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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 -
Scientific Reports Nov 2022Immune checkpoint inhibitors have been approved in the USA for tumours exhibiting mismatch repair deficiency (dMMR), microsatellite instability (MSI), or high tumour... (Meta-Analysis)
Meta-Analysis
Immune checkpoint inhibitors have been approved in the USA for tumours exhibiting mismatch repair deficiency (dMMR), microsatellite instability (MSI), or high tumour mutational burden (TMB), with regulatory and reimbursement applications in multiple other countries underway. As the estimated budget impacts of future reimbursements depend on the size of the potential target population, we performed a scoping review and meta-analysis of the prevalence of these pan-tumour biomarkers in different cancers. We systematically searched Medline/Embase and included studies reporting the prevalence of dMMR/MSI/high TMB in solid tumours published 01/01/2018-31/01/2021. Meta-analyses were performed separately for the pan-cancer prevalence of each biomarker, and by cancer type and stage where possible. The searches identified 3890 papers, with 433 prevalence estimates for 32 different cancer types from 201 studies included in meta-analyses. The pooled overall prevalence of dMMR, MSI and high TMB (≥ 10 mutations/Mb) in pan-cancer studies was 2.9%, 2.7% and 14.0%, respectively. The prevalence profiles of dMMR/MSI and high TMB differed across cancer types. For example, endometrial, colorectal, small bowel and gastric cancers showed high prevalence of both dMMR and MSI (range: 8.7-26.8% and 8.5-21.9%, respectively) and high TMB (range: 8.5-43.0%), while cervical, esophageal, bladder/urothelial, lung and skin cancers showed low prevalence of dMMR and MSI (< 5%), but high prevalence of high TMB (range: 23.7-52.6%). For other cancer types, prevalence of all three biomarkers was generally low (< 5%). This structured review of dMMR/MSI/high TMB prevalence across cancers and for specific cancer types and stages provide timely evidence to inform budget impact forecasts in health technology assessments for drug approvals based on these pan-tumour biomarkers.
Topics: Humans; Microsatellite Instability; Biomarkers, Tumor; Prevalence; Immune Checkpoint Inhibitors; Skin Neoplasms
PubMed: 36443366
DOI: 10.1038/s41598-022-23319-1 -
Clinical Colorectal Cancer Jun 2017Many studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Many studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little evidence supports their role in the decision-making of adjuvant therapy for patients with stage II disease.
MATERIALS AND METHODS
The aim of this systematic review was to evaluate the prognostic and/or predictive role of MSI status in patients with stage II colorectal cancer on disease-free survival and overall survival. MEDLINE, EMBASE, and Cochrane libraries were searched to identify eligible studies.
RESULTS
Only 2 of 389 articles identified fulfilled the eligibility criteria. In both treated and untreated patients, high-level MSI improved disease-free survival compared with low-level MSI, suggesting a prognostic role but not supporting the hypothesis of a predictive effect of MSI.
CONCLUSIONS
Further studies are needed to explore the predictive role of MSI/mismatch repair proteins, because available data do not allow definitive conclusions.
Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Clinical Decision-Making; Colorectal Neoplasms; DNA Mismatch Repair; Disease-Free Survival; Humans; Microsatellite Instability; Neoplasm Staging; Prognosis; Survival Rate
PubMed: 27670891
DOI: 10.1016/j.clcc.2016.08.007 -
Cancers May 2022Cancers with high microsatellite instability (MSI-H) have a better prognosis and respond well to immunotherapy. However, MSI is not tested in all cancers because of the... (Review)
Review
Cancers with high microsatellite instability (MSI-H) have a better prognosis and respond well to immunotherapy. However, MSI is not tested in all cancers because of the additional costs and time of diagnosis. Therefore, artificial intelligence (AI)-based models have been recently developed to evaluate MSI from whole slide images (WSIs). Here, we aimed to assess the current state of AI application to predict MSI based on WSIs analysis in MSI-related cancers and suggest a better study design for future studies. Studies were searched in online databases and screened by reference type, and only the full texts of eligible studies were reviewed. The included 14 studies were published between 2018 and 2021, and most of the publications were from developed countries. The commonly used dataset is The Cancer Genome Atlas dataset. Colorectal cancer (CRC) was the most common type of cancer studied, followed by endometrial, gastric, and ovarian cancers. The AI models have shown the potential to predict MSI with the highest AUC of 0.93 in the case of CRC. The relatively limited scale of datasets and lack of external validation were the limitations of most studies. Future studies with larger datasets are required to implicate AI models in routine diagnostic practice for MSI prediction.
