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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 -
Medicina (Kaunas, Lithuania) Jun 2022Background: Signet ring cell carcinoma (SC) accounts for 1% of total colorectal cancer (CRC) cases and is associated with aggressive behaviors, such as lymphatic... (Meta-Analysis)
Meta-Analysis Review
Background: Signet ring cell carcinoma (SC) accounts for 1% of total colorectal cancer (CRC) cases and is associated with aggressive behaviors, such as lymphatic invasion and distant metastases, resulting in poor prognosis. To date, there is still a lack of consensus on the genetic etiology underpinning this cancer subtype. This study aimed to clarify the molecular associations of SC by using meta-analysis and a systematic review. Methods: PubMed, Embase, and Cochrane Library were searched for studies evaluating the KRAS, BRAF, P53 statuses, and microsatellite instability (MSI) in CRC patients with different histological subtypes, including SC. The diagnosis of SC is defined as the signet ring cells comprising ≥50 percent of the tumor mass. By dividing the studies into subgroups based on the composition of control groups, such as classic adenocarcinoma (AC; no SC components) and non-SC (including those with SC components < 50%), the relative risk (RR) of molecular alterations for SC in each study were pooled using a random-effects model. Two reviewers identified trials for inclusion, assessed quality, and extracted data independently. Results: Data from 29 studies consisting of 9366 patients were included in this analysis. SC was associated positively with MSI (RR 1.78, 95% CI 1.34 to 2.37; 95% CI 0.77 to 4.15; p = 0.0005), BRAF mutation (RR 1.99, 95% CI 1.21 to 3.26; 95%CI 0.68 to 5.82; p = 0.0146), and negatively with KRAS mutation (RR 0.48, 95% CI 0.29 to 0.78; 95% CI 0.09 to 2.49; p = 0.0062). No association was found between SC and P53 expression (RR 0.92, 95% CI 0.76 to 1.13; 95%CI 0.61 to 1.39; p = 0.3790). Moreover, it was associated negatively with P53 gene mutations (RR 0.92, 95% CI 0.77 to 1.09; 95% CI 0.46 to 1.82; p = 0.1568), and P53 protein (RR 0.93, 95% CI 0.58 to 1.49; 95% CI 0.40 to 2.17; p = 0.6885). Conclusions: The molecular etiology of SC may be associated with the BRAF and MSI pathways. Its features, such as the high frequency of BRAF mutation, could partly explain its less favorable outcomes and limited effects of traditional chemotherapy.
Topics: Carcinoma, Signet Ring Cell; Colorectal Neoplasms; Humans; Microsatellite Instability; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53
PubMed: 35888555
DOI: 10.3390/medicina58070836 -
International Journal of Cancer Nov 2022Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five-year survival for OC is around 45% increasing the need for innovative... (Meta-Analysis)
Meta-Analysis
Ovarian cancer (OC) is the least survivable gynecological malignancy and presents late. Five-year survival for OC is around 45% increasing the need for innovative treatments. Checkpoint inhibitors have shown significant clinical efficacy in mismatch repair deficient (MMRd) cancers and could be a powerful treatment in OC. However, their application in OC is limited due to the lack of data on the prevalence of MMRd. The aim of our study was to conduct a systematic review of the literature and meta-analysis to provide an accurate estimate of the prevalence of MMRd in OC. We followed PRISMA guidelines throughout. Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science followed by citation searching. Studies not written in English were excluded. All studies were reviewed by at least two independent reviewers. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I score was used to assess heterogeneity across studies. In total 54 studies were included with 17 532 analyzed for MMRd. The overall proportions of MMRd by immunohistochemistry and microsatellite instability analysis were 6.7% and 10.4%, respectively. MMRd was reported in all histotypes of epithelial OC but was most common in endometrioid OC. We estimate that on average 46.7% (95% CI: 28.8-65.4) of ovarian carcinomas showing MMRd by IHC had a germline path_MMR variant identified. OC in those with Lynch syndrome seems to present at an earlier age and stage. Studies however were generally of low quality and there was a high degree of heterogeneity. A significant minority (up to 16%) of OC displays MMRd and, therefore, could be amenable to checkpoint inhibition therapy. However, the current literature base is of limited quality and therefore high-quality prospective studies exploring MMRd in OC with the use of multimodal testing are required. In addition, trials researching efficacy of checkpoint inhibition in MMRd OC are needed.
Topics: Brain Neoplasms; Carcinoma, Ovarian Epithelial; Colorectal Neoplasms; DNA Mismatch Repair; Female; Humans; Microsatellite Instability; Neoplastic Syndromes, Hereditary; Ovarian Neoplasms; Prevalence; Prospective Studies
PubMed: 35792468
DOI: 10.1002/ijc.34165 -
Journal of Clinical Oncology : Official... Sep 2022To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.
PURPOSE
To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.
