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Diagnostics (Basel, Switzerland) Dec 2023Mismatch repair deficiency (d-MMR)/microsatellite instability (MSI), , and mutational status are crucial for treating advanced colorectal cancer patients. Traditional... (Review)
Review
Mismatch repair deficiency (d-MMR)/microsatellite instability (MSI), , and mutational status are crucial for treating advanced colorectal cancer patients. Traditional methods like immunohistochemistry or polymerase chain reaction (PCR) can be challenged by artificial intelligence (AI) based on whole slide images (WSI) to predict tumor status. In this systematic review, we evaluated the role of AI in predicting MSI status, , and mutations in colorectal cancer. Studies published in PubMed up to June 2023 were included ( = 17), and we reported the risk of bias and the performance for each study. Some studies were impacted by the reduced number of slides included in the data set and the lack of external validation cohorts. Deep learning models for the d-MMR/MSI status showed a good performance in training cohorts (mean AUC = 0.89, [0.74-0.97]) but slightly less than expected in the validation cohort when available (mean AUC = 0.82, [0.63-0.98]). Contrary to the MSI status, the prediction of and mutations was less explored with a less robust methodology. The performance was lower, with a maximum of 0.77 in the training cohort, 0.58 in the validation cohort for , and 0.82 AUC in the training cohort for .
PubMed: 38201408
DOI: 10.3390/diagnostics14010099 -
Journal of Cancer Research and Clinical... Dec 2023Tumor immunotherapy has recently emerged as a crucial focal point in oncology treatment research. Among tumor immunotherapy approaches, tumor immune checkpoint... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Tumor immunotherapy has recently emerged as a crucial focal point in oncology treatment research. Among tumor immunotherapy approaches, tumor immune checkpoint inhibitors (ICIs) have attracted substantial attention in clinical research. However, this treatment modality has benefitted only a limited number of patients. We conducted a meta-analysis of various biomarkers to decipher their prognostic implications in patients with head and neck squamous cell carcinoma (HNSCC) who are treated with ICIs, and thus identify predictive markers with practical clinical relevance.
METHODS
A systematic search of electronic databases was conducted to identify clinical studies that examined the correlation between biomarkers and treatment outcomes in the HNSCC patients. The included articles were screened and analyzed to extract data regarding overall survival (OS) and progression-free survival (PFS).
RESULTS
The relationship between the biomarkers included in the summary and prognosis was as follows: HPV positivity was associated with improved OS (HR = 0.76, 95% CI = 0.58-1.99), PFS (HR = 1.16, 95% CI = 0.81-1.67), and response (OR = 1.67, 95% CI = 1.37-2.99). PD-L1 positivity was associated with OS (HR = 0.71, 95% CI = 0.59-0.85), PFS (HR = 0.56 95% CI = 0.43-0.73), and response (OR = 2.16, 95% CI = 1.51-3.10). Neither HPV positivity nor PD-L1 positivity was associated with DCR. The following markers were collected for OS and PFS data and were associated with longer OS: lower Glasgow prognostic score (GPS/mGPS) grading, lower PS grading, high body mass index (BMI), low neutrophil-to-lymphocyte ratio (NLR), low platelet-to-lymphocyte ratio (PLR), high albumin (Alb), low lactate dehydrogenase (LDH). Factors associated with better PFS were lower GPS/mGPS grading, lower PS grading, high BMI, low NLR, high absolute lymphocyte count, and low LDH. Hyperprogressive disease was associated with worse OS and PFS. Fewer clinical studies have been completed on the tumor microenvironment and hypoxia, microsatellite instability/DNA mismatch repair, and microbiome and systematic analysis is difficult.
CONCLUSION
In our meta-analysis, different immune checkpoint factors were associated with different prognoses in HNSCC patients receiving immunotherapy. HPV, PD-L1, BMI, Alb, HPD, PS, GPS/mGPS, LDH, NLR, and PLR predicted the ICI outcome in HNSCC patients.
