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Urology Jul 2022To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome... (Review)
Review
OBJECTIVE
To review the effect of universal screening of newly diagnosed upper tract urothelial carcinomas (UTUC) for mismatch repair (MMR) protein loss to aid in Lynch syndrome diagnostics.
MATERIALS AND METHODS
Studies were identified through PubMed on December 1, 2021. Eligibility criteria were universal immunohistochemical analyses for at least 2 MMR proteins in unselected, consecutively collected UTUC cohorts. Exclusion criteria included reviews, case-reports, non-English language, and non-humans. Risk of bias was assessed using a modified Newcastle-Ottawa scale. Meta-analyses were performed to compare the association between clinical criteria and Lynch syndrome diagnoses.
RESULTS
From 12 included studies, 1628 surgically removed UTUC from 1626 patients were screened for MMR protein loss. In 11 studies, 140 of the 1559 patients had tumors with loss (9.0%) with 80.7% showing loss of MSH2, MSH6, or both. In 7 studies, genetic testing confirmed Lynch syndrome diagnosis for 20 of 970 patients (2.1%). In 8 studies, 31 patients were given a clinical Lynch syndrome diagnosis (2.6%). In total, 51 assumed or verified Lynch syndrome patients were identified among 1087 patients (4.7%). Meta-analyses of 3 studies showed significant association between previous cancer diagnosis and Lynch syndrome-associated UTUC (P = .038).
CONCLUSION
Despite the few studies conducted and lack of genetic testing, current data suggests that universal screening for MMR protein loss in UTUC may result in Lynch syndrome diagnoses in 4.7%. However, for the screening to be effective for Lynch syndrome diagnostics, follow-up investigations, such as genetic testing for MMR variants, are needed.
Topics: Carcinoma, Transitional Cell; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Immunohistochemistry; MutL Protein Homolog 1; Urinary Bladder Neoplasms
PubMed: 35217028
DOI: 10.1016/j.urology.2022.02.006 -
Biomedicines Jan 2022Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system... (Review)
Review
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, , , and Other Genes.
Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to -mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with or somatic mutations had higher response rates to pembrolizumab. regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/ statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.
PubMed: 35203446
DOI: 10.3390/biomedicines10020236 -
Genetics in Medicine : Official Journal... May 2022Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, with an estimated prevalence of 2% to 3% of CRC. A prevalence study is needed to provide accurate estimates of the true prevalence of LS.
METHODS
MEDLINE (Ovid), Embase, and Web of Science were searched. Prevalence was calculated by random effects meta-analysis models. I score was used to assess heterogeneity across studies. Meta-regression was performed for between-study variance.
RESULTS
A total of 51 studies were included in this review. The overall pooled yield of LS screening was 2.2% based on all methods of detection. Studies performing germline tests on all participants with CRC reported higher prevalence (5.1%) as opposed to studies only performing germline tests on participants with tumors with mismatch repair deficiency (1.6%) or microsatellite instability (1.1%). Selected cohorts of CRC had a higher prevalence of germline LS diagnoses.
CONCLUSION
LS prevalence across multiple ethnic, geographic, and clinical populations is remarkably similar. Universal germline testing of patients presenting with cancer identifies that most CRCs are attributed to LS. Young patients presenting with CRC and those who fulfill criteria for a familial risk provide the highest returns for LS identification. Our study supports the universal germline CRC screening for LS.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Microsatellite Instability; Prevalence
PubMed: 35177335
DOI: 10.1016/j.gim.2022.01.014 -
Translational Cancer Research Oct 2021This study aimed to investigate the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers. (Review)
Review
Screening and identification of Lynch syndrome: a systematic review of the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers.
BACKGROUND
This study aimed to investigate the frequency of Lynch syndrome-associated clinicopathologic and molecular characteristics in Lynch syndrome gynecologic cancers.
METHODS
A systematic literature search was conducted in the literature databases (Medline, CINAHL, EMBASE, Google Scholar, Cochrane Library, and Clinicaltrials.gov) to identify the studies describing clinicopathologic characteristics, MMR protein immunohistochemistry and/or MSI, MLH1 methylation, and genetic testing in Lynch syndrome gynecologic cancer patients.
RESULTS
A total of 24 of the evaluated studies that met the inclusion criteria were identified. A clinicopathological examination confirmed 242 endometrial cancer, 17 clear cells endometrial cancer, 35 serous endometrial cancer, 30 mixed and 21 other endometrial cancer. Thus, a total of 345 endometrial cancer was confirmed from the screening of 1,317 gynaecological cancer. However, the morphological analysis demonstrated 236 patients with endometrial cancer associated with Lynch syndrome. The frequency of confirmed LS with endometrial cancer was 68.40%. At diagnosis, the median age was 49.94±4.34 years, and the average BMI was 26.07±3.77 kg/m. Endometrioid histology and stage I disease were the most frequent at 70.97% and 71.19% histological type and FIGO stage, respectively. Similarly, morphological and histological analysis demonstrated a higher degree of grade I cancer (47.28) and lymphovascular invasion (56.52%), respectively.