METHODS
An Expert Panel conducted a systematic review to identify randomized clinical trials and prospective-retrospective studies from January 2015 to January 2022.
RESULTS
The search identified 19 studies informing the evidence base.
RECOMMENDATIONS
Candidates for a regimen with a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine eligibility for alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used. Patients who are candidates for poly (ADP-ribose) polymerase (PARP) inhibitor therapy should undergo testing for germline and pathogenic or likely pathogenic mutations to determine eligibility for a PARP inhibitor. There is insufficient evidence for or against testing for a germline pathogenic variant to determine eligibility for PARP inhibitor therapy in the metastatic setting. Candidates for immune checkpoint inhibitor therapy should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells to determine eligibility for treatment with pembrolizumab plus chemotherapy. Candidates for an immune checkpoint inhibitor should also undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab, as well as testing for tumor mutational burden. Clinicians may test for fusions to determine eligibility for TRK inhibitors. There are insufficient data to recommend routine testing of tumors for mutations, for homologous recombination deficiency, or for TROP2 expression to guide MBC therapy selection. There are insufficient data to recommend routine use of ctDNA or circulating tumor cells to monitor response to therapy among patients with MBC.Additional information can be found at www.asco.org/breast-cancer-guidelines.
Topics: Adenosine Diphosphate; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Breast Neoplasms; Circulating Tumor DNA; Class I Phosphatidylinositol 3-Kinases; Female; Fulvestrant; Humans; Immune Checkpoint Inhibitors; Ligands; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerase Inhibitors; Prospective Studies; Retrospective Studies; Ribose
PubMed: 35759724
DOI: 10.1200/JCO.22.01063 -
Histopathology Sep 2022Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with...
AIM
Currently, compelling evidence illustrates the significance of determining microsatellite instability (MSI) in colorectal cancer (CRC). The association of MSI with proximal CRC is well established, however, its implications in patients with rectal cancer remain undefined. We therefore aimed to determine the role of MSI with respect to incidence and outcome in patients with rectal cancer.
METHODS AND RESULTS
For this we examined patients from two prospective phase III trials: TME trial and PROCTOR-SCRIPT trial (n = 1250). In addition, we performed a literature review to evaluate the overall prevalence, the effect on survival and the response to neo-adjuvant treatment in patients with MSI rectal cancer compared with microsatellite stable (MSS) rectal cancer. Our TME and PROCTOR-SCRIPT cohort showed no differences in terms of overall survival (OS) (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.69-1.47) and disease-free survival (DFS) (HR 1.00, 95% CI 0.68-1.45) in patients with MSI compared to MSS rectal cancer. The total number of MSI cases in all included studies (including our own) was 1220 (out of 16,526 rectal cancer patients), with an overall prevalence of 6.7% (standard error 1.19%). Both for OS as for DFS there was no impact of MSI status on prognosis (HR 1.00, 95% CI 0.77-1.29 and HR 0.86, 95% CI 0.60-1.22, respectively). The risk ratio (RR) for downstaging and pathological complete response showed also no impact of MSI status (RR 1.15, 95% CI 0.86-1.55 and RR 0.81, 95% CI 0.54-1.22, respectively).
CONCLUSION
Rectal cancer patients with MSI form a distinct and rare subcategory, however, there is no prognostic effect of MSI in rectal cancer patients.
Topics: Colorectal Neoplasms; Humans; Microsatellite Instability; Neoplasm Staging; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Rectal Neoplasms
PubMed: 35758193
DOI: 10.1111/his.14710 -
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 -
Archives of Gynecology and Obstetrics Feb 2023To investigate whether microsatellite instability (MSI) is an important prognostic biomarker for endometrioid endometrial cancer (EEC). (Meta-Analysis)
Meta-Analysis
INTRODUCTION
To investigate whether microsatellite instability (MSI) is an important prognostic biomarker for endometrioid endometrial cancer (EEC).
METHODS
The PubMed, EMBASE, and the Cochrane Cooperative Library databases were searched from inception to July 2021. Overall survival, disease-free survival, progression-free survival, EEC-specific survival, recurrence-free survival, and the recurrence rate were pooled to analyze the correlation between MSI and EEC. In addition, Egger's regression analysis and Begg's test were used to detect publication bias.
