.008), activated CD4 memory T cells (P=0.019), M1 macrophages (P=0.002), follicular helper T cells (P=0.034), activated Natural killer (NK cell) cells (P=0.017) increased remarkably, while M0 macrophages significantly reduced (P=0.025). The two immune model genes showed that secretin (SCT) was negatively correlated with survival, while Guanylate cyclase activator 2A (GUCA2A) was positively correlated.ConclusionsThis study conducted a systematically comprehensive analysis of the prediction and clinical significance of TMB in colon cancer in identification, monitoring, and prognosis of colon cancer, and providing reference information for immunotherapy.     

与早期胃癌复发有关的临床病理特性及生物指标的分析

Objective: The aim of this study was to identify the correlation between the clinicopathological characteristics and recurrence in early gastric cancer (EGC), what’s more, we attempt to look for a predictive biomarker to predict and treat for re-currence of EGC. Methods: This study retrospectively analyzed 178 early gastric cancer patients who had the complete post-operative and follow-up medical records in the First Affiliated Hospital of Yangtze University (China) between January 1995 to December 2005. Al...     

Targeted Next-Generation Sequencing of Circulating Tumor DNA Mutations among Metastatic Breast Cancer Patients

Liquid biopsy through the detection of circulating tumor DNA (ctDNA) has potential advantages in cancer monitoring and prediction. However, most previous studies in this area were performed with a few hotspot genes, single time point detection, or insufficient sequencing depth. In this study, we performed targeted next-generation sequencing (NGS) with a customized panel in metastatic breast cancer (MBC) patients. Fifty-four plasma samples were taken before chemotherapy and after the third course of treatment for detection and analysis. Paired lymphocytes were also included to eliminate clonal hematopoiesis (CH)-related alternatives. A total of 1182 nonsynonymous mutations in 419 genes were identified. More ctDNA mutations were detected in patients with tumors > 3 cm (p = 0.035) and HER2(−) patients (p = 0.029). For a single gene, the distribution of ctDNA mutations was also correlated with clinical characteristics. Multivariate regression analysis revealed that HER2 status was significantly associated with mutation burden (OR 0.02, 95% CI 0–0.62, p = 0.025). The profiles of ctDNA mutations exhibited marked discrepancies between two time points, and baseline ctDNA was more sensitive and specific than that after chemotherapy. Finally, elevated ctDNA mutation level was positively correlated with poor survival (p < 0.001). Mutations in ctDNA could serve as a potential biomarker for the evaluation, prediction, and clinical management guidance of MBC patients with chemotherapy.     

替吉奥与FLO治疗老年进展期胃癌的对照研究

目的：对比观察口服替吉奥胶囊与FLO化疗在老年进展期胃癌的疗效及毒副反应。方法：将2007年8月至2010年11月收治于河北大学附属医院的56例老年进展期胃癌患者分为两组：口服组（26例）,替吉奥胶囊,每次40mg/m2,2次/d,连续口服14天,休息7天,21天1周期;静脉组（30例）,L-OHP 85mg/m2,第1天,5-FU 2400mg/m2,48小时持续泵入,亚叶酸钙200mg/m2,第1天,21天1周期。结果：口服组与静脉组的疾病控制率（DCR）（76.9% vs 83.3%,P=0.547）,中位PFS（4.2 vs 5.5个月,P=0.422）,中位OS（9.6 vs 10.5个月,P=0.531）,两组未见显著性差异。两组1年生存率分别为24%与27%（P=0.626）。毒性反应主要为骨髓抑制及胃肠道反应,全组无Ⅳ度毒副反应发生,口服组在白细胞减少（46.2% vs 66.7%, P=0.050）及恶心呕吐（34.6% vs 83.3%,P=0.000）有统计学差异;口服组皮肤色素沉着发生率明显高于静脉组（57.7% vs 30.0%,P=0.010）。结论：老年进展期胃癌口服用药可减轻毒副反应,耐受性好,且与静脉给药疗效相当。     