DISCUSSION
Lynch syndrome-associated clinicopathologic and molecular characteristics occur significantly in Lynch syndrome gynecologic cancers and may improve risk stratification and triaging of gynecologic cancers for genetic testing.
PubMed: 35116308
DOI: 10.21037/tcr-21-677 -
Scientific Reports Jan 2022Clinical observations have demonstrated that microsatellite instability-high (MSI-H) and/or deficient MMR (dMMR) status are associated with favorable prognosis and no... (Meta-Analysis)
Meta-Analysis
Clinical observations have demonstrated that microsatellite instability-high (MSI-H) and/or deficient MMR (dMMR) status are associated with favorable prognosis and no benefit from 5-Fluorouracil (5-FU)-based adjuvant chemotherapy in patients with resected stage II colorectal cancer (CRC). This study represents a systematic review and meta-analysis exploring the predictive role of MSI-H status in stage III CRC undergoing or not adjuvant chemotherapy. Published articles that evaluated the role of adjuvant chemotherapy in resected stage III CRC from inception to September 2020 were identified by searching the PubMed, EMBASE, and Cochrane Library databases. The random-effects model was conducted to estimate the pooled effect size of OS and DFS. The primary outcome of interest was OS. 21,590 patients with MSI-H/dMMR stage III CRC, from n = 17 retrospective studies, were analyzed. Overall, OS was improved with any adjuvant chemotherapy vs. any control arm (single-agent 5-FU or surgery alone): HR 0.42, 95% CI 0.26-0.66; P < 0.01. Conversely, DFS was not significantly improved (HR 0.7, 95% CI 0.45-1.09; P = 0.11). In patients with stage III MSI-H/dMMR CRC, adjuvant chemotherapy is associated with a significant OS improvement. Thus, MSI-H/dMMR status does represent a predictive factor for postoperative chemotherapy benefit in stage III CRC beyond its prognostic role.
Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Colonic Neoplasms; DNA Mismatch Repair; Disease-Free Survival; Humans; Microsatellite Instability; Survival Analysis; Treatment Outcome
PubMed: 35058539
DOI: 10.1038/s41598-022-05065-6 -
Contemporary Oncology (Poznan, Poland) 2021Anaplastic thyroid carcinoma is a rare, rapidly progressing, highly aggressive thyroid malignancy. Responses to immune checkpoint inhibitors in mismatch... (Review)
Review
INTRODUCTION
Anaplastic thyroid carcinoma is a rare, rapidly progressing, highly aggressive thyroid malignancy. Responses to immune checkpoint inhibitors in mismatch repair-deficient/microsatellite instability-high tumours of other locations have shown promising results, and with the extended approval of the PD-1 receptor inhibitor pembrolizumab by the Food and Drug Administration, also anaplastic thyroid cancer (ATC) requires analysis for microsatellite instability (MSI) status.
MATERIAL AND METHODS
Systematic research for relevant literature was conducted in different databases. Prevalence, detection methods, and the potential prognostic/predictive value of MSI in view of the available targeted therapies were of special focus.
RESULTS
Selected citations revealed the prevalence of MSI in 7.4%, with mutations in the MSH2 gene (33%) being the most frequent, followed by MSH6 (25%) and MLH1 (16.7%) occurring in the following combinations: MLH1-MSH2 (8.3%), MSH2-MSH6 (8.3%), and MLH3-MSH5 (8.3%). No mutations in the PMS2 gene were reported. Sixty-six co-mutations in 9 cases were found, with TP53 (88.9%), NF1 (44.4 %), ATM (33.3%), and RB1 (33.3%) being the most frequent. No RAS mutations were noted. Survival ranged between 2.8 and 48 months, and patient age varied between 49 and 84 years. There are insufficient and heterogenous data concerning the predictive or prognostic value of mismatch repair-deficient/microsatellite instability status.
CONCLUSIONS
Tumour molecular profiling is fundamental in ATC for predictive, prognostic, as well as therapeutic reasons, and analysis of MSI status is strongly suggested because a small subgroup show the MSI signature and might profit from recently approved targeted therapies.
