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Chemotherapy 2023PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
PD-1 inhibitors have been approved for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced gastric/gastroesophageal junction cancer still needs to be precisely determined.
OBJECTIVE
This objective of this study is to evaluate the efficacy of anti-PD-1/PD-L1 therapy in advanced gastric/gastroesophageal junction adenocarcinoma patients through a systematic review and meta-analysis of relevant clinical trials.
METHOD
The PubMed, Embase, and Cochrane Library electronic databases were searched up to August 1, 2022, for clinical trials of anti-PD-1/PD-L1 immunotherapy for the first-line treatment of advanced gastroesophageal cancer. Hazard ratios and 95% confidence intervals for overall survival, progression-free survival, and objective response rates were extracted and pooled for meta-analysis. Prespecified subgroups included the following: agent type, PD-L1 expression, and high microsatellite instability.
RESULTS
This study analyzed 5 RCTs involving 3,355 patients. Compared with the chemotherapy group, the combined immunotherapy group had a significantly higher objective response rate (OR = 0.63, 95% CI: 0.55-0.72, p < 0.00001) and prolonged overall survival (HR = 0.82, 95% CI: 0.76-0.88, p < 0.00001) and progression-free survival (HR = 0.75, 95% CI: 0.69-0.82, p < 0.00001). The combination of immunotherapy and chemotherapy prolonged OS in both MSI-H (HR = 0.38, p = 0.002) and MSS (HR = 0.78, p < 0.00001) populations, but there was a significant difference between groups (p = 0.02). However, in improving ORR, the benefit of ICI combined with chemotherapy in the MSS group and MSI-H group was not significantly different between groups (p = 0.52). Combination therapy with ICIs was more effective than chemotherapy alone in prolonging OS in the subgroup with a high CPS, regardless of the CPS cutoff for PD-L1. However, when the cutoff of CPS was 1, the difference between subgroups did not reach statistical significance (p = 0.12), while the benefit ratio of the MSI-H group was higher when the cutoff was 10 (p = 0.004) than when the cutoff value was 5 (p = 0.002).
CONCLUSIONS
For first-line treatment of advanced gastroesophageal cancer, an ICI combination strategy is more effective than chemotherapy. The subgroup of patients with a CPS ≥10 has a more significant benefit, and CPS ≥10 has the potential to be used as an accurate marker of the dominant population of immuno-combined therapy.
Topics: Humans; Stomach Neoplasms; Immune Checkpoint Inhibitors; B7-H1 Antigen; Adenocarcinoma; Esophagogastric Junction
PubMed: 37331333
DOI: 10.1159/000531457 -
Critical Reviews in Oncology/hematology Aug 2023Lynch syndrome (LS) is a genetic predisposition leading to colorectal and non-colorectal tumors such as endometrial, upper urinary tract, small intestine, ovarian,... (Review)
Review
Lynch syndrome (LS) is a genetic predisposition leading to colorectal and non-colorectal tumors such as endometrial, upper urinary tract, small intestine, ovarian, gastric, biliary duct cancers and glioblastoma. Though not classically associated with LS, growing literature suggests that sarcomas might develop in patients with LS. This systematic review of literature identified 44 studies (N = 95) of LS patients who developed sarcomas. It seems that most sarcomas developed in patients with a germline mutation of MSH2 (57 %) exhibit a dMMR (81 %) or MSI (77 %) phenotype, as in other LS-tumors. Although undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, and liposarcoma remain the most represented histologic subtype, a higher proportion of rhabdomyosarcoma (10 %, especially pleomorphic rhabdomyosarcoma) is reported. Further studies are required to better characterize this sub-population.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Colorectal Neoplasms; Genetic Predisposition to Disease; Germ-Line Mutation; Sarcoma; Rhabdomyosarcoma; DNA Mismatch Repair; Microsatellite Instability
PubMed: 37301271
DOI: 10.1016/j.critrevonc.2023.104055 -
Medicina (Kaunas, Lithuania) Apr 2023This study aims to elucidate the prognostic implications of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a systematic review and... (Review)
Review
This study aims to elucidate the prognostic implications of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a systematic review and meta-analysis. In total, 57 eligible studies and 22,943 patients were included in this meta-analysis. We compared the prognoses of EBV-infected and non-infected GC patients. The subgroup analysis was performed based on the study location, molecular classification, and Lauren's classification. This study was checked according to the PRISMA 2020. The meta-analysis was performed using the Comprehensive Meta-Analysis software package. EBV infection was found in 10.4% (95% confidence interval (CI) 0.082-0.131) of GC patients. The EBV-infected GC patients had a better overall survival compared with the EBV-non-infected GC patients (hazard ratio (HR) 0.890, 95% CI 0.816-0.970). In the subgroup analysis based on molecular classification, no significant differences were found between EBV+ and microsatellite instability and microsatellite stable (MSS)/EBV- subgroups (HR 1.099, 95% CI 0.885-1.364 and HR 0.954, 95% CI 0.872-1.044, respectively). In the diffuse type of Lauren's classification, EBV-infected GCs have a better prognosis compared with the EBV-non-infected GCs (HR 0.400, 95% CI 0.300-0.534). The prognostic impact of EBV infection was found in the Asian and American subgroups but not in the European subgroup (HR 0.880, 95% CI 0.782-0.991, HR 0.840, 95% CI 0.750-0.941, and HR 0.915, 95% CI 0.814-1.028). EBV infection is a favorable survival factor for GCs. However, the prognostic implications of EBV infection in the new molecular classification are not clear.
