Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genet...Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart.Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing(NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC(LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes.Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas.Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC(TERT amplification),colorectal NEC(KRAS mutation), and bile tract NEC(ARID1A mutation). The gene disparities between small-cell NEC(SCNEC) and large-cell NEC(LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in22.2% of the patients, and they had longer progression-free survival(PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40(0.21-0.75), P=0.006].Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.展开更多
Background:Ovarian cancer(OC)is a leading cause of gynecological cancer-linked deaths worldwide.Exosomal miR-1825 and its target gene C-type lectin domain family 5 member A(CLEC5A)are associated with tumorigenesis in ...Background:Ovarian cancer(OC)is a leading cause of gynecological cancer-linked deaths worldwide.Exosomal miR-1825 and its target gene C-type lectin domain family 5 member A(CLEC5A)are associated with tumorigenesis in cancers that was further probed.Methods:Exosomal miR-1825 expression in exosomes and its impact on overall survival(OS)prediction were determined using Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)data.Target genes of miR-1825 were searched in five prediction databases and prognostically significant differentially expressed genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were carried out.The ability of CLEC5A to predict OS was evaluated using univariate and multivariate Cox regression analyses and Kaplan-Meier curves.The CLEC5A expression pattern in OC was validated using immunohistochemistry.The CIBERSORT algorithm was used to compare the immune cell landscape,and the results were validated in a GEO cohort.Finally,the predicted half maximal inhibitory concentration(IC50)values for five commonly used chemotherapy agents were also compared.Results:MiR-1825 level was higher in exosomes derived from OC cells and served as a tumor suppressor.The CLEC5A gene was found to be a target of miR-1825,the upregulation of which was correlated with a poor prognosis.M2 macrophage infiltration was significantly enhanced in the CLEC5A high expression group,while T follicular helper cell infiltration was reduced in it.While the predicted IC50 for cisplatin and doxorubicin was higher in the CLEC5A high expression group,that of docetaxel,gemcitabine,and paclitaxel was lower.Conclusion:MiR-1825,a promising OC biomarker,may promote OC progression by increasing CLEC5A expression via exosome-mediated efflux from tumor cells.展开更多
BACKGROUND In recent years,targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer(NSCLC).However,the clinical evidence for successful off-label use o...BACKGROUND In recent years,targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer(NSCLC).However,the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARY We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation.He received gefitinib combined with six cycles of vinorelbine,cisplatin,and recombinant human endostatin as the first-line therapy.Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy,resulting in a progression-free survival(PFS)of 14 mo.Chemoradiotherapy was added following progression(enlarged brain metastases)on maintenance treatment.Unfortunately,the brain lesions were highly refractory and progressed again after 15 mo,at which time next-generation sequencing(NGS)of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations.NGS revealed that the patient harbored a BRCA2 germline mutation,the EGFR exon 19 deletion mutation disappeared,and no additional targetable genetic variant was detected.Therefore,the patient received olaparib combined with gefitinib and recombinant human endostatin,with a rapid and long-lasting clinical response(PFS=13.5 mo).CONCLUSION This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment,suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.展开更多
We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early ...We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early TNBC received six cycles of apatinib,sintilimab,nab-paclitaxel,and carboplatin followed by surgery.The primary endpoint was pathological complete response(pCR)rate.Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment.Among 34 enrolled patients,24 achieved pCR(70.6%;95%confidence interval(CI),53.0-85.3),and 79.4%(95%CI,65.1-93.7)had residual cancer burden 0-I.Imaging evaluation showed 21 complete responses(61.8%)and 13 partial responses(38.2%).The most common grade 3-4 adverse events were leukopenia(47%),neutropenia(36%),and thrombocytopenia(24%).The 36-month disease-free survival rate stood at 94.1%with a median follow-up of 39.1 months.Notably,baseline high ImmuneScore,immune cell infiltration,and enrichment of interferon-related pathways correlated with pCR.Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets,thereby activating the tumor microenvironment.Moreover,higher oxeiptosis scores were associated with an increased likelihood of achieving pCR.Following neoadjuvant therapy,the pCR group showed a decrease in oxeiptosis score,whereas the non-pCR group exhibited an increase.Our study suggests that apatinib,sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study.ClinicalTrials.gov registration:NCT04722718.展开更多
The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance.In this study,we retrospectively analyzed 1071 metastatic breast cancer(MBC)patients and the ...The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance.In this study,we retrospectively analyzed 1071 metastatic breast cancer(MBC)patients and the circulating tumor DNA(ctDNA)to investigate clinicopathological and genetic alterations of HER2-low MBC patients.The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials(NCT03412383,NCT01917279)and a retrospective study.Ourfindings suggest TP53,PIK3CA,and ESR1 are frequently mutated genes in HER2-low MBC.Compared to the HER2-0 group,mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations.Additionally,among patients with ERBB2 mutations and treated with pyrotinib,the HER2-low group may experience superior prognosis when compared to the HER2-0 group.Notably,we did notfind any statistically significant disparity in the response to chemotherapy,endocrine therapy,or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients.Interestingly,within the subgroup of individuals with metabolic pathway-related gene mutations,we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group.Additionally,dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles,exhibited prolonged survival.Moreover,we classified HER2-low MBC into three clusters,providing a reference for subsequent treatment with enhanced precision.Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.展开更多
Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsisten...Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsistent results from the same samples.This highlights the urgent need for standardized benchmarks to evaluate HRD assay performance.In phases lla and Ilb of the Chinese HRD Harmonization Project,we de-veloped ten pairs of well-characterized DNA reference materials derived from lung,breast,and melanoma cancer cell lines and their matched normal cell lines,keeping each paired with seven cancer-to-normal mass ratios.Reference datasets for allele-specific copy number variations(AsCNVs)and HRD scores were established and validated using three sequencing methods and nine analytical pipelines.The genomic instabil-ity scores(GISs)of the reference materials ranged from 11 to 96,enabling validation across various thresholds.The AsCNV reference datasets covered a genomic span of 2340 to 2749 Mb,equivalent to 81.2%to 95.4%of the autosomes in the 37d5 reference genome.These bench-marks were subsequently utilized to assess the accuracy and reproducibility of four HRD panel assays,revealing significant variability in both ASCNV detection and HRD scores.The concordance between panel-detected GISs and reference GISs ranged from 0.81 to 0.94,with only two assays exhibiting high overall agreement with Myriad MyChoice CDx for HRD classification.This study also identified specific challenges in ASCNV detection in HRD-related regions and the profound impact of high ploidy on consistency.The established HRD reference materials and datasets providea robust toolkit forobjective evaluation of HRD testing.展开更多
Immune checkpoint inhibitors(ICIs)have changed the treatment landscape for patients with non-small cell lung cancer(NSCLC).In spite of durable responses in some patients,many patients develop early disease progression...Immune checkpoint inhibitors(ICIs)have changed the treatment landscape for patients with non-small cell lung cancer(NSCLC).In spite of durable responses in some patients,many patients develop early disease progression during the ICI treatment.Thus,early identification of patients with no durable benefit would facilitate the clinical decision for these patients.In this prospective,multicenter study,101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients.At the date of cutoff,83 patients were eligible for ICI efficacy evaluation,with 56 patients having progress-free survival(PFS)over 6 months,which was defined as durable clinical benefit(DCB).A multimodal model was established by integrating normalized bTMB,early dynamic of ctDNA and thefirst RECIST response.This model could robustly predict DCB with area under the curve(AUC)of 0.878,sensitivity of 79.2%at 86.4%specificity(accuracy=80.0%).This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887,sensitivity of 94.7%at 85.3%specificity(accuracy=90.3%).Patients with higher predict scores had substantially longer PFS than those with lower scores(training cohort:median PFS 13.6 vs 4.2 months,P<0.001,HR=0.24;validation cohort:median PFS 11.0 vs 2.2 months,P<0.001,HR=0.17).Taken together,these results demonstrate that integrating early changes of ctDNA,normalized bTMB,and thefirst RECIST response can provide accurate,noninvasive,and early prediction of durable benefits for NSCLC patients treated with ICIs.Further prospective studies are warranted to validate thesefindings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.展开更多
A dose-escalation and expansion,phase 1/2 study(ClinicalTrials.gov,NCT04818333)was conducted to assess the novel antibodydrug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer(NSCLC).H...A dose-escalation and expansion,phase 1/2 study(ClinicalTrials.gov,NCT04818333)was conducted to assess the novel antibodydrug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer(NSCLC).Here,we report results from the phase 1 portion.Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks.Dose escalation followed a Bayesian logistic regression model that included overdose control,with subsequent selection of tolerable levels for dose expansion.Overall,63 patients were enrolled,including 43 receiving a recommended dose for expansion of 4.8 mg/kg.All patients had HER2-mutant disease.Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort.Grade≥3 treatment-related adverse events occurred in 29(46.0%)patients.One patient in the 6.4 mg/kg cohort died due to interstitial lung disease.As of April 11,2023,the 4.8 mg/kg cohort showed an objective response rate of 41.9%(95%Cl 27.0-57.9),and a disease control rate of 95.3%(95%Cl 84.2-99.4).The median duration of response was 13.7 months,with 13 of 18 responses ongoing.The median progression-free survival was 8.4 months(95%CI 7.1-15.0).SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutantNSCLC.展开更多
Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Th...Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.展开更多
Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for th...Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.展开更多
Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are chara...Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and amplification of human epidermal growth factor receptor 2(HER2)[2].TNBC is well known for its rapid progressiveness,high rate of distant organ recurrence,and poor prognosis.Metastasis remains the major cause of death for patients with TNBCs.Up to date,the only direct treatment for metastatic TNBCs is chemotherapy,which has been challenged by tumor heterogeneity and drug resistance.Lack of effective targeted therapy for metastatic TNBCs impels researchers to focus on discovering potentially actionable targets through mutational profiling.展开更多
Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and pr...Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.展开更多
Dear editor,The tumor microenvironment(TME)heavily impacts disease biology and may influence responses to systemic treatments,and thereby,affects patients’prognosis.In our previous study,we found that immune features...Dear editor,The tumor microenvironment(TME)heavily impacts disease biology and may influence responses to systemic treatments,and thereby,affects patients’prognosis.In our previous study,we found that immune features could predict prognosis and guide the therapy choices for stage I-III colon cancer[1,2].Increasing evidence shows that therapyinduced TME changes can promote tumor progression,metastasis,and the development of resistance[3,4].However,the TME dynamics in colorectal liver metastases(CRLM)under treatment are still incompletely clear.展开更多
Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor ...Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].展开更多
Dear editor,Lung cancer is the leading cause of cancer-related death worldwide,with the predominant pathological type being non-small cell lung cancer(NSCLC)[1,2].Next-gener-ation sequencing(NGS)analysis is increasing...Dear editor,Lung cancer is the leading cause of cancer-related death worldwide,with the predominant pathological type being non-small cell lung cancer(NSCLC)[1,2].Next-gener-ation sequencing(NGS)analysis is increasingly used to help clinicians select appropriate target therapies,such as epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)for EGFR-mutant patients[3].Both pericarcinomatous tissues and peripheral blood lymphocytes are widely used as normal control for NGS analysis.However,whether pericarcinomatous tissue is suitable for background filtering in mutation analysis remains controversial.According to the whole-genome sequencing data from The Cancer Genome Atlas(TCGA)database,there were some genomic variations in peri-carcinomatous tissue from NSCLC patients,but no driver gene mutation was detected[4,5].Therefore,deep sequencing of pericarcinomatous and tumor tissues is necessary to confirm whether pericarcinomatous tissue harbors low-frequency mutations.展开更多
Background:Neuroendocrine carcinomas of the gastrointestinal tract(GINECs)remain a disease of grim prognosis with limited therapeutic options.Their molecular characteristics are still undefined.This study aimed to exp...Background:Neuroendocrine carcinomas of the gastrointestinal tract(GINECs)remain a disease of grim prognosis with limited therapeutic options.Their molecular characteristics are still undefined.This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs.Methods:Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed,paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation.Mutational signatures,somatic mutations,and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes.Survival analysis was conducted to identify the independent factors.Results:In total,143GI-NECswere examined:the stomach,87 cases(60.8%);the esophagus,29 cases(20.3%);the colorectum,20 cases(14.0%);and the small intestine,7 cases(4.9%).Eighty-three(58.0%)and 60(42.0%)cases were subclassified into small cell and large cell subtypes,respectively.GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations.Obvious heterogeneity of mutational signatures,somatic mutations,and copy number variations was revealed across anatomic locations rather than histological subtypes.Except for tumor protein p53(TP53)and retinoblastoma 1(RB1),the most frequently mutated genes in the stomach,esophagus,colorectum,and small intestine were low-density lipoprotein receptor-related protein 1B(LRP1B),notch receptor 1(NOTCH1),adenomatosis polyposis coli(APC),catenin beta 1(CTNNB1),respectively.Mutations in the WNT-β-catenin,NOTCH and erythroblastic leukemia viral oncogene B(ERBB)pathwayswere prevalently identified in gastric,esophageal,and colorectalNECs,respectively.Importantly,104(72.7%)GI-NECs harbored putative clinically relevant alterations,and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors.Furthermore,we found that tumor cells in GI-NECs first gain clonal mutations in TP53,RB1,NOTCH1 and APC,followed by subsequent wholegenome doubling(WGD)and post-WGD clonal mutations in LRP1B,CUB and Sushi multiple domains 3(CSMD3),FAT tumor suppressor homolog 4(FAT4)and erb-b2 receptor tyrosine kinase 4(ERBB4),and finally develop subclonal mutations.Conclusions:GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations.Moreover,potentially actionable alterations and prognostic factors were revealed for GI-NECs.展开更多
Gene fusions and MET alterations are rare and difficult to detect in plasma samples.The clinical detection efficacy of molecular residual disease(MRD)based on circulating tumor DNA(ctDNA)in patients with non-small cel...Gene fusions and MET alterations are rare and difficult to detect in plasma samples.The clinical detection efficacy of molecular residual disease(MRD)based on circulating tumor DNA(ctDNA)in patients with non-small cell lung cancer(NSCLC)with these mutations remains unknown.This prospective,non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions(ALK,ROS1,RET,and FGFR1),MET exon 14 skipping or de novo MET amplification.We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021-and 338-gene panels,respectively.Detectable MRD correlated with a significantly higher recurrence rate(P<0.001),yielding positive predictive values of 100%and 90.9%,and negative predictive values of 82.4%and 86.4%at landmark and longitudinal time points,respectively.Patients with detectable MRD showed reduced disease-free survival(DFS)compared to those with undetectable MRD(P<0.001).Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not(P=0.05).To our knowledge,this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations.Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.展开更多
基金supported by the Major Program of National Natural Science Foundation of China (No. 91959205)National Natural Science Foundation of China (No. 82141117)+3 种基金The Capital’s Funds for Health Improvement and Research (CFH) (No. 2022-2-1023)Beijing Xisike Clinical Oncology Research Foundation Ypierrefabre (No. 202101-0099)Beijing Municipal Administration of Hospitals Incubating Program (No. PX2020045)Science Foundation of Peking University Cancer Hospital (No. 2020-4)。
文摘Objective: There is an ongoing debate about whether the management of gastroenteropancreatic(GEP)neuroendocrine carcinoma(NEC) should follow the guidelines of small-cell lung cancer(SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart.Methods: We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing(NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC(LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes.Results: We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas.Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC(TERT amplification),colorectal NEC(KRAS mutation), and bile tract NEC(ARID1A mutation). The gene disparities between small-cell NEC(SCNEC) and large-cell NEC(LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in22.2% of the patients, and they had longer progression-free survival(PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40(0.21-0.75), P=0.006].Conclusions: This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.
