A 15-Inflammation-Related Gene Signature Predicts the Prognosis of Patients With Pancreatic Ductal Adenocarcinoma.

Chronic inflammation promotes the development of pancreatic ductal adenocarcinoma (PDAC) and PDAC-related inflammatory tumor microenvironment facilitates tumor growth and metastasis. Thus, we aimed to study the association between inflammatory response and prognosis in patients with PDAC. We conducted the whole transcriptomic sequencing using tissue samples collected from patients diagnosed with PDAC (n = 106) recruited from Shandong Cancer Hospital. We first constructed a prognostic signature using 15 inflammation-related genes in The Cancer Genome Atlas (TCGA) cohort (n = 177) and further validated it in an independent International Cancer Genome Consortium (ICGC) cohort (n = 90) and our in-house cohort. PDAC patients with a higher risk score had poorer overall survival (OS) (P < 0.001; HR, 3.02; 95% CI, 1.94-4.70). The association between the prognostic signature and OS remained significant in the multivariable Cox regression adjusting for age, sex, alcohol exposure, diabetes, and stage (P < 0.001; HR, 2.91; 95% CI, 1.73-4.89). This gene signature also robustly predicted prognosis in the ICGC cohort (P = 0.01; HR, 1.94; 95% CI, 1.14-3.30) and our cohort (P < 0.001; HR, 2.40; 95% CI, 1.45-3.97). Immune subtype C3 (inflammatory) was enriched and CD8+ T cells were higher in patients with a lower risk score (P < 0.05). Furthermore, PDAC patients with higher risk scores were more sensitive to chemotherapy, immunotherapy, and PARP inhibitors (P < 0.05). In sum, we identified a novel gene signature that was associated with inflammatory response for risk stratification, prognosis prediction, and therapy guidance in PDAC patients. Future studies are warranted to validate the clinical utility of the signature.

BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials.

BACKGROUND: In patients with advanced clear cell renal cell carcinoma, despite the undoubted benefits from immune checkpoint inhibitor (ICI)-based therapies over monotherapies of angiogenic/mTOR inhibitors in the intention-to-treat population, approximately a quarter of the patients can scarcely gain advantage from ICIs, prompting the search for predictive biomarkers for patient selection. METHODS: Clinical and multi-omic data of 2428 ccRCC patients were obtained from The Cancer Genome Atlas (TCGA, n = 537), JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib, n = 885), and CheckMate-009/010/025 (nivolumab vs. everolimus, n = 1006). RESULTS: BAP1 mutations were associated with large progression-free survival (PFS) benefits from ICI-based immunotherapies over sunitinib/everolimus (pooled estimate of interaction HR = 0.71, 95% CI 0.51-0.99, P = 0.045). Using the top 20 BAP1 mutation-associated differentially expressed genes (DEGs) generated from the TCGA cohort, we developed the BAP1-score, negatively correlated with angiogenesis and positively correlated with multiple immune-related signatures concerning immune cell infiltration, antigen presentation, B/T cell receptor, interleukin, programmed death-1, and interferon. A high BAP1-score indicated remarkable PFS benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors (avelumab plus axitinib vs. sunitinib: HR = 0.55, 95% CI 0.43-0.70, P < 0.001; nivolumab vs. everolimus: HR = 0.72, 95% CI 0.52-1.00, P = 0.045), while these benefits were negligible in the low BAP1-score subgroup (HR = 1.16 and 1.02, respectively). CONCLUSION: In advanced ccRCCs, the BAP1-score is a biologically and clinically significant predictor of immune microenvironment and the clinical benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors, demonstrating its potential utility in optimizing the personalized therapeutic strategies in patients with advanced ccRCC.

Tumor immune contexture predicts recurrence after prostatectomy and efficacy of androgen deprivation and immunotherapy in prostate cancer.