Topics: Humans; Epstein-Barr Virus Infections; Prognosis; Herpesvirus 4, Human; Microsatellite Instability; Carcinoma; Stomach Neoplasms
PubMed: 37241066
DOI: 10.3390/medicina59050834 -
Frontiers in Pharmacology 2023Evidence of efficacy and safety of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in oesophageal cancer (EC), gastric cancer...
Evidence of efficacy and safety of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) checkpoint inhibitors in oesophageal cancer (EC), gastric cancer (GC) and colorectal cancer (CRC) was inconsistent, obscuring their clinical application and decision-making. The aim of this study was to comprehensively evaluate the value of PD-1/PD-L1 inhibitors in EC, GC and CRC to select valuable PD-1/PD-L1 inhibitors, and to assess the association between the value and cost of PD-1/PD-L1 inhibitors. A comprehensive search of trials of PD-1/PD-L1 inhibitors in EC, GC and CRC was performed in Chinese and English medical databases with a cut-off date of 1 July 2022. Two authors independently applied the ASCO-VF and ESMO-MCBS to assess the value of PD-1/PD-L1 inhibitors. A receiver operating characteristic (ROC) curve was generated to establish the predictive value of the ASCO-VF score to meet the threshold of the ESMO-MCBS grade. Spearman's correlation was used to calculate the relationship between the cost and value of drugs. Twenty-three randomized controlled trials were identified: ten (43.48%) in EC, five (21.74%) in CRC, and eight (34.78%) in GC or gastroesophageal junction cancer (GEJC). For advanced diseases, ASCO-VF scores ranged from -12.5 to 69, with a mean score of 26.5 (95% 18.4-34.6). Six (42.9%) therapeutic regimens met the ESMO-MCBS benefit threshold grade. The area under the ROC curve was 1.0 ( = 0.002). ASCO-VF scores and incremental monthly cost were negatively correlated (Spearman's = -0.465, = 0.034). ESMO-MCBS grades and incremental monthly cost were negatively correlated (Spearman's = -0.211, = 0.489). PD-1/PD-L1 inhibitors did not meet valuable threshold in GC/GEJC. Pembrolizumab met valuable threshold in advanced microsatellite instability-high CRC. The value of camrelizumab and toripalimab may be more worth paying in EC.
PubMed: 37153768
DOI: 10.3389/fphar.2023.1106961 -
Lung Cancer (Amsterdam, Netherlands) May 2023Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares... (Meta-Analysis)
Meta-Analysis Review
Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares morphological and immunohistochemical features with lung and colorectal adenocarcinoma. Few data are available on patient prognosis, possible prognostic factors and systemic approach to metastatic disease. We performed a pooled analysis and a systematic review of published lung-ETAC, along with an additional case description. Thirty-one eligible publications were identified, providing data from 126 patients. In the 127 patients overall analyzed, median overall survival (OS) was 56.0 (range 36.7-75.3) months in early-stage patients and 14.0 (range 4.5-23.5) months in those with advanced/metastatic disease. Median disease-free survival (DFS) after radical surgery was 24 (range 22.6-35.1) months. Smoking status (HR 4.304, 95% CI: 1.261-14.693, p = 0.020) and node involvement (HR 1.853, 95% CI: 1.179-2.911, p = 0.007) were the negative independent prognostic factors at multivariate analysis. As regards systemic therapies for advanced cases, no firm conclusions were drawn about the efficacy of lung cancer-oriented chemotherapy regimens as opposed to colon cancer-oriented ones. Molecular analysis of lung-ETAC revealed a relatively high mutational rate, with alterations in several druggable molecular pathways, KRAS and NRAS (31%) were the most frequently mutated oncogenes, followed by ROS1 (15%), RET (13%), BRAF (11%), EGFR (8%) and ALK (6%). Moreover, 3 (15%) out of 20 cases showed DNA mismatch repair deficiency (dMMR). In conclusion, advanced lung-ETAC patients appeared to have a better prognosis compared to other subtypes of NSCLC. Moreover, the mutational rate and microsatellite instability found in lung-ETACs suggest that a significant proportion of these patients could benefit from target therapies and immunotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Mutation; Proto-Oncogene Proteins; Adenocarcinoma; Adenocarcinoma of Lung; Prognosis; Lung
PubMed: 37015149
DOI: 10.1016/j.lungcan.2023.107176 -
World Journal of Gastroenterology Feb 2023Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). However, whether the influence of methyl donor intake is modified...