PubMed: 35681570
DOI: 10.3390/cancers14112590 -
Cancers Aug 2022The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch... (Review)
Review
The objective of this systematic review was to summarize our current knowledge of the role of immunohistochemistry (IHC) markers for identifying mismatch repair-deficient (MMRd) tumors in endometrial cancer (EC). Identification of MMRd tumors, which occur in 13% to 30% of all ECs, has become critical for patients with colorectal and endometrial cancer for therapeutic management, clinical decision making, and prognosis. This review was conducted by two authors applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using the following terms: "immunohistochemistry and microsatellite instability endometrial cancer" or "immunohistochemistry and mismatch repair endometrial cancer" or "immunohistochemistry and mismatch repair deficient endometrial cancer". Among 596 retrieved studies, 161 fulfilled the inclusion criteria. Articles were classified and presented according to their interest for the diagnosis, prognosis, and theragnostics for patients with MMRd EC. We identified 10, 18, and 96 articles using IHC expression of two, three, or four proteins of the MMR system (MLH1, MSH2, MHS6, and PMS2), respectively. MLH1 promoter methylation was analyzed in 57 articles. Thirty-four articles classified MMRd tumors with IHC markers according to their prognosis in terms of recurrence-free survival (RFS), overall survival (OS), stage, grade, and lymph node invasion. Theragnostics were studied in eight articles underlying the important concentration of PD-L1 in MMRd EC. Even though the role of IHC has been challenged, it represents the most common, robust, and cheapest method for diagnosing MMRd tumors in EC and is a valuable tool for exploring novel biotherapies and treatment modalities.
PubMed: 35954447
DOI: 10.3390/cancers14153783 -
Future Oncology (London, England) Nov 2021The authors present a systematic review/meta-analysis of the impact of mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch... (Meta-Analysis)
Meta-Analysis
The authors present a systematic review/meta-analysis of the impact of mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in -mutated versus wild-type patients. After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in -mutated compared with wild-type stage I-IV patients (hazard ratio: 1.57; 95% CI: 1.23-1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48-2.25). mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.
Topics: Brain Neoplasms; Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Microsatellite Instability; Mutation; Neoplastic Syndromes, Hereditary; Prognosis; Proto-Oncogene Proteins B-raf
PubMed: 34323124
DOI: 10.2217/fon-2021-0552 -
Future Oncology (London, England) Jun 2022To compare pembrolizumab with competing interventions for previously untreated, unresectable or metastatic microsatellite instability-high or mismatch repair-deficient... (Meta-Analysis)
Meta-Analysis Review
Systematic literature review and network meta-analysis of pembrolizumab versus other interventions for previously untreated, unresectable or metastatic, MSI-high or MMR-deficient CRC.
To compare pembrolizumab with competing interventions for previously untreated, unresectable or metastatic microsatellite instability-high or mismatch repair-deficient colorectal cancer. Trials were identified via a systematic literature review and synthesized using a Bayesian network meta-analysis with time-varying hazard ratios (HRs). Using intention-to-treat data, HRs for overall survival were generally in favor of pembrolizumab but not statistically significant; however, statistical significance was reached versus all comparators by month 16 when accounting for crossover. Estimated HRs for progression-free survival significantly favored pembrolizumab versus all comparators by month 12. Pembrolizumab was also superior to all comparators in terms of grade ≥3 adverse events. These analyses suggest that pembrolizumab is a highly efficacious and safe treatment in this population.