BACKGROUND: Prostate cancer is one of the most common cancers in men with notable interpatient heterogeneity. Implications of the immune microenvironment in predicting the biochemical recurrence-free survival (BCRFS) after radical prostatectomy and the efficacy of systemic therapies in prostate cancer remain ambiguous. METHODS: The tumor immune contexture score (TICS) involving eight immune contexture-related signatures was developed using seven cohorts of 1120 patients treated with radical prostatectomy (training: GSE46602, GSE54460, GSE70769, and GSE94767; validation: GSE70768, DKFZ2018, and TCGA). The association between the TICS and treatment efficacy was investigated in GSE111177 (androgen deprivation therapy [ADT]) and EGAS00001004050 (ipilimumab). RESULTS: A high TICS was associated with prolonged BCRFS after radical prostatectomy in the training (HR = 0.32, 95% CI 0.24-0.45, P < 0.001) and the validation cohorts (HR = 0.45, 95% CI 0.32-0.62, P < 0.001). The TICS showed stable prognostic power independent of tumor stage, surgical margin, pre-treatment prostatic specific antigen (PSA), and Gleason score (multivariable HR = 0.50, 95% CI 0.39-0.63, P < 0.001). Adding the TICS into the prognostic model constructed using clinicopathological features significantly improved its 1/2/3/4/5-year area under curve (P < 0.05). A low TICS was associated with high homologous recombination deficiency scores, abnormally activated pathways concerning DNA replication, cell cycle, steroid hormone biosynthesis, and drug metabolism, and fewer tumor-infiltrating immune cells (P < 0.05). The patients with a high TICS had favorable BCRFS with ADT (HR = 0.25, 95% CI 0.06-0.99, P = 0.034) or ipilimumab monotherapy (HR = 0.23, 95% CI 0.06-0.81, P = 0.012). CONCLUSIONS: Our study delineates the associations of tumor immune contexture with molecular features, recurrence after radical prostatectomy, and the efficacy of ADT and immunotherapy. The TICS may improve the existing risk stratification systems and serve as a patient-selection tool for ADT and immunotherapy in prostate cancer.

A DNA Damage Response Related Signature to Predict Prognosis in Patients with Acute Myeloid Leukemia.

The prognosis of acute myeloid leukemia (AML) is disappointing in most subtypes and varies widely. DNA damage response (DDR) is associated with prognosis and immunotherapy in multiple cancers. Here, we identify a signature of eight DDR-related genes associated with overall survival, which stratifies AML patients into high- and low-risk groups. Patients in low-risk group were more likely to respond to sorafenib. The signature could be an independent prognostic predictor for patients treated with ADE and ADE plus gemtuzumab ozogamicin. Therefore, this DDR prognostic signature might be applied to prognostic stratification and treatment selection in AML patients, which warrants further studies.

Deciphering a cell death-associated signature for predicting prognosis and response to immunotherapy in lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a subtype of non-small cell carcinoma, accounting for about 30% of all lung cancers. Yet, the evaluation of prognostic outcome and therapy response of patients with LUSC remains to be resolved. This study aimed to explore the prognostic value of cell death pathways and develop a cell death-associated signature for predicting prognosis and guiding treatment in LUSC. METHODS: Transcriptome profiles and corresponding clinical information of LUSC patients were gathered from The Cancer Genome Atlas (TCGA-LUSC, n = 493) and Gene Expression Omnibus database (GSE74777, n = 107). The cell death-related genes including autophagy (n = 348), apoptosis (n = 163), and necrosis (n = 166) were retrieved from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases. In the training cohort (TCGA-LUSC), LASSO Cox regression was used to construct four prognostic signatures of respective autophagy, apoptosis, and necrosis pathway and genes of three pathways. After comparing the four signatures, the cell death index (CDI), the signature of combined genes, was further validated in the GSE74777 dataset. We also investigated the clinical significance of the CDI signature in predicting the immunotherapeutic response of LUSC patients. RESULTS: The CDI signature was significantly associated with the overall survival of LUSC patients in the training cohort (HR, 2.13; 95% CI, 1.62‒2.82; P < 0.001) and in the validation cohort (HR, 1.94; 95% CI, 1.01‒3.72; P = 0.04). The differentially expressed genes between the high- and low-risk groups contained cell death-associated cytokines and were enriched in immune-associated pathways. We also found a higher infiltration of naive CD4+ T cells, monocytes, activated dendritic cells, neutrophils, and lower infiltration of plasma cells and resting memory CD4+ T cells in the high-risk group. Tumor stemness indices, mRNAsi and mDNAsi, were both negatively correlated with the risk score of the CDI. Moreover, LUSC patients in the low-risk group are more likely to respond to immunotherapy than those in the high-risk group (P = 0.002). CONCLUSIONS: This study revealed a reliable cell death-associated signature (CDI) that closely correlated with prognosis and the tumor microenvironment in LUSC, which may assist in predicting the prognosis and response to immunotherapy for patients with LUSC.