PubMed: 34729042
DOI: 10.5114/wo.2021.110052 -
Frontiers in Immunology 2021For colorectal cancer patients, traditional biomarker deficient mismatch repair/microsatellite instability (dMMR/MSI) is an accurate predictor of immune checkpoint... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
For colorectal cancer patients, traditional biomarker deficient mismatch repair/microsatellite instability (dMMR/MSI) is an accurate predictor of immune checkpoint inhibitors (ICIs). Recent years, researchers considered tumor mutation burden (TMB) as another predictive biomarker which means the number of nonsynonymous mutations in cancer cells. Several studies have proven that TMB can evaluate the efficacy of ICI therapy in diverse types of cancer, especially in non-small cell lung cancer and melanoma. However, studies on the association between TMB and the response to ICI therapy in colorectal cancer alone are still lacking. In this study, we aim to verify the effect of TMB as a biomarker in predicting the efficacy of ICIs in colorectal cancer.
METHODS
We searched the PubMed and Ovid MEDLINE databases up to May 1, 2021 and screened studies for eligibility. Thirteen studies published from 2015 to 2021 with 5062 patients were included finally. We extracted and calculated hazard ratios (HRs) and odds ratios (ORs) of overall survival (OS) and objective response rates (ORRs) and their 95% confidence intervals (95% CIs). Pooled HR and OR were evaluated to compare OS and ORR between TMB-high and TMB-low groups in colorectal cancer patients. Meanwhile, we assessed heterogeneity with the statistic and p-values and performed publication bias assessments, sensitivity analyses, and subgroup analyses to search the cause of heterogeneity.
RESULTS
The TMB-high patient group had a longer OS than the TMB-low patient group (HR = 0.68, 95% CI: 0.51, 0.92, p = 0.013) among colorectal cancer patients receiving ICIs. In addition, the TMB-high patient group was superior in terms of ORR (OR = 19.25, 95% CI: 10.06, 36.82, p < 0.001) compared to the TMB-low patient group.
CONCLUSIONS
In conclusion, this meta-analysis revealed that TMB can be used as a potential predictive biomarker of colorectal cancer patients receiving ICI therapy. Nevertheless, this finding is not stable enough. Therefore, many more randomized controlled trials are needed to prove that TMB is reliable enough to be used clinically to predict the efficacy of immunotherapy in colorectal cancer. And the most relevant biomarker remains to be determined when TMB high overlaps with other biomarkers like MSI and TILs.
Topics: Biomarkers, Tumor; Cohort Studies; Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Mutation; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 34659255
DOI: 10.3389/fimmu.2021.751407 -
International Journal of Gynaecology... Jul 2022The TCGA molecular groups of endometrial carcinoma are "POLE-mutated" (POLEmut), "microsatellite-instable/mismatch repair-deficient" (MSI/MMRd),... (Review)
Review
BACKGROUND
The TCGA molecular groups of endometrial carcinoma are "POLE-mutated" (POLEmut), "microsatellite-instable/mismatch repair-deficient" (MSI/MMRd), "TP53-mutated/p53-abnormal" (TP53mut/p53abn), and "no specific molecular profile" (NSMP).
OBJECTIVE
Prognostic assessment of the TCGA groups in uterine carcinosarcoma (UCS).
SEARCH STRATEGY
Systematic review from January 2000 to January 2021.
SELECTION CRITERIA
Studies assessing the TCGA groups in UCS.
DATA COLLECTION AND ANALYSIS
Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier and Cox analyses (reference: TP53mut/p53abn group) and compared with endometrioid and serous carcinomas (original TCGA cohort), with a significant P < 0.050.
MAIN RESULTS
Five studies with 263 UCS were included. Compared with TP53mut/p53abn UCS, MSI/MMRd UCS showed significantly better PFS (P < 0.001) but similar OS (P = 0.788), whereas NSMP UCS showed similar PFS (P = 0.936) and OS (P = 0.240). Compared with their endometrioid/serous counterparts, NSMP and TP53mut/p53abn UCS showed significantly worse PFS (P < 0.001 and P = 0.004) and OS (P < 0.001 and P < 0.001), while MSI/MMRd UCS showed similar PFS (P = 0.595) but significantly worse OS (P < 0.001). The POLEmut group showed neither recurrences nor deaths in both the UCS and the endometrioid/serous carcinoma cohorts.
CONCLUSION
POLEmut UCS show excellent prognosis, whereas TP53mut/p53abn and NSMP UCS show a prognosis even worse than that of TP53mut/p53abn endometrioid/serous carcinomas. The prognosis of MSI/MMRd UCS remains to be defined.
Topics: Carcinoma, Endometrioid; Carcinosarcoma; Endometrial Neoplasms; Female; Humans; Prognosis; Uterine Neoplasms
PubMed: 34536971
DOI: 10.1002/ijgo.13937 -
Cancers Jun 2021Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be... (Review)
Review
Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology ( < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.
PubMed: 34206554
DOI: 10.3390/cancers13133119 -
Health Technology Assessment... Jun 2021Lynch syndrome is an inherited genetic condition that is associated with an increased risk of certain cancers. The National Institute for Health and Care Excellence has...