BACKGROUND
Dietary methyl donors might influence DNA methylation during carcinogenesis of colorectal cancer (CRC). However, whether the influence of methyl donor intake is modified by polymorphisms in such epigenetic regulators is still unclear.
AIM
To improve the current understanding of the molecular basis of CRC
METHODS
A literature search in the Medline database, (https:// www.referencecitationanalysis.com/), and manual reference screening were performed to identify observational studies published from inception to May 2022.
RESULTS
A total of fourteen case-control studies and five cohort studies were identified. These studies included information on dietary methyl donors, dietary components that potentially modulate the bioavailability of methyl groups, genetic variants of methyl metabolizing enzymes, and/or markers of CpG island methylator phenotype and/or microsatellite instability, and their possible interactions on CRC risk.
CONCLUSION
Several studies have suggested interactions between methylenetetrahydrofolate reductase polymorphisms, methyl donor nutrients (such as folate) and alcohol on CRC risk. Moreover, vitamin B, niacin, and alcohol may affect CRC risk through not only genetic but also epigenetic regulation. Identification of specific mechanisms in these interactions associated with CRC may assist in developing targeted prevention strategies for individuals at the highest risk of developing CRC.
Topics: Humans; Epigenesis, Genetic; Colorectal Neoplasms; Folic Acid; DNA Methylation; Microsatellite Instability; Nutrients; CpG Islands
PubMed: 36926668
DOI: 10.3748/wjg.v29.i7.1219 -
Scientific Reports Mar 2023NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in...
NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum sample size. Critical appraisal was performed using a custom 11-item checklist. Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03-0.70%, with higher rates found in RNA-based assays. In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and sample size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology.
Topics: Adult; Humans; Child; Receptor, trkA; Prevalence; Neoplasms; Genomics; Oncogene Proteins, Fusion; Gene Fusion
PubMed: 36914665
DOI: 10.1038/s41598-023-31055-3 -
Cancers Feb 2023Markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) are strongly needed. This meta-analysis... (Review)
Review
Predictive and Prognostic Value of Oncogene Mutations and Microsatellite Instability in Locally-Advanced Rectal Cancer Treated with Neoadjuvant Radiation-Based Therapy: A Systematic Review and Meta-Analysis.
Markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) are strongly needed. This meta-analysis aimed at elucidating the predictive/prognostic role of tumor markers in LARC. We systematically reviewed the impact of , , , and mutations and MSI status on response (pCR, downstaging) and prognosis (risk of recurrence, survival) in LARC according to PRISMA guidelines and the PICO model. PubMed, Cochrane Library, and Web of Science Core Collection were systematically searched to identify relevant studies published before October 2022. mutations were significantly associated with the risk of not achieving pCR after preoperative treatment (summary OR = 1.80, 95% CI: 1.23-2.64). This association was even more significant in patients not receiving cetuximab (summary OR = 2.17, 95% CI: 1.41-3.33) than in patients receiving cetuximab (summary OR = 0.89, 95% CI: 0.39-20.05). MSI status was not associated with pCR (summary OR = 0.80, 95% CI: 0.41-1.57). No effect of mutation or MSI status on downstaging was detected. Meta-analysis of survival outcomes was not possible due to the large heterogeneity among studies in endpoint assessment. The minimum number of eligible studies to assess the predictive/prognostic role of , , , and mutations was not reached. mutation, but not MSI status, proved to be a detrimental marker for response to preoperative radiation-based therapy in LARC. Translating this finding into the clinic could improve the management of LARC patients. More data are needed to clarify the clinical impact of , , , and mutations.
PubMed: 36900260
DOI: 10.3390/cancers15051469 -
Frontiers in Immunology 2023Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic colorectal cancer remains unclear. We tried to explore clinical effect of neoadjuvant immunotherapy in the treatment of non-metastatic colorectal cancer.
METHODS
We searched the databases (PubMed, Wanfang Embase, Cochrane Library and China National Knowledge Infrastructure databases) to obtain suitable articles up to September 2022. The primary outcomes of pathological complete response (pCRs), major pathological response (MPR), objective response rate (ORR), R0-resection and anus preserving rate were collected and evaluated. Secordary outcomes (pCRs and MPR) of subgroup analysis between deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable group (pMMR/MSS) and outcomes for rectal cancer were analyzed for the final results.
