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Gynecologic Oncology Jan 2021Lynch syndrome is an inherited genetic condition that is associated with an increased risk of cancer, including endometrial and colorectal cancer. We assessed the test...
Testing for lynch syndrome in people with endometrial cancer using immunohistochemistry and microsatellite instability-based testing strategies - A systematic review of test accuracy.
BACKGROUND
Lynch syndrome is an inherited genetic condition that is associated with an increased risk of cancer, including endometrial and colorectal cancer. We assessed the test accuracy of immunohistochemistry and microsatellite instability-based testing (with or without MLH1 promoter methylation testing) for Lynch syndrome in women with endometrial cancer.
METHODS
We conducted a systematic review of literature published up to August 2019. We searched bibliographic databases, contacted experts and checked reference lists of relevant studies. Two reviewers conducted each stage of the review.
RESULTS
Thirteen studies were identified that included approximately 3500 participants. None of the studies was at low risk of bias in all domains. Data could not be pooled due to the small number of heterogeneous studies. Sensitivity ranged from 60.7-100% for immunohistochemistry, 41.7-100% for microsatellite instability-based testing, and 90.5-100% for studies combining immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation testing. Specificity ranged from 60.9-83.3% (excluding 1 study with highly selective inclusion criteria) for immunohistochemistry, 69.2-89.9% for microsatellite instability-based testing, and 72.4-92.3% (excluding 1 study with highly selective inclusion criteria) for testing strategies that included immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation. We found no statistically significant differences in test accuracy estimates (sensitivity, specificity) in head-to-head studies of immunohistochemistry versus microsatellite instability-based testing. Reported test failures were rare.
CONCLUSIONS
Sensitivity of the index tests were generally high, though most studies had much lower specificity. We found no evidence that test accuracy differed between IHC and MSI based strategies. The evidence base is currently small and at high risk of bias.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Microsatellite Instability
PubMed: 33190932
DOI: 10.1016/j.ygyno.2020.10.003 -
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 -
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 -
Pathobiology : Journal of... 2022Recent studies suggested that microsatellite instability/mismatch repair deficiency (MSI/MMR-d) might define a clinicopathologically distinct subset of uterine...
INTRODUCTION
Recent studies suggested that microsatellite instability/mismatch repair deficiency (MSI/MMR-d) might define a clinicopathologically distinct subset of uterine carcinosarcomas (UCSs).
OBJECTIVE
The aim of this study was to compare clinicopathological features between MSI/MMR-d and microsatellite-stable/mismatch repair-proficient (MSS/MMR-p) UCSs.
METHODS
A quantitative systematic review was performed by searching electronic databases from January 2000 to January 2021. All studies assessing MSI/MMR status in UCS were included. Odds ratio (OR) with a significant two-tailed p value <0.05 was used to assess the association of MSI/MMR-d with clinicopathological features.
RESULTS
Eleven studies with 783 patients were included. MSI/MMR-d was directly associated with endometrioid (pure: p < 0.001; pure + mixed: p < 0.001), undifferentiated/dedifferentiated (p < 0.001), and clear cell carcinoma component (p = 0.046), and inversely associated with age >60 (p = 0.034), serous carcinoma component (pure: p < 0.001; pure + mixed: p < 0.001), heterologous sarcoma component (p = 0.027), TP53-mutation/p53-abnormal expression (p < 0.001), and recurrence (p < 0.001). MSI/MMR-d showed no significant association with advanced FIGO stage (OR = 1.259; p = 0.517), low-grade carcinoma component (pure: p = 0.596; pure + mixed: p = 0.307), mixed carcinoma component (p = 1), and proportion of patients "dead of disease" (p = 0.352), "alive with disease" (p = 1) or with "no evidence of disease" (p = 0.458).
CONCLUSION
MSI/MMR-d UCSs show younger age, more common endometrioid, undifferentiated or clear cell carcinoma component, and less common serous carcinoma component, heterologous sarcoma component, and TP53 mutation than MSS/MMR-p UCSs. Given the discrepancy between recurrence rate and oncologic outcomes at the last follow-up, further studies are necessary to define whether MSI/MMR-d UCSs have better prognosis.
Topics: Brain Neoplasms; Carcinoma; Carcinosarcoma; Colorectal Neoplasms; Cystadenocarcinoma, Serous; DNA Mismatch Repair; Humans; Microsatellite Instability; Neoplastic Syndromes, Hereditary; Sarcoma
PubMed: 35231921
DOI: 10.1159/000521876 -
BMC Cancer Dec 2017A systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for... (Review)
Review
BACKGROUND
A systematic review was conducted to assess the diagnostic test accuracy of polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing for identifying Lynch syndrome in patients with colorectal cancer (CRC). Unlike previous reviews, this was based on assessing MSI testing against best practice for the reference standard, and included CRC populations that were unselected, age-limited or high-risk for Lynch syndrome.
METHODS
Single- and two-gate diagnostic test accuracy studies, or similar, were identified, assessed for inclusion, data extracted and quality appraised by two reviewers according to a pre-specified protocol. Sensitivity of MSI testing was estimated for all included studies. Specificity, likelihood ratios and predictive values were estimated for studies that were not based on high-risk samples. Narrative synthesis was conducted.