Topics: Humans; Prognosis; Immune Checkpoint Inhibitors; B7-H1 Antigen; Squamous Cell Carcinoma of Head and Neck; Papillomavirus Infections; Head and Neck Neoplasms; Biomarkers; Tumor Microenvironment
PubMed: 38078963
DOI: 10.1007/s00432-023-05504-5 -
The Lancet. Gastroenterology &... Jul 2024Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating... (Meta-Analysis)
Meta-Analysis
Clinical significance of combined tumour-infiltrating lymphocytes and microsatellite instability status in colorectal cancer: a systematic review and network meta-analysis.
BACKGROUND
Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer.
METHODS
In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108).
FINDINGS
Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I=77·7%), disease-free survival (0·43, 0·32-0·58; I=61·6%), and cancer-specific survival (0·53, 0·43-0·66; I=0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I=77·7%), disease-free survival (0·52, 0·41-0·64; I=61·6%), and cancer-specific survival (0·55, 0·47-0·64; I=0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I=77·7%) and disease-free survival (0·93, 0·69-1·26; I=61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I=0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous.
INTERPRETATION
The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer.
FUNDING
German Research Council (HO 5117/2-2).
Topics: Humans; Microsatellite Instability; Lymphocytes, Tumor-Infiltrating; Colorectal Neoplasms; Prognosis; Network Meta-Analysis; Disease-Free Survival; Clinical Relevance
PubMed: 38734024
DOI: 10.1016/S2468-1253(24)00091-8 -
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 -
Frontiers in Oncology 2024Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations...
BACKGROUND
Early-onset colorectal cancer (CRC), defined as diagnosis before age 50, has increased in recent decades. Although more often diagnosed at advanced stage, associations with other histological and molecular markers that impact prognosis and treatment remain to be clarified. We conducted a systematic review and meta-analysis concerning the prevalence of prognostic and predictive tumor markers for early- vs. late-onset CRC, including oncogene mutations, microsatellite instability (MSI), and emerging markers including immune cells and the consensus molecular subtypes.
METHODS
We systematically searched PubMed for original research articles published between April 2013-January 2024. Included studies compared the prevalence of tumor markers in early- vs. late-onset CRC. A meta-analysis was completed and summary odds ratios (ORs) with 95% confidence intervals (CIs) were obtained from a random effects model via inverse variance weighting. A sensitivity analysis was completed to restrict the meta-analysis to studies that excluded individuals with Lynch syndrome, a hereditary condition that influences the distribution of tumor markers for early-onset CRC.
RESULTS
In total, 149 articles were identified. Tumors from early-onset CRC are less likely to include mutations in (OR, 95% CI: 0.91, 0.85-0.98), (0.63, 0.51-0.78), (0.70, 0.58-0.84), and (0.88, 0.78-1.00) but more likely to include mutations in (1.68, 1.04-2.73) and (1.34, 1.24-1.45). After limiting to studies that excluded Lynch syndrome, the associations between early-onset CRC and (0.77, 0.64-0.92) and mutation (0.81, 0.67-0.97) were attenuated, while an inverse association with mutation was also observed (0.88, 0.78-0.99). Early-onset tumors are less likely to develop along the CpG Island Methylator Phenotype pathway (0.24, 0.10-0.57), but more likely to possess adverse histological features including high tumor grade (1.20, 1.15-1.25), and mucinous (1.22, 1.16-1.27) or signet ring histology (2.32, 2.08-2.57). A positive association with MSI status (1.31, 1.11-1.56) was also identified. Associations with immune markers and the consensus molecular subtypes are inconsistent.
DISCUSSION
A lower prevalence of mutations in and is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and and mutations, which may serve as therapeutic targets.
PubMed: 38737895
DOI: 10.3389/fonc.2024.1349572 -
BMC Cancer Nov 2023Paclitaxel and carboplatin is the standard chemotherapy for the treatment of advanced or recurrent endometrial cancer. However, the benefit of adding programmed cell... (Meta-Analysis)
Meta-Analysis
PD-1/PD-L1 inhibitors plus carboplatin and paclitaxel compared with carboplatin and paclitaxel in primary advanced or recurrent endometrial cancer: a systematic review and meta-analysis of randomized clinical trials.