胃癌靶向治疗与免疫治疗的新进展

近几年,癌症基因组图谱计划的研究者们依据胃癌患者不同的临床与分子生物学特点将胃癌分为四种不同的亚型,以此来指导靶向药物的临床试验和应用。该分型的主要目的在于靶向药物的个体化治疗。有两种靶向药物,分别为曲妥珠单抗和雷莫卢单抗,已被批准用于晚期胃癌患者的治疗。而且,胃癌免疫治疗也取得了许多进展。虽然晚期胃癌的许多免疫治疗药物尚处于临床研究阶段,但是免疫治疗仍是一个充满应用前景的治疗手段。本文主要对胃癌领域靶向治疗与免疫治疗的最新研究进展做一系统综述。     

进展期胃癌的分子靶向治疗进展

胃癌是目前世界上危害人类健康的主要疾病之一,不能手术切除的进展期胃癌预后较差,寻求手术以外途径治疗胃癌的转移、复发具有重要意义。分子靶向治疗具有分子特异性和选择性,能高效并选择性地抑制或杀伤肿瘤细胞,同时减少对人体正常组织的损伤,是目前肿瘤治疗领域发展的新方向。随着胃癌分子病理学的研究深入,针对进展期胃癌的分子靶向治疗的药物研发成功并开始走向临床。本文综合近年来较有影响力的临床试验,阐述靶向药物在进展期胃癌中的地位,其中,贝伐单抗、西妥昔单抗联合氟尿嘧啶、铂类、紫杉类药物均表现出较好的疗效和安全性。ＴｏＧＡ试验确立了曲妥珠单抗在治疗进展期胃癌上的地位,但靶向治疗药物在进展期胃癌治疗中广泛应用有赖于更多的临床试验证据支持。     

年轻人与中老年人的胃癌特征及预后情况的比较

目的:比较不同年龄段胃癌患者的特征和预后。方法:收集418名胃癌患者,病理确诊为原发性胃腺癌。其中有29名年轻患者［≤40岁,年轻组(YG)］和389名中老年患者［>40岁,年长组(OG)］。分析人口统计学和临床病理特征的差异。结果:相对于中老年组,在年轻病人组中,女性患者的比例较高。5年总体生存YG组比OG组要显著降低。然而,接受根治性切除手术后,YG组与OG组5年生存率没有显著性差异;年轻组显示女性患者生存率明显低于男性患者。肿瘤类型、侵入深度、腹膜转移、远处转移和根治性切除治疗是独立的预后因素。结论:早期发现,早期诊断,积极行根治性切除是提高年轻人胃癌治疗水平及预后的关键,尤其是在女性患者中。     

Prognostic performance of different lymph node classification systems in young gastric cancer

BackgroundAccurate staging plays a pivotal role in cancer care. The lymph node (LN) ratio (LNR) and the log odds of positive LNs (LODDS) have been suggested as alternatives to the N staging since the TNM system has the risk of stage migration. The prognostic significance of LNR and LODDS in young patients with gastric cancer (GC) has not been reported. This study aims to investigate the correlations between LNR and LODDS and survival of young patients with GC, and compare the predictive performance of these LN staging methods.MethodsGC patients before the age of 40 from 2004 to 2016 in the Surveillance, Epidemiology and End Results database were enrolled. The prognostic evaluation of the N factor, LNR and LODDS was compared using the time-dependent receiver operating characteristic (ROC) analysis, area under the curve (AUC), C-index and Akaike information criterion (AIC).ResultsMultivariate survival analysis identified that the LNR and LODDS were significantly independent prognostic indicators for overall survival (OS) in young patients with GC and in the subgroups comprised of patients with ≤15 LNs examined. The time-dependent ROC curves of the LNR and LODDS were continuously superior to that of the N factor in predicting OS during the observation period. And the AUCs revealed that the predictive accuracy of the LNR and LODDS was remarkably superior to the N factor at 1 and 3 years (P<0.05). The model incorporating LNR or LODDS had higher C-index and lower AIC when comparing to the model incorporating the N factor.ConclusionsThe LNR and LODDS improve accuracy of survival risk prediction in young patients with GC when comparing to the N factor. These two novel LN classification methods should be considered as alternatives to the N staging for the prognostic prediction of young patients with GC.     