基金funded by a grant from the National Natural Science Foundation of China(81873045)the Natural Science Foundation of Fujian Province of China(2020J011115)+1 种基金the Medicine Innovation Project of Fujian Province of China(2020CXB007)the Joint Funds for the Innovation of Science and Technology(2021Y9209).
文摘Background:Ovarian cancer(OC)is a leading cause of gynecological cancer-linked deaths worldwide.Exosomal miR-1825 and its target gene C-type lectin domain family 5 member A(CLEC5A)are associated with tumorigenesis in cancers that was further probed.Methods:Exosomal miR-1825 expression in exosomes and its impact on overall survival(OS)prediction were determined using Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)data.Target genes of miR-1825 were searched in five prediction databases and prognostically significant differentially expressed genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were carried out.The ability of CLEC5A to predict OS was evaluated using univariate and multivariate Cox regression analyses and Kaplan-Meier curves.The CLEC5A expression pattern in OC was validated using immunohistochemistry.The CIBERSORT algorithm was used to compare the immune cell landscape,and the results were validated in a GEO cohort.Finally,the predicted half maximal inhibitory concentration(IC50)values for five commonly used chemotherapy agents were also compared.Results:MiR-1825 level was higher in exosomes derived from OC cells and served as a tumor suppressor.The CLEC5A gene was found to be a target of miR-1825,the upregulation of which was correlated with a poor prognosis.M2 macrophage infiltration was significantly enhanced in the CLEC5A high expression group,while T follicular helper cell infiltration was reduced in it.While the predicted IC50 for cisplatin and doxorubicin was higher in the CLEC5A high expression group,that of docetaxel,gemcitabine,and paclitaxel was lower.Conclusion:MiR-1825,a promising OC biomarker,may promote OC progression by increasing CLEC5A expression via exosome-mediated efflux from tumor cells.
文摘BACKGROUND In recent years,targeted therapy and immunotherapy have become important treatment strategies for patients with non-small cell lung cancer(NSCLC).However,the clinical evidence for successful off-label use of targeted drugs for patients with NSCLC following progression on multiple lines of treatment is still lacking.CASE SUMMARY We describe a 62-year-old male patient with a right lung adenocarcinoma who harbored an EGFR exon 19 deletion mutation.He received gefitinib combined with six cycles of vinorelbine,cisplatin,and recombinant human endostatin as the first-line therapy.Then gefitinib was administered in combination with recombinant human endostatin as maintenance therapy,resulting in a progression-free survival(PFS)of 14 mo.Chemoradiotherapy was added following progression(enlarged brain metastases)on maintenance treatment.Unfortunately,the brain lesions were highly refractory and progressed again after 15 mo,at which time next-generation sequencing(NGS)of 1021 cancer-related genes was performed using peripheral blood to identify potential actionable mutations.NGS revealed that the patient harbored a BRCA2 germline mutation,the EGFR exon 19 deletion mutation disappeared,and no additional targetable genetic variant was detected.Therefore,the patient received olaparib combined with gefitinib and recombinant human endostatin,with a rapid and long-lasting clinical response(PFS=13.5 mo).CONCLUSION This is a rare case of lung adenocarcinoma in a patient with a BRCA2 germline mutation who had long-term benefit from olaparib combination treatment,suggesting that NGS-based genetic testing may render the possibility of long-term survival in NSCLC patients after disease progression.
基金funded by the Provincial-Level Clinical Key Specialty Construction in Qinghai Province in China.