Topics: Antibodies, Monoclonal, Humanized; Bayes Theorem; Colorectal Neoplasms; DNA Mismatch Repair; Humans; Microsatellite Instability; Neoplasms; Network Meta-Analysis
PubMed: 35332802
DOI: 10.2217/fon-2021-1633 -
The Oncologist May 2024The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like...
The use of immune checkpoint inhibitors (ICIs) has revolutionized cancer care, particularly in immune-inflamed tumors and tumors with a high mutational burden, like microsatellite instable colorectal cancer (CRC). However, their effectiveness in microsatellite stable (MSS) CRC is limited. This systematic review aims to evaluate the efficacy of ICIs in MSS CRC and explore promising combination strategies. A comprehensive search from the Web of Science, Medline, and Embase databases, for studies published until 14 November 2022, identified 53 clinical trials included in the review. ICI monotherapy or ICI-ICI combinations demonstrated limited clinical activity for patients with MSS CRC, with overall response rates below (ORR) 10% in most studies. The ICI and tyrosine kinase inhibitor (TKI) garnered ORRs ranging from 10% to 40% and indicated a higher benefit for patients, particularly those without active liver metastases. The combination of ICIs with anti-VEGF agents showed modest ORRs, especially in the earlier treatment lines and in combination with chemotherapy. While these combinations could lead to modest improvements, well-defined biomarkers for long-term benefit are yet to be delineated. Combinations involving BRAF inhibitors with ICIs were studied, showing promising responses with combination approaches in molecularly defined subgroups. In conclusion, while ICI monotherapy has limited efficacy in MSS CRC, combination strategies hold promise to enhance survival outcomes. Further research is necessary to identify optimal combination approaches, predictive biomarkers for treatment response, as well as enrollment according to tumor molecular characteristics.
Topics: Humans; Immune Checkpoint Inhibitors; Colorectal Neoplasms; Microsatellite Instability
PubMed: 38309719
DOI: 10.1093/oncolo/oyae013 -
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 -
JCO Precision Oncology 2019The development and use of predictive biomarkers to guide treatment decisions are paramount not only for improving survival in patients with metastatic colorectal cancer... (Review)
Review
PURPOSE
The development and use of predictive biomarkers to guide treatment decisions are paramount not only for improving survival in patients with metastatic colorectal cancer (mCRC), but also for sparing them from unnecessary toxicity and reducing the economic burden of expensive treatments. We conducted a systematic review of published studies and evaluated the predictive biomarker landscape in the mCRC setting from a molecular and clinical viewpoint.
METHODS
Studies analyzing predictive biomarkers for approved therapies in patients with mCRC were identified systematically using electronic databases. Preclinical studies and those providing no relevant information were excluded.
RESULTS
A total of 173 studies comprising 148 biomarkers were selected for final analysis. Of all the biomarkers analyzed, 1.4% (two of 148) were explored in a prospective manner, whereas 98.6% (146 of 148) were evaluated in retrospective studies. Of the latter group, 78.8% (115 of 146) were not tested in subsequent phases, 9.6% (14 of 146) were tested in other retrospective cohorts, 8.9% (13 of 146) were retrospectively tested in at least one or more randomized cohorts, and only 2.7% (four of 146) were prospectively tested in a clinical trial. Finally, only 1.4% (two of 148) were validated sufficiently and are recognized as biomarkers for guiding treatment decision making in patients with mCRC. These markers were mutational status for anti-EGFR antibodies and microsatellite instability status for anti-programmed cell death-1 drugs.
CONCLUSION
Despite notable efforts to identify predictive biomarkers for various therapies used in the mCRC setting, because of a lack of data beyond retrospective studies and successful biomarker-driven approaches, only two molecular biomarkers have thus far found their translation into the clinic, highlighting the imperative need for implementing novel strategies and additional research in this clinically important field.
PubMed: 32914007
DOI: 10.1200/PO.18.00260