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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 -
Annals of Oncology : Official Journal... Aug 2019Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined...
ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.
BACKGROUND
Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy.
METHODS
To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression.
RESULTS
The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types.
CONCLUSIONS
This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Biomarkers, Tumor; DNA Mismatch Repair; DNA Mutational Analysis; European Union; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Medical Oncology; Microsatellite Instability; Mutation; Neoplasms; Patient Selection; Practice Guidelines as Topic; Programmed Cell Death 1 Receptor; Societies, Medical
PubMed: 31056702
DOI: 10.1093/annonc/mdz116 -
Journal of Clinical Oncology : Official... Apr 2020To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus. (Meta-Analysis)
Meta-Analysis
PURPOSE
To provide recommendations on genetic and tumor testing for women diagnosed with epithelial ovarian cancer based on available evidence and expert consensus.
METHODS
A literature search and prospectively defined study selection criteria sought systematic reviews, meta-analyses, randomized controlled trials (RCTs), and comparative observational studies published from 2007 through 2019. Guideline recommendations were based on the review of the evidence.
RESULTS
The systematic review identified 19 eligible studies. The evidence consisted of systematic reviews of observational data, consensus guidelines, and RCTs.
RECOMMENDATIONS
All women diagnosed with epithelial ovarian cancer should have germline genetic testing for and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic variant, somatic tumor testing for pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. Clinical decision making should not be made based on a variant of uncertain significance. Women with epithelial ovarian cancer should have testing at the time of diagnosis.
Topics: Carcinoma, Ovarian Epithelial; Female; Genes, BRCA1; Genes, BRCA2; Genetic Counseling; Genetic Testing; Germ-Line Mutation; Health Status Disparities; Humans; Ovarian Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic
PubMed: 31986064
DOI: 10.1200/JCO.19.02960 -
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 -
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 Pathology and Translational... May 2021Loss of mismatch repair (MMR) occurs frequently in endometrial carcinoma (EC) and is an important prognostic marker. However, the frequency of MMR deficiency (D-MMR) in...
BACKGROUND
Loss of mismatch repair (MMR) occurs frequently in endometrial carcinoma (EC) and is an important prognostic marker. However, the frequency of MMR deficiency (D-MMR) in EC remains inconclusive. This systematic review and meta-analysis addressed this inconsistency and evaluated related clinicopathology.
METHODS
Electronic databases were searched for articles: PubMed, Science Direct, Web of Science, EMBASE, and the Wiley Online Library. Data were extracted from 25 EC studies of D-MMR to generate a clinical dataset of 7,459 patients. A random-effects model produced pooled estimates of D-MMR EC frequency with 95% confidence interval (CI) for meta-analysis.
RESULTS
The overall pooled proportion of D-MMR was 24.477% (95% CI, 21.022 to 28.106) in EC. The Lynch syndrome subgroup had 22.907% pooled D-MMR (95% CI, 14.852 to 32.116). D-MMR was highest in type I EC (25.810) (95% CI, 22.503 to 29.261) compared to type II (13.736) (95% CI, 8.392 to 20.144). Pooled D-MMR was highest at EC stage and grades I-II (79.430% and 65.718%, respectively) and lowest in stages III-IV and grade III (20.168% and 21.529%). The pooled odd ratios comparing D-MMR to proficient MMR favored low-stage EC disease (1.565; 0.894 to 2.740), lymphovascular invasion (1.765; 1.293 to 2.409), and myometrial invasion >50% (1.271; 0.871 to 1.853).
CONCLUSIONS
Almost one-quarter of EC patients present with D-MMR tumors. The majority has less aggressive endometrioid histology. D-MMR presents at lower tumor stages compared to MMR-proficient cases in EC. However other metastatic parameters are comparatively higher in the D-MMR disease setting.
PubMed: 33845554
DOI: 10.4132/jptm.2021.02.19 -
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 -
HGG Advances Jan 2023To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics,...
