-
World Journal of Surgical Oncology Mar 2022Immunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immunotherapy for colorectal cancer has developed rapidly in the past decade. Many high-quality clinical trials examining the application of PD-1/PD-L1 inhibitors in patients with metastatic colorectal cancer (mCRC) have been conducted in recent years. However, the clinical benefits, including the efficacy and safety of these treatments against mCRC, remain controversial. Hence, we conducted this meta-analysis on the clinical benefits of PD-1/PD-L1 inhibitors in patients with mCRC.
METHODS
We searched online databases including MEDLINE, Embase, Cochrane Library, and Web of Science, from inception to January 4, 2021. The outcomes related to efficacy and safety were extracted and analyzed. Subgroup analyses were conducted according to the categories of dMMR-MSI-H (tumors with mismatch repair deficiency and high levels of microsatellite instability) ≥ 5% vs. dMMR-MSI-H < 5%, monotherapy vs. combination therapy, PD-1 inhibitors vs. PD-L1 inhibitors, and nivolumab vs. pembrolizumab.
RESULTS
Fourteen studies including 1129 subjects were included in our systematic review. The overall complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD) rates were 0.01 (95% CI 0.00-0.04), 0.04 (95% CI 0.05-0.26), 0.27 (95% CI 0.22-0.32), and 0.44 (95% CI 0.30-0.58), respectively. The overall objective response rate (ORR) and disease control rate (DCR) were 0.16 (95%CI 0.06-0.31) and 0.50 (95%CI 0.35-0.65), respectively. The overall rate of adverse events (AEs) and severe adverse responses (SAEs) were 0.84 (95% CI 0.72-0.92) and 0.30 (95% CI 0.20-0.41), respectively. The ORRs of the dMMR-MSI-H ≥ 5% and dMMR-MSI-H < 5% subgroups were 0.40 (95% CI 0.30-0.51) and 0.04 (95% CI 0.00-0.09), respectively.
CONCLUSIONS
PD-1/PD-L1 inhibitors produced encouraging clinical benefits including the response rate in the treatment of dMMR-MSI-H mCRC. They actually have been influenced by the present state of mCRC therapy including pMMR-MSI-L mCRC. Nevertheless, additional multi-center prospective studies are still expected.
TRIAL REGISTRATION
We have registered this study in the International Prospective Register of Systematic Reviews (PROSPERO), and the registration number is CRD42021249601 .
Topics: B7-H1 Antigen; Colonic Neoplasms; Colorectal Neoplasms; Humans; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Prospective Studies
PubMed: 35331250
DOI: 10.1186/s12957-022-02549-7 -
Discover Oncology Mar 2022The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated... (Review)
Review
OBJECTIVES
The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated gastric cancer (EBVaGC) and to estimate the expression rate of PD-L1 among this subtype of Gastric Cancer (GC).
MATERIALS AND METHODS
For this study, PubMed, EMBASE and Web of Science databases were searched for articles published until 1st November 2021. A total of 43 eligible publications with a total of 11,327 patients were included analysis based on inclusion and exclusion criteria. A total of 41 publications present data for proportion estimation and 33 for comparison of PD-L1 between EBV positive and negative GC. DerSimonian-Laird random-effects model was used for meta-analysis.
RESULTS
The analysis showed that in EBVaGC the pooled positivity rate for PD-L1 was 54.6% (p < 0.001), with a high heterogeneity between the included studies, which was associated with variation on positivity criteria for PD-L1 expression. Overall, the study reveals an increased association between PD-L1 and EBVaGC (OR = 6.36, 95% CI 3.91-10.3, p < 0.001). Furthermore, the study revealed that GC with lymphoid stroma (GCLS) is highly associated with EBV (OR = 17.4, 95% CI 6.83-44.1, p < 0.001), with a pooled EBV positivity rate of 52.9% (p < 0.001).
CONCLUSIONS
Patients with EBVaGC tend to show higher PD-L1 expression, which enhances EBV positivity as a promising marker for patient selection for immunotherapy targeted agents. A uniform criteria for PD-L1 positivity in tumor cells is needed, as well as further prospective studies to validate our findings and their prognostic significance.
PubMed: 35318527
DOI: 10.1007/s12672-022-00479-0 -
International Journal of Molecular... Feb 2022Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) is receiving more attention as a biomarker for eligibility for immune checkpoint inhibitors in... (Review)
Review
Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) is receiving more attention as a biomarker for eligibility for immune checkpoint inhibitors in advanced diseases. However, due to high costs and resource limitations, MSI/dMMR testing is not widely performed. Some attempts are in progress to predict MSI/dMMR status through histomorphological features on H&E slides using artificial intelligence (AI) technology. In this study, the potential predictive role of this new methodology was reviewed through a systematic review. Studies up to September 2021 were searched through PubMed and Embase database searches. The design and results of each study were summarized, and the risk of bias for each study was evaluated. For colorectal cancer, AI-based systems showed excellent performance with the highest standard of 0.972; for gastric and endometrial cancers they showed a relatively low but satisfactory performance, with the highest standard of 0.81 and 0.82, respectively. However, analyzing the risk of bias, most studies were evaluated at high-risk. AI-based systems showed a high potential in predicting the MSI/dMMR status of different cancer types, and particularly of colorectal cancers. Therefore, a confirmation test should be required only for the results that are positive in the AI test.