BACKGROUND
Paclitaxel and carboplatin is the standard chemotherapy for the treatment of advanced or recurrent endometrial cancer. However, the benefit of adding programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors to chemotherapy is still unclear.
METHOD
We searched PubMed, Scopus, Cochrane, and Web of Science databases for randomized controlled trials that investigated PD-1/PD-L1 inhibitors plus carboplatin and paclitaxel compared with carboplatin and paclitaxel in primary advanced or recurrent endometrial cancer. We computed hazard ratios (HRs) or risk ratios (RRs) for binary endpoints, with 95% confidence intervals (CIs). We used DerSimonian and Laird random-effect models for all endpoints. Heterogeneity was assessed using I statistics. R, version 4.2.3, was used for statistical analyses.
RESULTS
A total of three studies and 1,431 patients were included. Compared with carboplatin plus paclitaxel-based chemotherapy, progression-free survival (PFS) rate (HR 0.32; 95% CI 0.23-0.44; p < 0.001) and overall survival (OS) at 30 months (RR 3.13; 95% CI 1.26-7.78; p = 0.01) were significant in favor of the PD-1/PD-L1 inhibitors plus carboplatin and paclitaxel group in the mismatch repair-deficient subgroup. However, there were no significant differences in the mismatch repair-proficient subgroup for PFS (HR 0.74; 95% CI 0.50-1.08; p = 0.117) or OS at 30 months (RR 2.24; 95% CI 0.79-6.39; p = 0.13).
CONCLUSION
Immunotherapy plus carboplatin-paclitaxel increased significantly PFS and OS among patients with advanced or recurrent endometrial cancer, with a significant benefit in the mismatch repair-deficient and high microsatellite instability population.
Topics: Female; Humans; Carboplatin; Paclitaxel; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Randomized Controlled Trials as Topic; Endometrial Neoplasms; B7-H1 Antigen; Lung Neoplasms
PubMed: 38031003
DOI: 10.1186/s12885-023-11654-z -
European Journal of Cancer (Oxford,... Aug 2023Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any.
METHODS
A PubMed search for phase I/II clinical trials with drugs approved by the Food and Drug Administration (labelled, off-label, combined with investigational ICIs or other treatment modalities) from 2018 to 2020 was performed. The objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between biomarker-positive and biomarker-negative groups, using studies that explored the correlation of biomarkers with outcomes.
RESULTS
Overall, 174 clinical studies that included 19,178 patients were identified, and 132 studies investigated>30 correlative biomarkers that included PD-L1 expression (≥1%, 111 studies), tumour mutational burden (20 studies) and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46 and 30 cohorts (drugs, tumour types or biomarkers) with 11,692, 3065, and 2256 patient outcomes for ORR, PFS and OS, respectively, were analysed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumours were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p < 0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p < 0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p < 0.0001) compared with those with biomarker-negative tumours. Significance for ORR and PFS was retained in multivariate analysis (p < 0.001) (OS, not included owing to the small number of trials reporting OS).
CONCLUSION
Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.
Topics: Humans; Neoplasms; Treatment Outcome; Immunotherapy; Biomarkers; Progression-Free Survival
PubMed: 37364526
DOI: 10.1016/j.ejca.2023.05.015 -
Open Medicine (Warsaw, Poland) 2024Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the... (Review)
Review
Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.
PubMed: 38859878
DOI: 10.1515/med-2024-0976 -
Frontiers in Immunology 2023Accurate prediction of efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors is of critical importance. To address this... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Accurate prediction of efficacy of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors is of critical importance. To address this issue, a network meta-analysis (NMA) comparing existing common measurements for curative effect of PD-1/PD-L1 monotherapy was conducted.
METHODS
We searched PubMed, Embase, the Cochrane Library database, and relevant clinical trials to find out studies published before Feb 22, 2023 that use PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), microsatellite instability (MSI), multiplex IHC/immunofluorescence (mIHC/IF), other immunohistochemistry and hematoxylin-eosin staining (other IHC&HE) and combined assays to determine objective response rates to anti-PD-1/PD-L1 monotherapy. Study-level data were extracted from the published studies. The primary goal of this study was to evaluate the predictive efficacy and rank these assays mainly by NMA, and the second objective was to compare them in subgroup analyses. Heterogeneity, quality assessment, and result validation were also conducted by meta-analysis.