To identify Lynch syndrome (LS) carriers, DNA mismatch repair (MMR) immunohistochemistry (IHC) is performed on colorectal cancers (CRCs). Upon subsequent LS diagnostics, MMR deficiency (MMRd) sometimes remains unexplained (UMMRd). Recently, the importance of complete LS diagnostics to explain UMMRd, involving MMR methylation, germline, and somatic analyses, was stressed. To explore why some MMRd CRCs remain unsolved, we performed a systematic review of the literature and mapped patients with UMMRd diagnosed in our center. A systematic literature search was performed in Ovid Medline, Embase, Web of Science, Cochrane CENTRAL, and Google Scholar for articles on UMMRd CRCs after complete LS diagnostics published until December 15, 2021. Additionally, UMMRd CRCs diagnosed in our center since 1993 were mapped. Of 754 identified articles, 17 were included, covering 74 patients with UMMRd. Five CRCs were microsatellite stable. Upon complete diagnostics, 39 patients had single somatic MMR hits, and six an MMR germline variant of unknown significance (VUS). Ten had somatic pathogenic variants (PVs) in , , , and . The remaining 14 patients were the only identifiable cases in the literature without a plausible identified cause of the UMMRd. Of those, nine were suspected to have LS. In our center, complete LS diagnostics in approximately 5,000 CRCs left seven MMRd CRCs unexplained. All had a somatic MMR hit or MMR germline VUS, indicative of a missed second MMR hit. In vitually all patients with UMMRd, complete LS diagnostics suggest MMR gene involvement. Optimizing detection of currently undetectable PVs and VUS interpretation might explain all UMMRd CRCs, considering UMMRd a case closed.
Topics: Humans; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms, Hereditary Nonpolyposis; Brain Neoplasms
PubMed: 36624813
DOI: 10.1016/j.xhgg.2022.100167 -
Journal of Clinical Medicine Aug 2020Intestinal metaplasia/differentiation in primary endometrial carcinomas is an uncommon phenomenon, with only few cases described. (Review)
Review
BACKGROUND
Intestinal metaplasia/differentiation in primary endometrial carcinomas is an uncommon phenomenon, with only few cases described.
MATERIAL AND METHODS
We performed a systematic review of endometrial carcinomas with intestinal metaplasia/differentiation interrogating the electronic databases Pubmed, Web of Science, and Scopus, and we reported an additional case arising in a 49-year-old woman.
RESULTS
We identified only eight patients diagnosed with endometrial carcinomas exhibiting intestinal metaplasia/differentiation, and additionally our case. Endometrial carcinomas with intestinal-type features can present in pure or mixed forms in association with usual-type endometrioid carcinomas; in mixed forms, the two neoplastic components may derive from a common neoplastic progenitor, as evidenced by the concomitant loss of MSH2 and MSH6 protein expression in our case. Disease recurrences occur in a significant fraction of the cases, including patients diagnosed in low-stage disease.
CONCLUSIONS
Endometrial carcinomas with intestinal metaplasia/differentiation are rare and they may represent a more aggressive tumor variant, thus requiring a proper treatment despite the low-tumor stage. The ProMise classification should be performed also in these unusual tumors, since they can be associated with mismatch repair system defects.
PubMed: 32781666
DOI: 10.3390/jcm9082552 -
Molecular Oncology Feb 2024In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA... (Review)
Review
In 2021, Suwala et al. described Primary Mismatch Repair Deficient IDH-mutant Astrocytoma (PMMRDIA) as a distinct group of gliomas. In unsupervised clustering, PMMRDIA forms distinct cluster, separate from other IDH-mutant gliomas, including IDH-mutant gliomas with secondary mismatch repair (MMR) deficiency. In the published cohort, three patients received treatment with an immune checkpoint blocker (ICB), yet none exhibited a response, which aligns with existing knowledge about the decreased immunogenicity of IDH-mutant gliomas in comparison to IDH-wildtype. In the case of PMMRDIA, the inherent resistance to the standard-of-care temozolomide caused by MMR deficiency is an additional challenge. It is known that a gain-of-function mutation of IDH1/2 genes produces the oncometabolite R-2-hydroxyglutarate (R-2-HG), which increases DNA and histone methylation contributing to the characteristic glioma-associated CpG island methylator phenotype (G-CIMP). While other factors could be involved in remodeling the tumor microenvironment (TME) of IDH-mutant gliomas, this systematic review emphasizes the role of R-2-HG and the subsequent G-CIMP in immune suppression. This highlights a potential actionable pathway to enhance the response of ICB, which might be relevant for addressing the unmet therapeutic challenge of PMMRDIA.
PubMed: 38339779
DOI: 10.1002/1878-0261.13598