The clinical features,management, and survival of elderly patients with gastric cancer

BackgroundIt is anticipated that the number of elderly patients with gastric cancer (GC) will increase with population aging; however, most studies on GC set the upper age limit at 80 years old, studies on the prognosis of elderly patients with GC over 80 years old is very limited. In this study, we conducted a retrospective analysis of this sub-cohort.MethodsThis retrospective cohort study aimed to analyze the clinical data of patients aged >80 who died of GC in People’s Liberation Army General Hospital between 1985 and 2020. We collected clinical informations about pathological GC types, differentiation degrees, clinical stages, anatomic sites and Bormann types of the selected case. Characteristics of participants, such as smoking, drinking, and tumor history, age, gender, and complications, were also recorded. The Kaplan-Meier method, a multivariate Cox multivariate proportional hazard model, and logistic regression were used to analyze the patient overall survival (OS) rates and treatment outcomes.ResultsThe study included 92 patients (83.7% men) with a median OS of 45 months. The most common site for GC was the gastric antrum (GA), the most common site of metastatic spread was the liver, and the most common pathological GC type was tubular adenocarcinoma/papillary adenocarcinoma (TAC/PAC). Furthermore, the prevalent complications were hypertension, coronary heart disease, and diabetes. Diabetes was a risk factor affecting the total survival time [hazard ratio (HR) =2.326, P=0.029]. The most often-used GC treatment was curative surgery. The survival time was significantly longer in the curative surgery group and curative surgery + adjuvant chemotherapy group compared with the support care group (HR =0.119, P=0.001; HR =0.110, P=0.001). There was no significant difference in survival time among the palliative chemotherapy group, palliative surgery group, and support care group. Tumor staging was significantly correlated with OS rate, the median survival time of patients at stage III and stage IV GC were significantly lower than the median survival time of patients at stage I GC (HR =6.235, P=0.001; HR =30.955, P=0.001).ConclusionsFor patients over 80 years old with good physical conditions in the early stage of GC, more active treatment can still bring better prognosis.     

胃癌分子靶向治疗的研究新进展

分子靶向治疗是近几年来胃癌治疗领域的热点。目前,西妥昔单抗、帕尼单抗、吉非替尼、拉帕替尼、曲妥珠单抗等为胃癌治疗的主要靶向药物。本文结合最新研究报道对胃癌分子靶向治疗的最新进展作如下综述。     

老年人特殊型早期胃癌的特点及内镜诊断

本文报道了２９例老年人特殊型早期胃癌，包括多发癌３例，＂一点癌＂４例，胃炎样癌２２例，探讨了老年人的临床特点，各型内镜下表现及具体操作方法，以提高老年人早期癌的检出率。     

Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with a microsatellite stable status in Chinese gastric cancer patients

BackgroundGastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of HER2 amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients.MethodsA total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score.ResultsThe most frequently amplified genes in the GC patients included cyclin E1 (CCNE1), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 2 (FGFR2), cyclin D1 (CCND1), fibroblast growth factor 19 (FGF19), fibroblast growth factor 3 (FGF3), and fibroblast growth factor 4 (FGF4). The frequency of HER2 amplification was 9.38% (18/192). HER2 amplification was higher in females than in males (14.52% vs. 6.92%, respectively, P=0.091), however, MSI was higher in males compared to females (7.69% vs. 4.84%, respectively, P=0.46). HER2 amplification was higher in metastatic loci compared to primary lesions (23.08% vs. 8.38%, respectively, P=0.079) and was lower in patients with high TMB (TMB-H) compared to those with low TMB (TMB-L) (4.0% vs. 11.35%, respectively, P=0.12). While the frequency of MSI in metastatic foci was higher than that in primary lesions (15.38% vs. 6.15%, respectively, P=0.48), MSI status was highly associated with TMB-H (20% vs. 0%, respectively, P=3.66×10⁻⁷). Furthermore, HER2 amplification was negatively correlated with MSI status in Chinese GC patients.ConclusionsHER2 amplification was negatively correlated with TMB-H and MSI status, and MSI status was significantly associated with TMB-H in Chinese GC patients. These data suggested that HER2 amplification might be a negative indicator for GC immunotherapy.     