Common DNA methylation changes in biliary tract cancers identify subtypes with different immune characteristics and clinical outcomes.

BACKGROUND: DNA methylation-associated studies on biliary tract cancer (BTC), including cholangiocarcinoma (CCA) and gallbladder cancer (GBC), may improve the BTC classification scheme. We proposed to identify the shared methylation changes of BTCs and investigate their associations with genomic aberrations, immune characteristics, and survival outcomes. METHODS: Multi-dimensional data concerning mutation, DNA methylation, immune-related features, and clinical data of 57 CCAs and 48 GBCs from Eastern Hepatobiliary Surgery Hospital (EHSH) and 36 CCAs in the TCGA-CHOL cohort were analyzed. RESULTS: In our cohort including 24 intrahepatic CCAs (iCCAs), 20 perihilar CCAs (pCCAs), 13 distal CCAs (dCCAs), and 48 GBCs, 3369 common differentially methylated regions (DMRs) were identified by comparing tumor and non-tumor samples. A lower level of methylation changes of these common DMRs was associated with fewer copy number variations, fewer mutational burden, and remarkably longer overall survival (OS, hazard ratio [HR] = 0.07, 95% confidence interval [CI] 0.01-0.65, P = 0.017). Additionally, a 12-marker model was developed and validated for prognostication after curative surgery (HR = 0.21, 95% CI 0.10-0.43, P < 0.001), which exhibited undifferentiated prognostic effects in subgroups defined by anatomic location (iCCAs, d/pCCAs, GBCs), TNM stage, and tumor purity. Its prognostic utility remained significant in multivariable analysis (HR = 0.26, 95% CI 0.11-0.59, P = 0.001). Moreover, the BTCs with minimal methylation changes exhibited higher immune-related signatures, infiltration of CD8+ lymphocytes, and programmed death-ligand 1 (PD-L1) expression, indicating an inflamed tumor immune microenvironment (TIME) with PD-L1 expression elicited by immune attack, potentially suggesting better immunotherapy efficacy. CONCLUSIONS: In BTCs, DNA methylation is a powerful tool for molecular classification, serving as a robust indicator of genomic aberrations, survival outcomes, and tumor immune microenvironment. Our integrative analysis provides insights into the prognostication after curative surgery and patient selection for immunotherapy.

Efficacy and safety of pyrotinib in advanced lung adenocarcinoma with HER2 mutations: a multicenter, single-arm, phase II trial.

BACKGROUND: There is currently a lack of effective treatments for non-small cell lung cancer (NSCLC) patients harboring HER2 mutations. We examined the efficacy and safety of, and potential resistance mechanism to, pyrotinib, a pan-HER inhibitor, in advanced NSCLC carrying HER2 mutations. METHODS: In this multicenter, single-arm, phase II trial, stage IIIB-IV NSCLC patients harboring HER2 mutations, as determined using next-generation sequencing, were enrolled and treated with pyrotinib at a dose of 400 mg/day. The primary endpoint was 6-month progression-free survival (PFS) rate, and secondary endpoints were objective response rate (ORR), PFS, overall survival (OS), disease control rate (DCR), and safety. The impact of different HER2 mutation types on sensitivity to pyrotinib and the potential of utilizing mutational profile derived from circulating tumor DNA (ctDNA) to predict disease progression were also explored. RESULTS: Seventy-eight patients were enrolled for efficacy and safety analysis. The 6-month PFS rate was 49.5% (95% confidence interval [CI], 39.2-60.8). Pyrotinib produced an ORR of 19.2% (95% CI, 11.2-30.0), with median PFS of 5.6 months (95% CI, 2.8-8.4), and median OS of 10.5 months (95% CI, 8.7-12.3). The median duration of response was 9.9 months (95% CI, 6.2-13.6). All treatment-related adverse events (TRAEs) were grade 1-3 (all, 91.0%; grade 3, 20.5%), and the most common TRAE was diarrhea (all, 85.9%; grade 3, 16.7%). Patients with exon 20 and non-exon 20 HER2 mutations had ORRs of 17.7% and 25.0%, respectively. Brain metastases at baseline and prior exposure to afatinib were not associated with ORR, PFS, or OS. Loss of HER2 mutations and appearance of amplification in HER2 and EGFR were detected upon disease progression. CONCLUSIONS: Pyrotinib exhibited promising efficacy and acceptable safety in NSCLC patients carrying exon 20 and non-exon 20 HER2 mutations and is worth further investigation. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR1800020262.