RESULTS
17 studies met the inclusion criteria and were included in our meta-analysis with a sample size of 4723, and the included patients with endometrioid cancer (EC) all were EEC. The pooled hazard ratios (HR) in patients with EEC showed that MSI was significantly associated with shorter overall survival [HR = 1.37, 95% confidence interval (CI) (1.00-1.86), p = 0.048, I = 60.6%], shorter disease-free survival [HR = 1.99, 95% CI (1.31-3.01), p = 0.000, I = 67.2%], shorter EEC-specific survival [HR = 2.07, 95% CI (1.35-3.18), p = 0.001, I = 31.6%] and a higher recurrence rate [Odds ratios (OR) = 2.72, 95% CI (1.56-4.76), p = 0.000, I = 0.0%]. In the early-stage EEC subgroup, MSI was significantly associated with shorter overall survival [HR = 1.47, 95% CI (1.11-1.95), p = 0.07], shorter disease-free survival [HR = 4.17, 95% CI (2.37-7.41), p = 0.000], and shorter progression-free survival [HR = 2.41, 95% CI (1.05-5.54), p = 0.039]. No significant heterogeneity was observed in overall survival (I = 20.9%), disease-free survival (I = 0.0%), or progression-free survival (I = 0.0%) in patients with early-stage EEC. Meanwhile, publication bias was not observed, and the p-value for Egger's test of overall survival, disease-free survival, and EEC-specific survival were p = 0.131, p = 0.068, and p = 0.987, respectively.
CONCLUSION
MSI is likely an important biomarker for poor prognosis in patients with EEC, and this correlation is even more certain in patients with early-stage EEC.
Topics: Female; Humans; Microsatellite Instability; Prognosis; Carcinoma, Endometrioid; Endometrial Neoplasms; Disease-Free Survival
PubMed: 35665848
DOI: 10.1007/s00404-022-06636-8 -
Frontiers in Oncology 2022Endometrial cancer (EC) represents the sixth most common female tumor. In the advanced setting, the prognosis is dismal with limited treatment options. Platinum-based...
BACKGROUND
Endometrial cancer (EC) represents the sixth most common female tumor. In the advanced setting, the prognosis is dismal with limited treatment options. Platinum-based chemotherapy represents the actual standard of care in first-line chemotherapy, but no standard second-line chemotherapy is approved, with less than 1/4 of patients responding to second-line chemotherapy. In the last 10 years, immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many solid tumors.
METHODS
The review was conducted according to the PRISMA guidelines. We searched EMBASE, MEDLINE, Cochrane Database, and conference abstracts from international societies, up to November 2021. Clinical trials employing ICIs in advanced EC, written in English, were included. Reviews, letters, and commentaries were excluded. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety (number and grade of treatment-related adverse events [TRAEs]) were evaluated.
RESULTS
15 studies, for a total of 1,627 patients, were included: 14 non-randomized phase I/II trials and 1 randomized phase III trial. Anti-PD1 (pembrolizumab, nivolumab, dostarlimab) and anti-PD-L1 agents (avelumab, atezolizumab, durvalumab) were administered as single agents; pembrolizumab and nivolumab were combined with the tyrosine-kinase inhibitors (TKI) lenvatinib and cabozantinib, respectively; and durvalumab was associated with anti-CTLA4 tremelimumab. 4 studies selected only MSI patients. Single agents determined an ORR from 26.7% to 58% among MSI patients, from 3% to 26.7% among MSS patients. DCR ranged from 53.5% to 88.9% in MSI, 31.4% to 35.2% in MSS patients. The combination of TKI and ICIs determined 32% to 63.6% of ORR in all-comers, 32%-36.2% in MSS patients. 54.2% to 76% of patients developed TRAEs. The combination of ICIs and TKI achieved a higher toxicity rate than single agents (≥G3 TRAEs 88.9%).
CONCLUSION
ICIs represent an effective option for pretreated advanced EC patients with a tolerable profile. Given the encouraging results in MSI patients, every woman diagnosed with EC should be investigated for MS status. In MSS women, the combination of ICIs and TKI is more effective than monotherapy, notwithstanding safety concerns. PD-L1 cannot predict ICI response, whereas other biomarkers such as MSI and tumor mutational burden seem more accurate. Ongoing randomized trials will further clarify the role of these therapeutic options.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO, CRD42021293538.
PubMed: 35494078
DOI: 10.3389/fonc.2022.844801 -
Diagnostics (Basel, Switzerland) Mar 2022Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men, with an increasing incidence. Pathology diagnosis complemented with... (Review)
Review
Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men, with an increasing incidence. Pathology diagnosis complemented with prognostic and predictive biomarker information is the first step for personalized treatment. The increased diagnostic load in the pathology laboratory, combined with the reported intra- and inter-variability in the assessment of biomarkers, has prompted the quest for reliable machine-based methods to be incorporated into the routine practice. Recently, Artificial Intelligence (AI) has made significant progress in the medical field, showing potential for clinical applications. Herein, we aim to systematically review the current research on AI in CRC image analysis. In histopathology, algorithms based on Deep Learning (DL) have the potential to assist in diagnosis, predict clinically relevant molecular phenotypes and microsatellite instability, identify histological features related to prognosis and correlated to metastasis, and assess the specific components of the tumor microenvironment.
PubMed: 35453885
DOI: 10.3390/diagnostics12040837 -
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