Topics: Artificial Intelligence; Colorectal Neoplasms; DNA Mismatch Repair; Endometrial Neoplasms; Female; Humans; Microsatellite Instability
PubMed: 35269607
DOI: 10.3390/ijms23052462 -
Oncology Letters Apr 2022Currently, standard treatment of patients with metastatic colorectal cancer (mCRC) comprises chemotherapy (CT) and/or biological therapy (BT) and/or best supportive care...
Currently, standard treatment of patients with metastatic colorectal cancer (mCRC) comprises chemotherapy (CT) and/or biological therapy (BT) and/or best supportive care (BSC). The present study performed a meta-analysis on five phase II-III randomized clinical trials, which compared CT/BT/BSC as the control arm with the immune checkpoint inhibitors (ICIs) anti-programmed cell death protein 1 (PD-1) or its ligand (PD-L1) alone or in combination with cytotoxic T lymphocyte antigen 4 or mitogen activated protein kinase kinase inhibitors as the experimental arm, to evaluate whether a standard approach could be overcome using the novel target therapy strategy. Pooled hazard ratio (HR) for progression-free survival was 0.95 in favor of the experimental arm [95% confidence interval (CI), 0.74-1.22; P=0.68]. Heterogeneity was significant: Cochran's Q, 21.0; P=0.0082; I index, 76%. Pooled HR for overall survival was 0.88 in favor of the experimental arm (95% CI, 0.75-1.02; P=0.08). Heterogeneity was not significant (Cochran's Q, 6.0; P=0.31; I index, 16%). The present meta-analysis demonstrated a trend toward the improvement of survival by PD-1/PD-L1 blockade in mCRC. Further homogeneous studies are necessary to strengthen these results, beyond the known benefits of ICIs in deficient mismatch repair/high microsatellite instability tumors.
PubMed: 35251353
DOI: 10.3892/ol.2022.13254 -
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 -
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 -
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 -
Journal of Clinical Oncology : Official... Mar 2022To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.
PURPOSE
To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.
METHODS
ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.
RESULTS
Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria.
RECOMMENDATIONS
Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Neoplasm Staging; Neoplastic Syndromes, Hereditary; Oxaliplatin
PubMed: 34936379
DOI: 10.1200/JCO.21.02538 -
JNCI Cancer Spectrum Dec 2021The therapeutic role of immune checkpoint inhibitors (ICIs) has represented the cutting edge of clinical research in upper gastrointestinal (GI) malignancies, with these...
BACKGROUND
The therapeutic role of immune checkpoint inhibitors (ICIs) has represented the cutting edge of clinical research in upper gastrointestinal (GI) malignancies, with these agents now included in the armamentarium of treatment options for advanced gastric and esophageal cancers.
METHODS
We performed a systematic literature review and pooled analysis to map out the currently available robust clinical evidence for the use of ICIs in upper GI cancers. Immunotherapy (IO), either as monotherapy or in combination with chemotherapy, and its role in first-line, maintenance, and second-line settings, as well as in specific clinical and biological subgroups, were critically appraised. All statistical tests were 2-sided.
RESULTS
ICIs, in combination with chemotherapy, have provided statistically significant overall survival benefit in the first-line setting in gastric and gastro-esophageal adenocarcinomas (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.76 to 0.90, < .001; based on 4 studies) and esophageal squamous cell carcinoma (HR = 0.72, 95% CI 0.64 to 0.81, < .001; based on 3 studies), albeit with heterogeneous efficacy according to biomarker expression. Patients with esophageal squamous cell carcinoma, and in particular high programmed cell death ligand-1 expression, derive survival benefit when treated with IO in the second-line setting (HR = 0.74, 95% CI = 0.68 to 0.82, < .001; for any level of programmed cell death ligand-1 expression). Clinical trials interrogating the combination of IO with chemotherapy in second-line treatment should be seriously considered in upper GI adenocarcinomas. The role of maintenance IO after initial disease control is still unclear and cannot be recommended. Impressive response rates and survival benefit from IO have been reported in patients with microsatellite instability-high tumors (HR = 0.33, 95% CI = 0.19 to 0.57, < .001), and this warrants further prospective biomarker-driven studies.
CONCLUSIONS
IO is changing the treatment landscape in upper GI malignancies. The rapidly developing evidence in the field needs to be critically appraised while further validation of the existing information from ongoing trials is awaited.
Topics: Adenocarcinoma; Antineoplastic Agents; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Maintenance Chemotherapy; Randomized Controlled Trials as Topic; Stomach Neoplasms
PubMed: 34926989
DOI: 10.1093/jncics/pkab088