Identification and validation of tissue or ctDNA PTPRD phosphatase domain deleterious mutations as prognostic and predictive biomarkers for immune checkpoint inhibitors in non-squamous NSCLC.

BACKGROUND: With the revolutionary progress of immune checkpoint inhibitors (ICIs) achieved in non-small cell lung cancers (NSCLC), identifying patients benefiting from ICIs becomes critical and urgent. The associations of genomic alterations in protein tyrosine phosphatase receptor-type (PTPRs) and ICIs responses are unknown. METHODS: Whole-exome sequencing (WES) of 73 advanced NSCLC tumors sampled before anti-PD-(L)1 therapy was carried out with corresponding clinical data collected as a discovery cohort to find the associations of PTPR mutations and ICI responses. Three validation cohorts consolidated by 7 public cohorts of 1920 NSCLC patients with WES or target sequencing data of tumor tissue-derived DNA or circulating tumor DNA (ctDNA) and relevant clinical data were applied as validation cohorts. The lung adenocarcinoma (LUAD) cohort (n=586) in The Cancer Genome Atlas (TCGA) database was used for analyzing the potential anti-tumor immunologic mechanisms. RESULTS: With the highest mutation frequency among all PTPRs, PTPRD mutations in non-squamous NSCLC (ns-NSCLC) were linked to longer progression-free survivals (PFS, 324 vs 63 days, hazard ratio (HR)=0.36, p= 0.0152) and higher objective response rate (ORR, p=0.0099). In validation cohort 1 (n=377), ns-NSCLC patients with tissue PTPRD mutations had favorable PFS (9.10 vs 4.33 months, HR=0.62, p=0.0184) and ORR (p=0.013). In validation cohort 2 (n=406), ns-NSCLC patients with tissue PTPRD mutations had favorable overall survivals (OS, over 40 vs 11.94 months, HR=0.57, p=0.011). In validation cohort 3 (n=1137), ns-NSCLC patients with ctDNA PTPRD mutations had longer PFS (6.97 vs 2.73 months, HR=0.63, p=0.028) and higher ORR (p=0.047). Moreover, it was deleterious mutations in phosphatase domains (phosphatase-mut), rather than other mutations (other-mut), that were responsible of PTPRD's prediction efficiency. In addition, in validation cohort 3, ctDNA phosphatase-mut also functioned as a predictive biomarker helping identify patients benefiting more from ICIs than chemotherapy (interaction P for PFS=0.0506, for OS=0.04). Univariate and multivariate regression analysis revealed that phosphatase-mut was independent on PD-L1 expression and tumor mutation burden (TMB) to predict. In silico analysis based on TCGA LUAD cohort discovered enhanced anti-tumor immunity in phosphatase-mut patients. CONCLUSIONS: Tissue or ctDNA PTPRD phosphatase domain deleterious mutations might function as a both prognostic and predictive biomarker predicting clinical outcomes of ICIs in ns-NSCLC patients, independent on TMB or PD-L1 expression.

Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: a case-control study.

BACKGROUND: Plasma cell-free DNA (cfDNA) methylation has shown promising results in the early detection of multiple cancers recently. Here, we conducted a study to investigate the performance of cfDNA methylation in the early detection of esophageal cancer (ESCA). METHODS: Specific methylation markers for ESCA were identified and optimized based on esophageal tumor and paired adjacent tissues (n = 24). Age-matched participants with ESCA (n = 85), benign esophageal diseases (n = 10), and healthy controls (n = 125) were randomized into the training and test sets to develop a classifier to differentiate ESCA from healthy controls and benign esophageal disease. The classifier was further validated in an independent plasma cohort of ESCA patients (n = 83) and healthy controls (n = 98). RESULTS: In total, 921 differentially methylated regions (DMRs) between tumor and adjacent tissues were identified. The early detection classifier based on those DMRs was first developed and tested in plasma samples, discriminating ESCA patients from benign and healthy controls with a sensitivity of 76.2% (60.5-87.9%) and a specificity of 94.1% (85.7-98.4%) in the test set. The performance of the classifier was consistent irrespective of sex, age, and pathological diagnosis (P > 0.05). In the independent plasma validation cohort, similar performance was observed with a sensitivity of 74.7% (64.0-83.6%) and a specificity of 95.9% (89.9-98.9%). Sensitivity for stage 0-II was 58.8% (44.2-72.4%). CONCLUSION: We demonstrated that the cfDNA methylation patterns could distinguish ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Further prospective evaluation of the classifier in the early detection of ESCAs in high-risk individuals is warranted.

