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Scientific Reports Mar 2023NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in...
NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum sample size. Critical appraisal was performed using a custom 11-item checklist. Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03-0.70%, with higher rates found in RNA-based assays. In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and sample size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology.
Topics: Adult; Humans; Child; Receptor, trkA; Prevalence; Neoplasms; Genomics; Oncogene Proteins, Fusion; Gene Fusion
PubMed: 36914665
DOI: 10.1038/s41598-023-31055-3 -
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 2023Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Immunotherapy has been approved for the treatment of metastatic colorectal cancer. The efficacy and safety of neoadjuvant immunotherapy for the treatment of non-metastatic colorectal cancer remains unclear. We tried to explore clinical effect of neoadjuvant immunotherapy in the treatment of non-metastatic colorectal cancer.
METHODS
We searched the databases (PubMed, Wanfang Embase, Cochrane Library and China National Knowledge Infrastructure databases) to obtain suitable articles up to September 2022. The primary outcomes of pathological complete response (pCRs), major pathological response (MPR), objective response rate (ORR), R0-resection and anus preserving rate were collected and evaluated. Secordary outcomes (pCRs and MPR) of subgroup analysis between deficient mismatch repair/microsatellite instability-high group (dMMR/MSI-H) and proficient mismatch repair/microsatellite stable group (pMMR/MSS) and outcomes for rectal cancer were analyzed for the final results.
RESULTS
We included ten articles and 410 cases of non-metastatic colorectal cancer with neoadjuvant immunotherapy. There were 113 (27.5%) cases with the dMMR/MSI-H status and 167 (40.7%) cases with the pMMR/MSS status. pCRs was found in 167/373 (44.6%) patients (ES: 0.49, 95% CI: 0.36 to 0.62, <0.01, chi = 65.3, <0.01, = 86.2%) and MPR was found in 194/304 (63.8%) patients (ES: 0.66, 95% CI: 0.54 to 0.78, <0.01, chi = 42.55, <0.01, = 81.2%) with the random-effects model and huge heterogeneity. In the subgroup analysis, pCRs was higher in the dMMR/MSI-H group than the pMMR/MSS group in the fixed-effects model with minimal heterogeneity (OR: 3.55, 95% CI: 1.74 to 7.27, <0.01, chi = 1.86, =0.6, = 0%). pCRs was found in 58/172 (33.9%) rectal cancer patients (ES: 0.33, 95% CI: 0.26 to 0.40, <0.01, chi = 3.04, =0.55, = 0%) with the fixed-effects model and little heterogeneity.
CONCLUSION
Neoadjuvant immunotherapy could increase pCRs and MPR rate for non-metastatic colorectal cancer. Neoadjuvant immunotherapy could achieve better pCRs rate in dMMR/MSI-H group than in the pMMR/MSS group. Neoadjuvant immunotherapy could be another treatment option for non-metastatic colorectal cancer.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42022350523.
Topics: Humans; Colorectal Neoplasms; Neoadjuvant Therapy; Colonic Neoplasms; Immunotherapy; Rectal Neoplasms; Microsatellite Instability
PubMed: 36776899
DOI: 10.3389/fimmu.2023.1044353 -
La Radiologia Medica Feb 2023This study aimed to systematically summarize the performance of the machine learning-based radiomics models in the prediction of microsatellite instability (MSI) in... (Review)
Review
This study aimed to systematically summarize the performance of the machine learning-based radiomics models in the prediction of microsatellite instability (MSI) in patients with colorectal cancer (CRC). It was conducted according to the preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies (PRISMA-DTA) guideline and was registered at the PROSPERO website with an identifier CRD42022295787. Systematic literature searching was conducted in databases of PubMed, Embase, Web of Science, and Cochrane Library up to November 10, 2022. Research which applied radiomics analysis on preoperative CT/MRI/PET-CT images for predicting the MSI status in CRC patients with no history of anti-tumor therapies was eligible. The radiomics quality score (RQS) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) were applied to evaluate the research quality (full score 100%). Twelve studies with 4,320 patients were included. All studies were retrospective, and only four had an external validation cohort. The median incidence of MSI was 19% (range 8-34%). The area under the receiver operator curve of the models ranged from 0.78 to 0.96 (median 0.83) in the external validation cohort. The median sensitivity was 0.76 (range 0.32-1.00), and the median specificity was 0.87 (range 0.69-1.00). The median RQS score was 38% (range 14-50%), and half of the studies showed high risk in patient selection as evaluated by QUADAS-2. In conclusion, while radiomics based on pretreatment imaging modalities had a high performance in the prediction of MSI status in CRC, so far it does not appear to be ready for clinical use due to insufficient methodological quality.