文摘We aimed to evaluate the efficacy and safety of adding apatinib,to sintilimab and chemotherapy in the neoadjuvant treatment of early triple-negative breast cancer(TNBC).In the phase 2 NeoSAC trial,patients with early TNBC received six cycles of apatinib,sintilimab,nab-paclitaxel,and carboplatin followed by surgery.The primary endpoint was pathological complete response(pCR)rate.Specimens collected pre-neoadjuvant therapy and post-surgery were retained for comprehensive analysis of predictive biomarkers and the impact on the tumor microenvironment.Among 34 enrolled patients,24 achieved pCR(70.6%;95%confidence interval(CI),53.0-85.3),and 79.4%(95%CI,65.1-93.7)had residual cancer burden 0-I.Imaging evaluation showed 21 complete responses(61.8%)and 13 partial responses(38.2%).The most common grade 3-4 adverse events were leukopenia(47%),neutropenia(36%),and thrombocytopenia(24%).The 36-month disease-free survival rate stood at 94.1%with a median follow-up of 39.1 months.Notably,baseline high ImmuneScore,immune cell infiltration,and enrichment of interferon-related pathways correlated with pCR.Comparison of pre-neoadjuvant and post-surgery data revealed that the pCR group treated with this novel regimen exhibited an upregulation of distinct immune cell subsets,thereby activating the tumor microenvironment.Moreover,higher oxeiptosis scores were associated with an increased likelihood of achieving pCR.Following neoadjuvant therapy,the pCR group showed a decrease in oxeiptosis score,whereas the non-pCR group exhibited an increase.Our study suggests that apatinib,sintilimab combined with carboplatin and nab-paclitaxel chemotherapy showed a promising clinical activity and manageable safety profile in early TNBC and merits further study.ClinicalTrials.gov registration:NCT04722718.
基金supported by the National Science Fund of China(Grant No.82303823)the CAMS Innovation Fund for Medical Sciences(Grant Nos.2021-I2M-1-014,2023-12M-2-004)+1 种基金the Wuhan Municipal Science and Technology Bureau Knowledge Innovation Special Project“Dawn Plan”Project(Grant No.KYXM2022011)the Youth Interdisciplinary Special Fund of Zhongnan Hospital of Wuhan University(Grant No.ZNQNJC2022006).
文摘The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance.In this study,we retrospectively analyzed 1071 metastatic breast cancer(MBC)patients and the circulating tumor DNA(ctDNA)to investigate clinicopathological and genetic alterations of HER2-low MBC patients.The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials(NCT03412383,NCT01917279)and a retrospective study.Ourfindings suggest TP53,PIK3CA,and ESR1 are frequently mutated genes in HER2-low MBC.Compared to the HER2-0 group,mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations.Additionally,among patients with ERBB2 mutations and treated with pyrotinib,the HER2-low group may experience superior prognosis when compared to the HER2-0 group.Notably,we did notfind any statistically significant disparity in the response to chemotherapy,endocrine therapy,or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients.Interestingly,within the subgroup of individuals with metabolic pathway-related gene mutations,we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group.Additionally,dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles,exhibited prolonged survival.Moreover,we classified HER2-low MBC into three clusters,providing a reference for subsequent treatment with enhanced precision.Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.
基金supported by the National Key R&D Program of China(Grant No.2022YFF1202203)the NIFDC Fund for Key Technology Research,China(Grant No.GJJS-2022-2-1).
文摘Homologous recombination deficiency(HRD)has emerged as a critical prognostic and predictive biomarker in oncology.However,current test-ing methods,especially those reliant on targeted panels,are plagued by inconsistent results from the same samples.This highlights the urgent need for standardized benchmarks to evaluate HRD assay performance.In phases lla and Ilb of the Chinese HRD Harmonization Project,we de-veloped ten pairs of well-characterized DNA reference materials derived from lung,breast,and melanoma cancer cell lines and their matched normal cell lines,keeping each paired with seven cancer-to-normal mass ratios.Reference datasets for allele-specific copy number variations(AsCNVs)and HRD scores were established and validated using three sequencing methods and nine analytical pipelines.The genomic instabil-ity scores(GISs)of the reference materials ranged from 11 to 96,enabling validation across various thresholds.The AsCNV reference datasets covered a genomic span of 2340 to 2749 Mb,equivalent to 81.2%to 95.4%of the autosomes in the 37d5 reference genome.These bench-marks were subsequently utilized to assess the accuracy and reproducibility of four HRD panel assays,revealing significant variability in both ASCNV detection and HRD scores.The concordance between panel-detected GISs and reference GISs ranged from 0.81 to 0.94,with only two assays exhibiting high overall agreement with Myriad MyChoice CDx for HRD classification.This study also identified specific challenges in ASCNV detection in HRD-related regions and the profound impact of high ploidy on consistency.The established HRD reference materials and datasets providea robust toolkit forobjective evaluation of HRD testing.
基金supported by the National Natural Science Foundation of China(82030045 and 82241227 to S.L.)National Multi-disciplinary Treatment Project for Major Diseases(2020NMDTP to S.L.)+7 种基金Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education&Shanghai(CCTS-202204 and CCTS202304 to S.L.)Shanghai Chest Hospital Basic Research Project(2023YNKT-1 to S.L.)the Natural Science Foundation of Shanghai(22ZR1457500 to X.A.)the National Natural Science Foundation of China(82141117 to M.Z.)the Capital’s Funds for Health Improvement and Research(2022-2-1023 to M.Z.)WU JIEPING MEDICAL FOUNDATION(320.6750.2021-16-19 to M.Z.)Guangzhou Life oasis public service center Research and exchange program in thefield of health(1-35 to M.Z.)Beijing Xisike Clinical Oncology Research Foundation(Y-pierrefabre202101-0099 to M.Z.).