FINDINGS
144 diagnostic index tests in 49 studies covering 5322 patients were eligible for inclusion. mIHC/IF exhibited highest sensitivity (0.76, 95% CI: 0.57-0.89), the second diagnostic odds ratio (DOR) (5.09, 95% CI: 1.35-13.90), and the second superiority index (2.86). MSI had highest specificity (0.90, 95% CI: 0.85-0.94), and DOR (6.79, 95% CI: 3.48-11.91), especially in gastrointestinal tumors. Subgroup analyses by tumor types found that mIHC/IF, and other IHC&HE demonstrated high predictive efficacy for non-small cell lung cancer (NSCLC), while PD-L1 IHC and MSI were highly efficacious in predicting the effectiveness in gastrointestinal tumors. When PD-L1 IHC was combined with TMB, the sensitivity (0.89, 95% CI: 0.82-0.94) was noticeably improved revealed by meta-analysis in all studies.
INTERPRETATION
Considering statistical results of NMA and clinical applicability, mIHC/IF appeared to have superior performance in predicting response to anti PD-1/PD-L1 therapy. Combined assays could further improve the predictive efficacy. Prospective clinical trials involving a wider range of tumor types are needed to establish a definitive gold standard in future.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Network Meta-Analysis; Prospective Studies; Biomarkers, Tumor; Gastrointestinal Neoplasms
PubMed: 37822932
DOI: 10.3389/fimmu.2023.1265202 -
Cancer Cell International Dec 2023Lymphocyte-activation gene 3 (LAG3) is a recently discovered immune checkpoint molecule that has been linked to immunosuppression and the advancement of cancer in... (Review)
Review
BACKGROUND
Lymphocyte-activation gene 3 (LAG3) is a recently discovered immune checkpoint molecule that has been linked to immunosuppression and the advancement of cancer in different types of solid tumors. This study aimed to evaluate the prognostic importance of LAG3 and its role in the immune system within solid tumors.
METHODS
Extensive literature searches were conducted using the Pubmed, EMBASE, and Cochrane Library databases to identify relevant studies exploring the effect of LAG3 on survival outcomes. Pooled hazard ratios (HRs) with its 95% confidence intervals (CIs) were calculated to evaluate the prognostic values of LAG3. Afterwards, subgroup analysis and sensitivity analysis were conducted. Pan-cancer analysis investigated the possible relationships between LAG3 expression and genetic alterations, RNA methylation modification-related genes, genomic instability, immune checkpoint genes, and infiltration of immune cells.
RESULTS
A total of 43 studies with 7,118 patients were included in this analysis. Higher expression of LAG3 was associated with worse overall survival (HR = 1.10, 95% CI 1.01-1.19, P = 0.023), but not disease-free survival (HR = 1.41, 95% CI 0.96-2.07, P = 0.078), progression-free survival (HR = 1.12, 95% CI 0.90-1.39, P = 0.317) or recurrence-free survival (HR = 0.98, 95% CI 0.81-1.19, P = 0.871). Subgroup analysis showed that LAG3 might play different prognostic roles in different solid tumors. LAG3 expression was positively associated with immune cell infiltration and immune checkpoint genes in all of the cancers included. LAG3 expression was also found to be associated with microsatellite instability (MSI), copy number variation (CNV), simple nucleoside variation (SNV), tumor mutation burden (TMB), and neoantigen in various types of cancers.
CONCLUSIONS
Elevated expression of LAG3 is linked to poorer prognosis among patients diagnosed with solid cancers. LAG3 might play varying prognostic roles in different types of solid tumors. Given its substantial involvement in cancer immunity and tumorigenesis, LAG3 has garnered attention as a promising prognostic biomarker and a potential target for immunotherapy.
PubMed: 38041068
DOI: 10.1186/s12935-023-03157-5