A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer.

BACKGROUND: Mismatch repair (MMR)/microsatellite instability (MSI) and tumor mutational burden (TMB) are independent biomarkers that complement each other for predicting immune checkpoint inhibitors (ICIs) efficacy. Here we aim to establish a strategy that integrates MSI and TMB determination for colorectal cancer (CRC) in one single assay. METHODS: Surgical or biopsy specimens retrospectively collected from CRC patients were subjected to NGS analysis. Immunohistochemistry (IHC) and polymerase chain reaction (PCR) were also used to determine MMR/MSI for those having enough tissues. The NGS-MSI method was validated against IHC and PCR. The MSI-high (MSI-H) or microsatellite stable (MSS) groups were further stratified based on tumor mutational burden, followed by validation using the The Cancer Genome Atlas (TCGA) CRC dataset. Immune microenvironment was evaluated for each subgroup be profiling the expression of immune signatures. RESULTS: Tissues from 430 CRC patients were analyzed using a 381-gene NGS panel. Alterations in KRAS, NRAS, BRAF, and HER2 occurred at a significantly higher incidence among MSI-H tumors than in MSS patients (83.6% vs. 58.4%, p = 0.0003). A subset comprising 98 tumors were tested for MSI/MMR using all three techniques, where NGS proved to be 99.0 and 93.9% concordant with PCR and IHC, respectively. Four of the 7 IHC-PCR discordant cases had low TMB (1.1-8.1 muts/Mb) and were confirmed to have been misdiagnosed by IHC. Intriguingly, 4 of the 66 MSS tumors (as determined by NGS) were defined as TMB-high (TMB-H) using a cut-off of 29 mut/Mb. Likewise, 15 of the 456 MSS tumors in the TCGA CRC cohort were also TMB-H with a cut-off of 9 muts/Mb. Expression of immune signatures across subgroups (MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-L) confirmed that the microenvironment of the MSS-TMB-H tumors was similar to that of the MSI-H-TMB-H tumors, but significantly more immune-responsive than that of the MSS-TMB-L tumors, indicating that MSI combined with TMB may be more precise than MSI alone for immune microenvironment prediction. CONCLUSION: This study demonstrated that NGS panel-based method is both robust and tissue-efficient for comprehensive molecular diagnosis of CRC. It also underscores the importance of combining MSI and TMB information for discerning patients with different microenvironment.

Immune checkpoint inhibitors combined with chemotherapy for the treatment of advanced pancreatic cancer patients.

Immune checkpoint inhibitors (ICIs) represent a major breakthrough for cancer treatment. However, evidence regarding the use of ICIs in pancreatic cancer (PC) remained scarce. To assess the efficacy and safety of ICIs plus chemotherapy, patients with advanced PC were retrospectively recruited and were treated with either chemotherapy alone or chemotherapy plus ICIs. Patients previously treated with any agents targeting T-cell co-stimulation or checkpoint pathways were excluded. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), overall response rate (ORR) and safety. In total, 58 patients were included (combination, n = 22; chemotherapy, n = 36). The combination group showed a significantly longer OS than the chemotherapy group [median, 18.1 vs 6.1 months, hazard ratio (HR) 0.46 (0.23-0.90), P = 0.021]. The median PFSs were 3.2 months in the combination group and 2.0 months in the chemotherapy group [HR 0.57 (0.32-0.99), P = 0.041]. The combination group and the chemotherapy group had similar ORRs (18.2% vs 19.4%, P = 0.906). All patients who achieved a partial response received a doublet chemotherapy regimen regardless of co-treatment with ICIs. Grade 3 or higher adverse events occurred in 31.8% of the patients in the combination group and in 16.9% of those receiving chemotherapy. Although the incidence of serious treatment-related adverse events was higher in the combination group than in the chemotherapy group, the difference was not significant (P = 0.183). Our findings suggest that the combination of ICIs with chemotherapy is both effective and tolerable for advanced PC. ICIs combined with a doublet chemotherapy regimen might be a preferable choice.