文摘Immune checkpoint inhibitors(ICIs)have changed the treatment landscape for patients with non-small cell lung cancer(NSCLC).In spite of durable responses in some patients,many patients develop early disease progression during the ICI treatment.Thus,early identification of patients with no durable benefit would facilitate the clinical decision for these patients.In this prospective,multicenter study,101 non-EGFR/ALK patients who received ICI treatment were enrolled after screening 328 stage III-IV NSCLC patients.At the date of cutoff,83 patients were eligible for ICI efficacy evaluation,with 56 patients having progress-free survival(PFS)over 6 months,which was defined as durable clinical benefit(DCB).A multimodal model was established by integrating normalized bTMB,early dynamic of ctDNA and thefirst RECIST response.This model could robustly predict DCB with area under the curve(AUC)of 0.878,sensitivity of 79.2%at 86.4%specificity(accuracy=80.0%).This model was further validated in the independent cohort of the DIREct-On study with AUC of 0.887,sensitivity of 94.7%at 85.3%specificity(accuracy=90.3%).Patients with higher predict scores had substantially longer PFS than those with lower scores(training cohort:median PFS 13.6 vs 4.2 months,P<0.001,HR=0.24;validation cohort:median PFS 11.0 vs 2.2 months,P<0.001,HR=0.17).Taken together,these results demonstrate that integrating early changes of ctDNA,normalized bTMB,and thefirst RECIST response can provide accurate,noninvasive,and early prediction of durable benefits for NSCLC patients treated with ICIs.Further prospective studies are warranted to validate thesefindings and guide clinical decision-making for optimal immunotherapy in NSCLC patients.
基金This study was funded by Jiangsu Hengrui Pharmaceuticals.
文摘A dose-escalation and expansion,phase 1/2 study(ClinicalTrials.gov,NCT04818333)was conducted to assess the novel antibodydrug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer(NSCLC).Here,we report results from the phase 1 portion.Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks.Dose escalation followed a Bayesian logistic regression model that included overdose control,with subsequent selection of tolerable levels for dose expansion.Overall,63 patients were enrolled,including 43 receiving a recommended dose for expansion of 4.8 mg/kg.All patients had HER2-mutant disease.Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort.Grade≥3 treatment-related adverse events occurred in 29(46.0%)patients.One patient in the 6.4 mg/kg cohort died due to interstitial lung disease.As of April 11,2023,the 4.8 mg/kg cohort showed an objective response rate of 41.9%(95%Cl 27.0-57.9),and a disease control rate of 95.3%(95%Cl 84.2-99.4).The median duration of response was 13.7 months,with 13 of 18 responses ongoing.The median progression-free survival was 8.4 months(95%CI 7.1-15.0).SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutantNSCLC.
基金supported by the National Natural Science Foundation of China to H.Z.(Grant Nos.81770184,81970143,and 82270167)and L.Z.(Grant No.81800174)the Talent Young Program of Guangdong Province(2021B1515020017),and the Leading Talents Program from The First Affiliated Hospital of Jinan University to H.Z.
文摘Acute myeloid leukemia(AML)is a common hematological malignancy with overall poor prognosis.Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory(RR)AML patients.Through clinical specimens,animal models and cell-level studies,we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1(HMGCS1)in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation,increase chemotherapy sensitivity and improve the occurrence and development of AML.Here,we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival(OS).Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity,while stable overexpression of HMGCS1 had the opposite effects.Mechanistically,we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase(MAPK)pathway activity,while overexpression of HMGCS1 could remarkably enhance the pathway.U0126,a MEK1 inhibitor,offset the effects of HMGCS1 overexpression,indicating that HMGCS1 promotes RR AML through the MAPK pathway.Further,we verified that hymeglusin,a specific inhibitor of HMGCS1,decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients.Furthermore,combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin(ADR)had synergistic toxic effects on AML cells.Our study demonstrates the important role of HMGCS1 in AML,and targeting this protein is promising for the treatment of RR AML.
基金supported by the grants from the Chinese Academy of Medical Sciences(CAMS)Initiative for InnovativeMedicine(CAMS-12 M-1-010,2017-I2M-3-004)the National Natural Science Foundation of China(81874122).