Topics: Humans; Colorectal Neoplasms; Machine Learning; Microsatellite Instability; Positron Emission Tomography Computed Tomography; Retrospective Studies
PubMed: 36648615
DOI: 10.1007/s11547-023-01593-x -
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 -
Familial Cancer Apr 2023A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early... (Review)
Review
A subset of patients with Lynch Syndrome demonstrates cutaneous manifestations of the disorder. Characterization of these Lynch-related skin lesions could help in early recognition of patients with Lynch Syndrome. A broad search of the literature on OVID Medline and Embase was carried out to capture papers reporting cutaneous manifestations in Lynch Syndrome patients. The results were uploaded into Mendeley reference management software. The PRISMA workflow was used in the literature selection process. In this systematic review, data were collected from 961 cases from 413 studies, including 380 molecularly confirmed Lynch Syndrome cases. The main skin lesions were: Sebaceous adenomas (43%), sebaceous carcinomas (27%), keratoacanthomas (16%), sebaceomas (13%), squamous cell carcinomas (23%), and basal cell carcinomas (10%). MSH2 variants were the most common underlying genotype (72%). Assessment of mismatch repair by immunohistochemistry, microsatellite instability analysis, or both were performed on 328 skin lesions from 220 (58%) molecularly confirmed cases. In those skin lesions, 95% of Immunohistochemistry and 90% of the microsatellite instability test results were concordant with the underlying genotype. Sebaceous skin lesions are well-recognised phenotypic features of Lynch Syndrome. Our results show that squamous and basal cell carcinomas are relatively common in patients with Lynch syndrome; however, available evidence cannot confirm that Lynch syndrome is causal. Immunohistochemistry and/or microsatellite instability testing of skin tumours in patients with a family history of Lynch Syndrome-associated cancers may be a useful approach in identifying patients requiring referral to Clinical Genetics and/or consideration of germline genetic testing for Lynch Syndrome.
Topics: Humans; Muir-Torre Syndrome; Microsatellite Instability; Sebaceous Gland Neoplasms; Genotype; Carcinoma, Basal Cell; MutS Homolog 2 Protein
PubMed: 36418753
DOI: 10.1007/s10689-022-00319-8 -
Biomolecules & Biomedicine Mar 2023Some patients with microsatellite instability-high colorectal cancer (MSI-H CRC) have shown a poor response to immunotherapy in clinical trials. We investigated the... (Meta-Analysis)
Meta-Analysis Review
Some patients with microsatellite instability-high colorectal cancer (MSI-H CRC) have shown a poor response to immunotherapy in clinical trials. We investigated the intrinsic resistance to and efficacy of immunotherapy in patients with MSI-H CRC. The PubMed and Web of Science databases were searched using keywords such as "colorectal cancer," "immunotherapy," and "clinical experiment." Random-effects models were used to generate the combined complete response, partial response, stable disease, progressive disease, objective response rate (ORR), disease control rate (DCR), and incidence of adverse events. We then performed a subgroup analysis based on the ORR and incidence of intrinsic resistance. The meta-analysis included seven clinical trials. The incidences of complete response, partial response, stable disease, and progressive disease summarized by the random-effects model were 8%, 37%, 26%, and 25%, respectively. The ORR and DCR were 45% and 71%, respectively. The ORRs of programmed cell death protein 1 inhibitor (anti-PD-1), programmed death ligand 1 inhibitor (anti-PD-L1), and anti-PD-1 combined with cytotoxic T lymphocyte-associated antigen 4 inhibitor (anti-CTLA-4) immunotherapy were 38%, 54%, and 57%, respectively. The ORR of immune checkpoint inhibitors for first- and third-line therapy was 56% and 32%, respectively. Dual-drug immunotherapy significantly reduced the incidence of intrinsic resistance to immunotherapy (12% vs 31%). The incidences of intrinsic resistance to first-line therapy and second-line and later therapy were 29% and 26%, respectively. Approximately 25% of patients with MSI-H CRC had intrinsic resistance to immunotherapy. Anti-PD-1 combined with anti-CTLA-4 significantly increased the ORR, thereby reducing the incidence of intrinsic resistance. Moving immunotherapy into earlier lines of therapy, although not reducing the incidence of intrinsic resistance, can improve the ORR in patients with MSI-H CRC.
Topics: Humans; Microsatellite Instability; Colonic Neoplasms; Immunotherapy
PubMed: 36408953
DOI: 10.17305/bjbms.2022.8286 -
Frontiers in Oncology 2022While the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently...
BACKGROUND
While the efficacy of immune checkpoint inhibitors (ICIs) is increasingly recognized in advanced gastric cancer (aGC), overall survival (OS) has not been consistently improved across the different randomized controlled trials (RCTs). This meta-analysis aimed to quantify the efficacy and safety of ICI and explore potential predictive tumor tissue biomarkers in aGC.
METHODS
A random-effect pairwise meta-analysis was used to evaluate the primary outcome of OS. Sensitivity analysis was performed to investigate the effects of ICIs on PD-L1 status, TMB, MSI-H, and the Asian patient population. We extracted the OS Kaplan-Meier curves from the included trials to compare the effect of PD-L1 status on response to ICIs using DigitizeIt 2.5 and Guyot's algorithm.