Pathogenic Germline Mutations in Chinese Patients with Gastric Cancer Identified by Next-Generation Sequencing.

BACKGROUND: Gastric cancer (GC) is one of the leading causes of cancer death in China, while the nature of genetic factors related to GC has not been well-studied. OBJECTIVES: To assess the inherited genetic factors regarding pathogenic germline mutations in Chinese GC population. METHODS: Genomic profiling of DNA was performed through next-generation sequencing with 381 cancer-related genes on tissue from patients with GC between January 1, 2017, and May 7, 2019. RESULTS: 470 GC patients were included for analysis. A total of 28 (6.0%) patients were identified to harbor 25 different pathogenic or very likely pathogenic germline mutations in 15 genes. The variants fell most frequently in BRCA2 (n = 6, 1.28%), CHEK2 (n = 5, 1.06%), MUTYH (n = 3, 0.64%), CDH1 (n = 2, 0.43%), and ATM (n = 2, 0.43%). Of all the germline-mutated genes, 66.7% (n = 10) lay in the DNA damage repair pathways. Seven patients were identified to have a high TMB status, among whom two were also identified as MSI-H. Overall, 20 out of the 28 patients (71.4%) carried clinically actionable mutations. CONCLUSIONS: Our study has depicted the spectrum of pathogenic germline mutations in Chinese GC patients, which may provide valuable clues for the assessment of the genetic susceptibility and clinical management in GC.

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer.

BACKGROUND: Evidence for the efficacy of immunotherapy in biliary tract cancer (BTC) is limited and unsatisfactory. METHODS: Chinese BTC patients receiving a PD-1 inhibitor with chemotherapy, PD-1 inhibitor monotherapy or chemotherapy alone were retrospectively analyzed. The primary outcome was overall survival (OS). The key secondary outcomes were progression-free survival (PFS) and safety. Patients previously treated with any agent targeting T cell costimulation or immune checkpoints were excluded. RESULTS: The study included 77 patients (a PD-1 inhibitor plus chemotherapy, n = 38; PD-1 inhibitor monotherapy, n = 20; chemotherapy alone, n = 19). The median OS was 14.9 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 4.1 months with PD-1 inhibitor monotherapy (HR 0.37, 95% CI 0.17-0.80, P = 0.001) and the 6.0 months with chemotherapy alone (HR 0.63, 95% CI 0.42-0.94, P = 0.011). The median PFS was 5.1 months with a PD-1 inhibitor plus chemotherapy, significantly longer than the 2.2 months with PD-1 inhibitor monotherapy (HR 0.59, 95% CI 0.31-1.10, P = 0.014) and the 2.4 months with chemotherapy alone (HR 0.61, 95% CI 0.45-0.83, P = 0.003). Grade 3 or 4 treatment-related adverse events were similar between the anti-PD-1 combination group and the chemotherapy alone group (34.2% and 36.8%, respectively). CONCLUSIONS: Anti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC.

A Novel Online Calculator Based on Serum Biomarkers to Detect Hepatocellular Carcinoma among Patients with Hepatitis B.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV)-infected patients remains a challenge, especially in China. We sought to create an online calculator of serum biomarkers to detect HCC among patients with chronic hepatitis B (CHB). METHODS: Participants with HBV-HCC, CHB, HBV-related liver cirrhosis (HBV-LC), benign hepatic tumors, and healthy controls (HCs) were recruited at 11 Chinese hospitals. Potential serum HCC biomarkers, protein induced by vitamin K absence or antagonist-II (PIVKA-II), α-fetoprotein (AFP), lens culinaris agglutinin A-reactive fraction of AFP (AFP-L3) and α-l-fucosidase (AFU) were evaluated in the pilot cohort. The calculator was built in the training cohort via logistic regression model and validated in the validation cohort. RESULTS: In the pilot study, PIVKA-II and AFP showed better diagnostic sensitivity and specificity compared with AFP-L3 and AFU and were chosen for further study. A combination of PIVKA-II and AFP demonstrated better diagnostic accuracy in differentiating patients with HBV-HCC from patients with CHB or HBV-LC than AFP or PIVKA-II alone [area under the curve (AUC), 0.922 (95% CI, 0.908-0.935), sensitivity 88.3% and specificity 85.1% for the training cohort; 0.902 (95% CI, 0.875-0.929), 87.8%, and 81.0%, respectively, for the validation cohort]. The nomogram including AFP, PIVKA-II, age, and sex performed well in predicting HBV-HCC with good calibration and discrimination [AUC, 0.941 (95% CI, 0.929-0.952)] and was validated in the validation cohort [AUC, 0.931 (95% CI, 0.909-0.953)]. CONCLUSIONS: Our results demonstrated that a web-based calculator including age, sex, AFP, and PIVKA-II accurately predicted the presence of HCC in patients with CHB. CLINICALTRIALSGOV IDENTIFIER: NCT03047603.