文摘Background:TP53 mutations are common in breast cancer.There is currently no large-scale cohort study to investigate the TP53 landscape in breast cancer patients from China.The predictive value of TP53 mutations for the efficacy of human epidermal growth factor receptor 2(HER2)-targeted therapy in breast cancer remains controversial.In the present study,we aimed to analyze the clinical spectrum and prognostic value of TP53 mutations in circulating tumor DNA(ctDNA)from breast cancer patients in China.Methods:We retrospectively analyzed the clinical data and TP53 mutation features in ctDNA samples from 804 patients withmetastatic breast cancer.TP53 mutations were detected by target region capture-based next-generation sequencing.The relationship between TP53 mutation status and disease-free survival(DFS)was analyzed in 444 patientswithmetastatic breast cancer.Moreover,the relationship between TP53 mutation status and progression-free survival(PFS)was analyzed in 55 HER2-positive patients treated with first-line trastuzumab-based therapy.Kaplan-Meier analysis was performed to estimate the survival curves of the different subgroups,and the log-rank test was used to compare the curves.A Cox regression model was used to estimate multivariable-adjusted hazard ratios and their 95%confidence intervals(CIs)associated with the DFS and PFS.Results:Among the 804 investigated patients,431(53.6%)patients harbored TP53 mutations.TP53 mutations were differentially distributed among different molecular subtypes of breast cancer(P<0.05).Patients with TP53 mutations had a shorter DFS than those with wild-type TP53(hazard ratio=1.32,95%CI=1.09-1.61,P=0.005).TP53 mutations in exons 5-8 were associated with worse outcome(hazard ratio=1.50,95%CI=1.11-2.03,P=0.009).However,TP53 mutation status was not significantly associated with PFS in HER2-positive patients who received firstline trastuzumab-based therapy(P=0.966).Interestingly,in the taxane combination group,patients with TP53 mutations exhibited longer PFS than those without TP53 mutations(hazard ratio=0.08,95%CI=0.02-0.30,P<0.001).However,in the nontaxane combination group,patients with TP53 mutations displayed shorter PFS than those with wild-type TP53(hazard ratio=4.84,95%CI=1.60-14.66,P=0.005).Conclusions:TP53 mutations in exons 5-8 may be an independent prognostic marker for short DFS in patients with metastatic breast cancer.TP53 mutations had opposite effects on trastuzumab-treated patients treated with and without taxanes.
基金This work was supported by the National Key R&D Program of China(2018YFC1312101)Chinese Academy of Medical Sciences(CAMS)Initiative for Innovative Medicine(CAMS-12M-1-010,2017-12M-3-004)+2 种基金Major Project of Beijing Municipal Science and Technology Commission(D161100000816004)National Science and Technology Major Project of the Ministry of Science and Technology,China(2015ZX09101007)Beijing Municipal Science and Technology Project(D161100000816004).
文摘Dear editor,Breast cancer has been considered as the most common malignancy and the leading cause of death in women worldwide[1].Triple-negative breast cancer(TNBC)accounts for 10%-20%of breast cancers,which are characterized by the absence of estrogen receptor(ER),progesterone receptor(PR),and amplification of human epidermal growth factor receptor 2(HER2)[2].TNBC is well known for its rapid progressiveness,high rate of distant organ recurrence,and poor prognosis.Metastasis remains the major cause of death for patients with TNBCs.Up to date,the only direct treatment for metastatic TNBCs is chemotherapy,which has been challenged by tumor heterogeneity and drug resistance.Lack of effective targeted therapy for metastatic TNBCs impels researchers to focus on discovering potentially actionable targets through mutational profiling.
基金This work was supported by‘National Natural Science Foundation of China’(Grant Number:81874122)‘CAMS Initiative for Innovative Medicine’(Grant Number:2017-I2M-3-004)‘Major Project of the Beijing Municipal Science and Technology Commission’(Grant Number:D161100000816004).
文摘Circulating tumor DNA(ctDNA)is a potential biomarker of prognosis and therapeutic response.We conducted this study to explore the role of the molecular tumor burden index(mTBI)in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study.We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study(NCT01917279).Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples.The pretreatment mTBI value was correlated with tumor burden(P=0.025).Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI,and the median overall survival was 40.9 months and 68.4 months,respectively(P=0.011).Patients with mTBI decrease to less than 0.02%at the first tumor evaluation had longer progression-free survival and overall survival(P<0.001 and P=0.007,respectively).The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans(88.5%and 87.5%,respectively).The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort(P<0.001 and P=0.036,respectively),as well as in the cohort in which computed tomography scans were defined as representing stable disease(P=0.027 and P=0.015,respectively).The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.
基金This work was supported by grants from the National Natural Science Foundation of China(81772580)Natural Science Foundation of Guangdong Province,China(2021A1515011705)the Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education(LC2016ZD014).
文摘Dear editor,The tumor microenvironment(TME)heavily impacts disease biology and may influence responses to systemic treatments,and thereby,affects patients’prognosis.In our previous study,we found that immune features could predict prognosis and guide the therapy choices for stage I-III colon cancer[1,2].Increasing evidence shows that therapyinduced TME changes can promote tumor progression,metastasis,and the development of resistance[3,4].However,the TME dynamics in colorectal liver metastases(CRLM)under treatment are still incompletely clear.
文摘Dear editor,The scarcity of routinemetastatic biopsies or resection limits the finding of biomarkers of diagnosis and prognosis in patients with brain metastases.Derived from necrosis,apoptosis,and secretion of tumor cells,circulating tumor DNA(ctDNA)is widely distributed in various body fluids,including peripheral blood and cerebrospinal fluid(CSF),as an alternative biomarker for tumor-associated analysis[1].Fortunately,genomic alterations of blood ctDNA and CSF ctDNA have been proven as prognostic markers in non-small cell lung cancer(NSCLC)patients with brain metastasis[2,3].