RESULTS
Nine study samples were included. When MSI-Low results were considered to be negative, sensitivity estimates ranged from 67% (95% CI 47, 83) to 100% (95% CI 94, 100). Three studies contributed to estimates of both sensitivity and specificity, with specificity ranging from 61% (95% CI 57, 65), to 93% (95% CI 89, 95). Good sensitivity was achieved at the expense of specificity. When MSI-L was considered to be positive (effectively lowering the threshold for a positive index test result) sensitivity increased and specificity decreased. Between-study heterogeneity in both the MSI and reference standard testing, combined with the low number of studies contributing to both sensitivity and specificity estimates, precluded pooling by meta-analysis.
CONCLUSIONS
MSI testing is an effective screening test for Lynch syndrome. However, there is significant uncertainty surrounding what balance of sensitivity and specificity will be achieved in clinical practice and how this relates to specific characteristics of the test (such as the panel of markers used or the thresholds used to denote a positive test).
Topics: Adult; Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Humans; Male; Microsatellite Instability; Middle Aged; Molecular Diagnostic Techniques; Reproducibility of Results; Young Adult
PubMed: 29221446
DOI: 10.1186/s12885-017-3820-5 -
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 -
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 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 -
Anticancer Research Dec 2017The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND/AIM
The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients.
MATERIALS AND METHODS
Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio (HR) according to the method of Peto.
RESULTS
Analysis was performed on 19 studies including 5,998 patients. A 47.3% of patients received postoperative chemotherapy and included 52.8% males and 47.2% females. Eight studies included some rectal cancer patients although this cohort was not clearly defined in 3 of these. MSI observed in 20.8% (mean) of patients (median 19.9%). HR for overall survival (OS) of MSI vs. microsatellite stable (MSS) tumors for the entire population: 0.73 (95% confidence interval (CI)=0.33-1.65); HR for disease-free survival (DFS):0.60 (95%CI=0.27-1.32). No statistical significant difference was found when studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) were compared separately (MG vs. IHC: HR OS 0.45, 95%CI=0.10-2.05 vs. 0.95, 95%CI=0.57-1.58; HR DFS 0.51, 95%CI=0.14-1.85 vs. 0.67, 95%CI=0.26-1.70). However, numerically MSI determination with genotyping shows significantly lower hazard ratios for both DFS and OS. Separate analysis of studies describing colon cancer patients only showed HR OS 0.72 (95%CI=0.31-1.71); HR DFS 0.60 (95%CI=0.27-1.31).
CONCLUSION
No significant relation was found between MSI status and OS or DFS. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended. New large scale high quality studies are needed to answer this question definitively, since currently analyzed studies vary considerably.
Topics: Colonic Neoplasms; Disease-Free Survival; Humans; Microsatellite Instability; Neoplasm Staging; Outcome Assessment, Health Care; Prognosis; Proportional Hazards Models
PubMed: 29187431
DOI: 10.21873/anticanres.12113 -
Journal of Pathology and Translational... May 2021Loss of mismatch repair (MMR) occurs frequently in endometrial carcinoma (EC) and is an important prognostic marker. However, the frequency of MMR deficiency (D-MMR) in...
BACKGROUND
Loss of mismatch repair (MMR) occurs frequently in endometrial carcinoma (EC) and is an important prognostic marker. However, the frequency of MMR deficiency (D-MMR) in EC remains inconclusive. This systematic review and meta-analysis addressed this inconsistency and evaluated related clinicopathology.
METHODS
Electronic databases were searched for articles: PubMed, Science Direct, Web of Science, EMBASE, and the Wiley Online Library. Data were extracted from 25 EC studies of D-MMR to generate a clinical dataset of 7,459 patients. A random-effects model produced pooled estimates of D-MMR EC frequency with 95% confidence interval (CI) for meta-analysis.
RESULTS
The overall pooled proportion of D-MMR was 24.477% (95% CI, 21.022 to 28.106) in EC. The Lynch syndrome subgroup had 22.907% pooled D-MMR (95% CI, 14.852 to 32.116). D-MMR was highest in type I EC (25.810) (95% CI, 22.503 to 29.261) compared to type II (13.736) (95% CI, 8.392 to 20.144). Pooled D-MMR was highest at EC stage and grades I-II (79.430% and 65.718%, respectively) and lowest in stages III-IV and grade III (20.168% and 21.529%). The pooled odd ratios comparing D-MMR to proficient MMR favored low-stage EC disease (1.565; 0.894 to 2.740), lymphovascular invasion (1.765; 1.293 to 2.409), and myometrial invasion >50% (1.271; 0.871 to 1.853).
CONCLUSIONS
Almost one-quarter of EC patients present with D-MMR tumors. The majority has less aggressive endometrioid histology. D-MMR presents at lower tumor stages compared to MMR-proficient cases in EC. However other metastatic parameters are comparatively higher in the D-MMR disease setting.
PubMed: 33845554
DOI: 10.4132/jptm.2021.02.19