Notch activation defines immune-suppressive subsets of ccRCCs with unfavorable benefits from immunotherapy over VEGFR/mTOR inhibitors.

The evolutionarily conserved Notch pathway, involved in cancer stem cell capacity and cancer immunity, may predict the benefit from immune checkpoint inhibitors (ICIs) in clear cell renal cell carcinoma (ccRCC). In the TCGA dataset, mRNA expression of Notch pathway genes identified three clusters with different prognoses and molecular characteristics. Based on the differentially expressed Notch pathway genes between clusters, we constructed the Notch-score, correlated with Notch activation, angiogenesis, PI3K-AKT-mTOR activity, and sensitivities to VEGFR/mTOR inhibitors. A high Notch-score was linked with more "resting"/"anti-inflammatory" rather than "activated"/"pro-inflammatory" tumor-infiltrating immune cells, inactivated immune pathways, and scarce any benefits from ICI-based therapies over VEGFR/mTOR inhibitors in the JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib) and the CheckMate-009/010/025 trials (nivolumab vs. everolimus). For the Notch-activated ccRCCs, ICIs provide limited advantages and might not be strongly recommended, by which the cost-effectiveness of treatments in ccRCCs may be potentially improved.

MAEL in human cancers and implications in prognostication and predicting benefit from immunotherapy over VEGFR/mTOR inhibitors in clear cell renal cell carcinoma: a bioinformatic analysis.

Maelstrom (MAEL), a novel cancer/testis-associated gene, may facilitate the initiation and progression of human malignancies, warranting comprehensive investigations. Single-cell and tissue-bulk transcriptomic data demonstrated higher MAEL expression in testis (spermatogonia/spermatocyte), kidney (proximal tubular cell), and brain (neuron/astrocyte), and corresponding cancers, including testicular germ cell tumor, glioma, papillary renal cell carcinoma, and clear cell renal cell carcinoma (ccRCC). Of these cancers, only in ccRCC did MAEL expression exhibit associations with both recurrence-free survival and overall survival. High MAEL expression was associated with an anti-inflammatory tumor immune microenvironment and VEGFR/mTOR activation in ccRCC tissues and high sensitivities to VEGFR/PI3K-AKT-mTOR inhibitors in ccRCC cell lines. Consistent with these, low rather than high MAEL expression indicated remarkable progression-free survival benefits from immune checkpoint inhibitor (ICI)-based immunotherapies over VEGFR/mTOR inhibitors in two large phase III trials (JAVELIN Renal 101 and CheckMate-025). MAEL is a biologically and clinically significant determinant with potential for prognostication after nephrectomy and patient selection for VEGFR/mTOR inhibitors and immunotherapy-based treatments.

Evaluation of Molecular Residual Disease by a Fixed Panel in Resectable Colorectal Cancer.