RESULTS
We included ten articles and 410 cases of non-metastatic colorectal cancer with neoadjuvant immunotherapy. There were 113 (27.5%) cases with the dMMR/MSI-H status and 167 (40.7%) cases with the pMMR/MSS status. pCRs was found in 167/373 (44.6%) patients (ES: 0.49, 95% CI: 0.36 to 0.62, <0.01, chi = 65.3, <0.01, = 86.2%) and MPR was found in 194/304 (63.8%) patients (ES: 0.66, 95% CI: 0.54 to 0.78, <0.01, chi = 42.55, <0.01, = 81.2%) with the random-effects model and huge heterogeneity. In the subgroup analysis, pCRs was higher in the dMMR/MSI-H group than the pMMR/MSS group in the fixed-effects model with minimal heterogeneity (OR: 3.55, 95% CI: 1.74 to 7.27, <0.01, chi = 1.86, =0.6, = 0%). pCRs was found in 58/172 (33.9%) rectal cancer patients (ES: 0.33, 95% CI: 0.26 to 0.40, <0.01, chi = 3.04, =0.55, = 0%) with the fixed-effects model and little heterogeneity.
CONCLUSION
Neoadjuvant immunotherapy could increase pCRs and MPR rate for non-metastatic colorectal cancer. Neoadjuvant immunotherapy could achieve better pCRs rate in dMMR/MSI-H group than in the pMMR/MSS group. Neoadjuvant immunotherapy could be another treatment option for non-metastatic colorectal cancer.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42022350523.
Topics: Humans; Colorectal Neoplasms; Neoadjuvant Therapy; Colonic Neoplasms; Immunotherapy; Rectal Neoplasms; Microsatellite Instability
PubMed: 36776899
DOI: 10.3389/fimmu.2023.1044353 -
Gynecologic Oncology Mar 2023Investigating for mismatch repair protein deficiency (MMRd), microsatellite instability (MSI), and Lynch syndrome (LS) is widely accepted in endometrial cancer, but... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Investigating for mismatch repair protein deficiency (MMRd), microsatellite instability (MSI), and Lynch syndrome (LS) is widely accepted in endometrial cancer, but knowledge is limited on its value in epithelial ovarian cancer (EOC). The primary objective was to evaluate the prevalence of mismatch repair protein deficiency (MMRd), microsatellite instability (MSI)-high, and Lynch syndrome (LS) in epithelial ovarian cancer (EOC), as well as the diagnostic accuracy of LS screening tests. The secondary objective was to determine the prevalence of MMRd, MSI-high, and LS in synchronous ovarian endometrial cancer and in histological subtypes.
METHODS
We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, and Embase databases. We included studies analysing MMR, MSI, and/or LS by sequencing.
RESULTS
A total of 55 studies were included. The prevalence of MMRd, MSI-high, and LS in EOC was 6% (95% confidence interval (CI) 5-8%), 13% (95% CI 12-15%), and 2% (95% CI 1-3%) respectively. Hypermethylation was present in 76% of patients with MLH1 deficiency (95% CI 64-84%). The MMRd prevalence was highest in endometrioid (12%) followed by non-serous non-mucinous (9%) and lowest in serous (1%) histological subtypes. MSI-high prevalence was highest in endometrioid (12%) and non-serous non-mucinous (12%) and lowest in serous (9%) histological subtypes. Synchronous and endometrioid EOC had the highest prevalence of LS pathogenic variants at 7% and 3% respectively, with serous having lowest prevalence (1%). Synchronous ovarian and endometrial cancers had highest rates of MMRd (28%) and MSI-high (28%). Sensitivity was highest for IHC (91.1%) and IHC with MSI (92.8%), while specificity was highest for IHC with methylation (92.3%).
CONCLUSION
MMRd and germline LS testing should be considered for non-serous non-mucinous EOC, particularly for endometrioid.
PRECIS
The rates of mismatch repair deficiency, microsatellite instability high, and mismatch repair germline mutations are highest in endometrioid subtype and non-serous non-mucinous ovarian cancer. The rates are lowest in serous histologic subtype.
Topics: Humans; Female; Colorectal Neoplasms, Hereditary Nonpolyposis; Carcinoma, Ovarian Epithelial; Microsatellite Instability; Ovarian Neoplasms; Carcinoma, Endometrioid; Endometrial Neoplasms; Protein Deficiency; DNA Mismatch Repair; MutL Protein Homolog 1
PubMed: 36682091
DOI: 10.1016/j.ygyno.2022.12.008