基金This work was supported by the National Key R&D Program of China(Grant No.2016YFC0905500,2016YFC0905503)Science and Technology Program of Guangdong(Grant No.2017B020227001,2016A020215084)+3 种基金Science and Technology Program of Guangzhou(Grant No.201607020031,201400000001-2)Chinese National Natural Science Foundation Project(Grant No.81772476,81572659,81602011)Pearl River Nova Program of Guangzhou(Grant No.201610010048)National Natural Science Funds for Young Scholars of China(Grant No.81502355).
文摘Dear editor,Lung cancer is the leading cause of cancer-related death worldwide,with the predominant pathological type being non-small cell lung cancer(NSCLC)[1,2].Next-gener-ation sequencing(NGS)analysis is increasingly used to help clinicians select appropriate target therapies,such as epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs)for EGFR-mutant patients[3].Both pericarcinomatous tissues and peripheral blood lymphocytes are widely used as normal control for NGS analysis.However,whether pericarcinomatous tissue is suitable for background filtering in mutation analysis remains controversial.According to the whole-genome sequencing data from The Cancer Genome Atlas(TCGA)database,there were some genomic variations in peri-carcinomatous tissue from NSCLC patients,but no driver gene mutation was detected[4,5].Therefore,deep sequencing of pericarcinomatous and tumor tissues is necessary to confirm whether pericarcinomatous tissue harbors low-frequency mutations.
基金Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-002National High Level Hospital Clinical Research Funding,Grant/Award Number:2022-PUMCH-A-001National Natural Science Foundation of China,Grant/Award Numbers:82072747,82072749。
文摘Background:Neuroendocrine carcinomas of the gastrointestinal tract(GINECs)remain a disease of grim prognosis with limited therapeutic options.Their molecular characteristics are still undefined.This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs.Methods:Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed,paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation.Mutational signatures,somatic mutations,and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes.Survival analysis was conducted to identify the independent factors.Results:In total,143GI-NECswere examined:the stomach,87 cases(60.8%);the esophagus,29 cases(20.3%);the colorectum,20 cases(14.0%);and the small intestine,7 cases(4.9%).Eighty-three(58.0%)and 60(42.0%)cases were subclassified into small cell and large cell subtypes,respectively.GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations.Obvious heterogeneity of mutational signatures,somatic mutations,and copy number variations was revealed across anatomic locations rather than histological subtypes.Except for tumor protein p53(TP53)and retinoblastoma 1(RB1),the most frequently mutated genes in the stomach,esophagus,colorectum,and small intestine were low-density lipoprotein receptor-related protein 1B(LRP1B),notch receptor 1(NOTCH1),adenomatosis polyposis coli(APC),catenin beta 1(CTNNB1),respectively.Mutations in the WNT-β-catenin,NOTCH and erythroblastic leukemia viral oncogene B(ERBB)pathwayswere prevalently identified in gastric,esophageal,and colorectalNECs,respectively.Importantly,104(72.7%)GI-NECs harbored putative clinically relevant alterations,and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors.Furthermore,we found that tumor cells in GI-NECs first gain clonal mutations in TP53,RB1,NOTCH1 and APC,followed by subsequent wholegenome doubling(WGD)and post-WGD clonal mutations in LRP1B,CUB and Sushi multiple domains 3(CSMD3),FAT tumor suppressor homolog 4(FAT4)and erb-b2 receptor tyrosine kinase 4(ERBB4),and finally develop subclonal mutations.Conclusions:GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations.Moreover,potentially actionable alterations and prognostic factors were revealed for GI-NECs.
基金supported by funding from the National Natural Science Foundation of China Major Joint Project on Key Scientific Issues of Lung Cancer(No.82241235)the National Natural Science Foundation of China(No.81872510)+3 种基金Guangdong Provincial People’s Hospital Young Talent Project(No.GDPPHYTP201902)Guangdong Basic and Applied Basic Research Foundation(No.2019B1515130002)High-level Hospital Construction Project(No.DFJH201801)Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer(No.2017B030314120).
文摘Gene fusions and MET alterations are rare and difficult to detect in plasma samples.The clinical detection efficacy of molecular residual disease(MRD)based on circulating tumor DNA(ctDNA)in patients with non-small cell lung cancer(NSCLC)with these mutations remains unknown.This prospective,non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions(ALK,ROS1,RET,and FGFR1),MET exon 14 skipping or de novo MET amplification.We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021-and 338-gene panels,respectively.Detectable MRD correlated with a significantly higher recurrence rate(P<0.001),yielding positive predictive values of 100%and 90.9%,and negative predictive values of 82.4%and 86.4%at landmark and longitudinal time points,respectively.Patients with detectable MRD showed reduced disease-free survival(DFS)compared to those with undetectable MRD(P<0.001).Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not(P=0.05).To our knowledge,this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations.Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.