Purpose: Molecular residual disease (MRD) is a promising biomarker in colorectal cancer (CRC) for prognosis and guiding treatment, while the whole-exome sequencing (WES) based tumor-informed assay is standard for evaluating MRD based on circulating tumor DNA (ctDNA). In this study, we assessed the feasibility of a fixed-panel for evaluating MRD in CRC. Materials and Methods: 75 patients with resectable stage I-III CRC were enrolled. Tumor tissues obtained by surgery, and pre-operative and post-operative day 7 blood samples were collected. The ctDNA was evaluated using the tumor-agnostic and tumor-informed fixed assays, as well as the WES-based and panel-based personalized assays in randomly selected patients. Results: The tumor-informed fixed assay had a higher pre-operative positive rate than the tumor-agnostic assay (73.3% vs 57.3%). The pre-op ctDNA status failed to predict disease-free survival (DFS) in either of the fixed assays, while the tumor-informed fixed assay-determined post-op ctDNA positivity was significantly associated with worse DFS (HR, 20.74, 95%CI 7.19-59.83; p<0.001), which was an independent predictor by multivariable analysis (HR, 28.57, 95%CI 7.10-114.9; p<0.001). Sub-cohort analysis indicated the WES-based personalized assay had the highest pre-operative positive rate (95.1%). The two personalized assays and the tumor-informed fixed assay demonstrated same results in post-op landmark (HR, 26.34, 95%CI, 6.01-115.57; p<0.001), outperforming the tumor-agnostic fixed panel (HR, 3.04, 95%CI, 0.94-9.89; p=0.052). Conclusion: Our study confirmed the prognostic value of the ctDNA positivity at post-op day 7 by the tumor-informed fixed panel. The tumor-informed fixed panel may be a cost-effective method to evaluate MRD, which warrants further studies in future.

T proliferating cells derived autophagy signature associated with prognosis and immunotherapy resistance in a pan-cancer analysis.

Despite autophagy modulating tumor immunity in the tumor microenvironment (TME), the immunotherapeutic efficacy and potential mechanism of autophagy signature was not explicit. We manually curated an autophagy gene set and defined a pan-cancer autophagy signature by comparing malignant tissues and normal tissues in The Cancer Genome Atlas (TCGA) cohort. The pan-cancer autophagy signature was derived from T proliferating cells as demonstrated in multiple single-cell RNA sequencing (scRNA-seq) datasets. The pan-cancer autophagy signature could influence the cell-cell interactions in the TME and predict the responsiveness of immune checkpoint inhibitors (ICIs) in the metastatic renal cell carcinoma, non-small cell lung cancer, bladder cancer, and melanoma cohorts. Metabolism inactivation accompanied with dysregulation of autophagy was investigated with transcriptomic and proteomic data. The immunotherapeutic predictive role and mechanism regulation of the autophagy signature was validated in an in-house cohort. Our study provides valuable insights into the mechanisms of ICI resistance.

The prognostic significance and clinical relevance of stem cell characteristic in bladder cancer.

Background: Bladder cancer (BLCA) is a common malignant tumor of urinary system and prognostic biomarkers are needed for better clinical decision-making and patient management. Cancer stem cells (CSCs) are involved in carcinogenesis, development, metastasis and recurrence of BLCA. This study explored the prognostic and predictive value of CSCs-related genes and laid the groundwork for precision treatment development in BLCA. Methods: The mRNA data and corresponding clinical information obtained from TCGA-BLCA cohort was used to discover biomarkers and develop CSCs-related prognostic model, which was further validated in GSE32548 and GSE32894 datasets. In addition, the association between CSCs-related risk score and therapeutic efficacy was analyzed to explore the potential predictive value of the prognostic model. Results: We identified four CSCs-related subtypes and 900 differentially expressed genes (DEGs) among subtypes. Then the CSCs-related prognostic model was built based on 16 CSCs-related DEGs with the most significant prognostic value. Patients in the low-risk group had better overall survival than those in high-risk group (P < 0.001; HR, 0.42; 95 %CI, 0.31-0.57). Multivariable Cox analysis in training and test sets confirmed the independence of CSCs-related risk score as a prognostic factor (P < 0.05). The difference of survival between two risk groups were probably due to the significantly varied immune microenvironment based on the analysis of infiltrated immune cells. Additionally, the risk score was significantly associated with chemotherapy sensitivity and the response to anti-PD-L1 therapy (P < 0.05) which suggested a potential predictive value of CSCs-related risk model. Conclusion: We established a risk classifier based on 16 CSCs-related genes for predicting survival in patients with BLCA. The CSCs-related risk model has both prognostic value and potential predictive value for therapeutic efficacy, which brings us closer to understanding the important role of CSCs in BLCA and may provide guidance for clinical treatment decision-making and patient management. The clinical utility of the CSCs-related risk classifier warrants further studies.

Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.

Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.