RESULTS
A pairwise meta-analysis of seven RCTs included in this study showed that ICIs were more effective than the comparator in improving OS (pooled HR: 0.84). We demonstrated that PD-1 ICIs were additive when combined with the comparator arm (pooled HR: 0.79). A sensitivity analysis showed that PD-1 ICIs were associated with better OS outcomes in the Asian patient population as monotherapy (pooled HR: 0.66) or in combination with chemotherapy (pooled HR: 0.83). We demonstrated that tumors with PD-L1 ≥1 ( = 0.02) and PD-L1 ≥10 ( = 0.006) derived OS benefit from ICI monotherapy. Equally, MSI-H (0.00001) and TMB-high (0.0001) tumors derived favorable survival benefits from ICIs.
CONCLUSIONS AND RELEVANCE
The results of this meta-analysis suggest that ICIs result in improved OS outcomes in aGC. The benefits varied with different ethnicities, class of ICI, PD-L1 expression, MSI status, and TMB.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier (CRD42019137829).
PubMed: 36387109
DOI: 10.3389/fonc.2022.908026 -
Journal of Clinical Oncology : Official... Jan 2023To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC).
PURPOSE
To develop recommendations for treatment of patients with metastatic colorectal cancer (mCRC).
METHODS
ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.
RESULTS
Five systematic reviews and 10 randomized controlled trials met the systematic review inclusion criteria.
RECOMMENDATIONS
Doublet chemotherapy should be offered, or triplet therapy may be offered to patients with previously untreated, initially unresectable mCRC, on the basis of included studies of chemotherapy in combination with anti-vascular endothelial growth factor antibodies. In the first-line setting, pembrolizumab is recommended for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumors; chemotherapy and anti-epidermal growth factor receptor therapy is recommended for microsatellite stable or proficient mismatch repair left-sided treatment-naive wild-type mCRC; chemotherapy and anti-vascular endothelial growth factor therapy is recommended for microsatellite stable or proficient mismatch repair wild-type right-sided mCRC. Encorafenib plus cetuximab is recommended for patients with previously treated V600E-mutant mCRC that has progressed after at least one previous line of therapy. Cytoreductive surgery plus systemic chemotherapy may be recommended for selected patients with colorectal peritoneal metastases; however, the addition of hyperthermic intraperitoneal chemotherapy is not recommended. Stereotactic body radiation therapy may be recommended following systemic therapy for patients with oligometastases of the liver who are not considered candidates for resection. Selective internal radiation therapy is not routinely recommended for patients with unilobar or bilobar metastases of the liver. Perioperative chemotherapy or surgery alone should be offered to patients with mCRC who are candidates for potentially curative resection of liver metastases. Multidisciplinary team management and shared decision making are recommended. Qualifying statements with further details related to implementation of guideline recommendations are also included.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Endothelial Growth Factors; Rectal Neoplasms; Practice Guidelines as Topic
PubMed: 36252154
DOI: 10.1200/JCO.22.01690 -
Journal of Cancer Research and Clinical... Jan 2023Lynch-like syndrome (LLS) tumors have similar clinicopathological features to Lynch syndrome (LS) tumors but have no identifiable pathogenic germline mismatch repair...
BACKGROUND
Lynch-like syndrome (LLS) tumors have similar clinicopathological features to Lynch syndrome (LS) tumors but have no identifiable pathogenic germline mismatch repair gene variant. However, cancer risks in LLS patients and first-degree relatives (FDRs) are not well defined.
METHODS
To clarify LLS-associated cancer risks, a systematic review of all studies examining all cancer risks in LLS was performed. Searching of Medline, Embase, Pubmed, Cochrane and CINAHL databases and reference/citation checking identified relevant studies published between January 1, 1980 and February 11, 2021. Joanna Briggs Institute Appraisal Tools assessed the risk of bias.
RESULTS
Six studies (five cohort/one cross-sectional) were eligible for study inclusion. One study found no difference in colorectal cancer (CRC) incidence between LLS and LS patients or CRC risks at aged 70 years. Three studies found CRC incidence in LLS FDRs was higher than the general population but lower than LS FDRs. Two studies showed no difference in CRC diagnosis age between LLS patients and LS patients. Endometrial cancer risks in LLS patients were higher than the general population but lower than LS patients.
CONCLUSION
Evidence of elevated CRC risks in LLS patients and FDRs supports increased colonoscopy surveillance strategies for LLS patients and FDRs in line with current recommendations for LS. Due to heterogeneity amongst LLS populations, extended intervals between screening may be advised for low-risk families. Studies to resolve the molecular characterization and definition of LLS are needed to clarify cancer risks associated with LLS which in turn may individualize surveillance strategies for LLS patients and families.
Topics: Female; Humans; Cross-Sectional Studies; Microsatellite Instability; Colorectal Neoplasms, Hereditary Nonpolyposis; Germ-Line Mutation; Endometrial Neoplasms; DNA Mismatch Repair; Colorectal Neoplasms
PubMed: 36251064
DOI: 10.1007/s00432-022-04397-0