BACKGROUND
Lynch syndrome is an inherited genetic condition that is associated with an increased risk of certain cancers. The National Institute for Health and Care Excellence has recommended that people with colorectal cancer are tested for Lynch syndrome. Routine testing for Lynch syndrome among people with endometrial cancer is not currently conducted.
OBJECTIVES
To systematically review the evidence on the test accuracy of immunohistochemistry- and microsatellite instability-based strategies to detect Lynch syndrome among people who have endometrial cancer, and the clinical effectiveness and the cost-effectiveness of testing for Lynch syndrome among people who have been diagnosed with endometrial cancer.
DATA SOURCES
Searches were conducted in the following databases, from inception to August 2019 - MEDLINE ALL, EMBASE (both via Ovid), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (both via Wiley Online Library), Database of Abstracts of Reviews of Effects, Health Technology Assessment Database (both via the Centre for Reviews and Dissemination), Science Citation Index, Conference Proceedings Citation Index - Science (both via Web of Science), PROSPERO international prospective register of systematic reviews (via the Centre for Reviews and Dissemination), NHS Economic Evaluation Database, Cost-Effectiveness Analysis Registry, EconPapers (Research Papers in Economics) and School of Health and Related Research Health Utilities Database. The references of included studies and relevant systematic reviews were also checked and experts on the team were consulted.
REVIEW METHODS
Eligible studies included people with endometrial cancer who were tested for Lynch syndrome using immunohistochemistry- and/or microsatellite instability-based testing [with or without mutL homologue 1 () promoter hypermethylation testing], with Lynch syndrome diagnosis being established though germline testing of normal (non-tumour) tissue for constitutional mutations in mismatch repair. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, the Consolidated Health Economic Reporting Standards and the Philips' checklist. Two reviewers independently conducted each stage of the review. A meta-analysis of test accuracy was not possible because of the number and heterogeneity of studies. A narrative summary of test accuracy results was provided, reporting test accuracy estimates and presenting forest plots. The economic model constituted a decision tree followed by Markov models for the impact of colorectal and endometrial surveillance, and aspirin prophylaxis with a lifetime time horizon.
RESULTS
The clinical effectiveness search identified 3308 studies; 38 studies of test accuracy were included. (No studies of clinical effectiveness of endometrial cancer surveillance met the inclusion criteria.) Four test accuracy studies compared microsatellite instability with immunohistochemistry. No clear difference in accuracy between immunohistochemistry and microsatellite instability was observed. There was some evidence that specificity of immunohistochemistry could be improved with the addition of methylation testing. There was high concordance between immunohistochemistry and microsatellite instability. The economic model indicated that all testing strategies, compared with no testing, were cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Immunohistochemistry with promoter hypermethylation testing was the most cost-effective strategy, with an incremental cost-effectiveness ratio of £9420 per quality-adjusted life-year. The second most cost-effective strategy was immunohistochemistry testing alone, but incremental analysis produced an incremental cost-effectiveness ratio exceeding £130,000. Results were robust across all scenario analyses. Incremental cost-effectiveness ratios ranged from £5690 to £20,740; only removing the benefits of colorectal cancer surveillance produced an incremental cost-effectiveness ratio in excess of the £20,000 willingness-to-pay threshold. A sensitivity analysis identified the main cost drivers of the incremental cost-effectiveness ratio as percentage of relatives accepting counselling and prevalence of Lynch syndrome in the population. A probabilistic sensitivity analysis showed, at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year, a 0.93 probability that immunohistochemistry with promoter hypermethylation testing is cost-effective, compared with no testing.
LIMITATIONS
The systematic review excluded grey literature, studies written in non-English languages and studies for which the reference standard could not be established. Studies were included when Lynch syndrome was diagnosed by genetic confirmation of constitutional variants in the four mismatch repair genes (i.e. , mutS homologue 2, mutS homologue 6 and postmeiotic segregation increased 2). Variants of uncertain significance were reported as per the studies. There were limitations in the economic model around uncertainty in the model parameters and a lack of modelling of the potential harms of gynaecological surveillance and specific pathway modelling of genetic testing for somatic mismatch repair mutations.
CONCLUSION
The economic model suggests that testing women with endometrial cancer for Lynch syndrome is cost-effective, but that results should be treated with caution because of uncertain model inputs.
FUTURE WORK
Randomised controlled trials could provide evidence on the effect of earlier intervention on outcomes and the balance of benefits and harms of gynaecological cancer surveillance. Follow-up of negative cases through disease registers could be used to determine false negative cases.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42019147185.
FUNDING
This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in ; Vol. 25, No. 42. See the NIHR Journals Library website for further project information.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Cost-Benefit Analysis; Endometrial Neoplasms; Female; Humans; Quality-Adjusted Life Years
PubMed: 34169821
DOI: 10.3310/hta25420