The Clinically Actionable Molecular Profile of Early versus Late-Stage Non-Small Cell Lung Cancer,an Individual Age and Sex Propensity-Matched Pair Analysis

Background: Despite meticulous surgery for non-small cell lung cancer (NSCLC), relapse is as high as 70% at 5 years. Many institutions do not conduct reflexive molecular testing on early stage specimens, although targeted gene therapy may extend life by years in the event of recurrence. This ultimately delays definitive treatment with additional biopsy risking suboptimal tissue acquisition and quality for molecular testing. Objective: To compare molecular profiles of genetic alterations in early and late NSCLC to provide evidence that reflexive molecular testing provides clinically valuable information. Methods: A single-center propensity matched retrospective analysis was conducted using prospectively collected data. Adults with early and late-stage NSCLC had tissue subject to targeted panel-based NGS. Frequencies of putative drivers were compared, with 1:3 matching on the propensity score; p < 0.05 deemed statistically significant. Results: In total, 635 NSCLC patients underwent NGS (59 early, 576 late); 276 (43.5%) females; age 70.9 (±10.2) years; never smokers 140 (22.0%); 527 (83.0%) adenocarcinomas. Unadjusted frequencies of EGFR mutations were higher in the early cohort (30% vs. 18%). Following adjustment for sex and smoking status, similar frequencies for both early and late NSCLC were observed for variants in EGFR, KRAS, ALK, MET, and ROS1. Conclusion: The frequency of clinically actionable variants in early and late-stage NSCLC was found to be similar, providing evidence that molecular profiling should be performed on surgical specimens. This pre-determined profile is essential to avoid treatment delay for patients who will derive clinical benefit from targeted systemic therapy, in the high likelihood of subsequent relapse.     

Tumor mutation burden determined by a 645-cancer gene panel and compared with microsatellite instability and mismatch repair genes in colorectal cancer

BackgroundTumor mutation burden (TMB) assessed by tumor-related gene panels (CRGP), microsatellite instability (MSI), and mismatch repair (MMR) has been proven to be associated with prognosis, and these factors are prognostic indicators in predicting the benefits of immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CRGPs, MSI, and MMR is associated with overall survival (OS) in patients with colorectal cancer (CRC) remains to be explored.MethodsThe prognostic threshold of the panel-TMB was explored by a panel of 645 genes (GP645) from 41 CRC patients in Jiangsu Cancer Hospital (JCH dataset). The results were further validated using 531 CRC patients from The Cancer Genome Atlas (TCGA) database.ResultsMutations of the GP645 genes were distributed on 21 chromosomes. Spearman correlation analysis showed that the panel-TMB was positively correlated with TMB measured by whole-exome sequencing (WES) (wTMB) in the TCGA dataset (R=0.75, P<0.001). Kaplan-Meier survival analysis demonstrated that higher panel-TMB in CRC patients was significantly associated with a poor OS (P=0.0062). MSI and MMR status were determined using the GP645 by next-generation sequencing (NGS). The proportions of MSI-H and dMMR accounted for less than 10% in CRC, the vast majority of MSI-H/dMMR samples also had high TMB [positive predictive value (PPV) =66.6%], and only 13.3% of samples with high TMB were classified as MSI-high/dMMR. In addition, patients with low-TMB were associated with MSS/pMMR (96.2%), and these results are consistent with earlier studies.ConclusionsGP645 was constructed to evaluate OS in Chinese CRC patients. Panel-TMB and MSI/MMR might be potential prognostic predictors of CRC patients using the GP645.     

Assessment of microsatellite instability status for the prediction of metachronous recurrence after initial endoscopic submucosal dissection for early gastric cancer

The technique of endoscopic submucosal dissection (ESD) has been developed for en bloc resection of early gastric cancer (EGC); however, little is known about the risk of metachronous cancer in the remnant stomach after initial ESD. In this study, we investigated the correlation between microsatellite instability (MSI) status and the incidence of metachronous recurrence of gastric cancer. According to the genetic/molecular background determined with MSI status and expression levels of hMLH1 and p53 tumour suppressor, 110 EGCs removed with ESD were subclassified into three groups: the mutator/MSI-type (8%), suppressor/p53-type (45%) and unclassified type (47%). Interestingly, patients with the mutator/MSI-type tumour had a high incidence (67%) of metachronous recurrence of gastric cancer within a 3-year observation after initial ESD, which was significantly higher than those with the suppressor/p53-type and unclassified type tumours (P<0.01). Although we investigated mucin phenotypes, there was no correlation between mucin phenotype and the recurrence of EGC. These findings suggest that subclassification of molecular pathological pathways in EGCs is required for the assessment of patients with a high risk of recurrent gastric cancer. The information delivered from our investigation is expected to be of value for decisions about therapy and surveillance after ESD.