High Microsatellite Instability Research Articles

Insights of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles.

FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles. Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures, determined in accordance with professional guidelines. Interventional clinical trials with targeted therapies or immune checkpoint inhibitors were matched to tumor profiles based on evidence that the genomic finding may be an actionable, investigational, or hypothetical target in the patient's tumor type. In 14 predefined cancer types (80.7% of analyzed solid tumors), predictive, prognostic, and diagnostic markers were reported in 47.6%, 13.2%, and 4.5% of samples, respectively, accounting for a total of 51.2% of tumor profiles. Pan-cancer predictive markers of tumor mutational burden (TMB) of 10 or more mutations per megabase, high microsatellite instability (MSI), or NTRK1/2/3 fusions were observed in 15.6%, 2.0%, and 0.1% of solid tumors, respectively. Most solid tumor profiles (89.2%) had genomic results that could theoretically inform decisions on the selection of immunotherapy and targeted therapy clinical trials. For this real-world population of patients with FoundationOneCDx solid tumor profiles in the routine course of clinical care, clinically significant findings were reported for approximately half of patients with genomic results.

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer.

Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed. To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization. The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node. The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.

Pan-Cancer Prevalence of Microsatellite Instability-High (MSI-H) Identified by Circulating Tumor DNA and Associated Real-World Clinical Outcomes.

Immune checkpoint inhibitors are approved for advanced solid tumors with microsatellite instability-high (MSI-H). Although several technologies can assess MSI-H status, detection and outcomes with circulating tumor DNA (ctDNA)-detected MSI-H are lacking. As such, we examined pan-cancer MSI-H prevalence across 21 cancers and outcomes after ctDNA-detected MSI-H. Patients with advanced cancer who had ctDNA testing (Guardant360) from October 1, 2018, to June 30, 2022, were retrospectively assessed for prevalence. GuardantINFORM, which includes anonymized genomic and structured payer claims data, was queried to assess outcomes. Patients who initiated new treatment within 90 days of MSI-H detection were sorted into immunotherapy included in treatment (IO) or no immunotherapy included (non-IO) groups. Real-world time to treatment discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed in months as proxies of progression-free survival (PFS); real-world overall survival (rwOS) was assessed in months. Cox regression tests analyzed differences. Colorectal cancer, non-small-cell lung cancer (NSCLC), prostate cancer, gastroesophageal cancer, and uterine cancer (UC) were assessed independently; all other cancers were grouped. In total, 1.4% of 171,881 patients had MSI-H detected. Of 770 patients with outcomes available, rwTTD and rwTTNT were significantly longer for patients who received IO compared with non-IO for all cancers (P ≤ .05; hazard ratio [HR] range, 0.31-0.52 and 0.25-0.54, respectively) except NSCLC. rwOS had limited follow-up for all cohorts except UC (IO 39 v non-IO 23 months; HR, 0.18; P = .004); however, there was a consistent trend toward prolonged OS in IO-treated patients. These data support use of a well-validated ctDNA assay to detect MSI-H across solid tumors and suggest prolonged PFS in patients treated with IO-containing regimens after detection. Tumor-agnostic, ctDNA-based MSI testing may be reliable for rapid decision making.

Adoption of Universal Testing in Endometrial Cancers for Microsatellite Instability Using Next-Generation Sequencing.

To assess implementation of a next-generation sequencing (NGS) assay to detect microsatellite instability (MSI) as a screen for Lynch syndrome (LS) in endometrial cancer (EC), while determining and comparing characteristics of the four molecular subtypes. A retrospective review was performed of 408 total patients with newly diagnosed EC: 140 patients who underwent universal screening with NGS and 268 patients who underwent screening via mismatch repair immunohistochemistry (MMR IHC) as part of a historical screening paradigm. In the NGS cohort, incidental POLE and TP53 mutations along with MSI were identified and used to characterize EC into molecular subtypes: POLE-ultramutated, MSI high (MSI-H), TP53-mutated, and no specific molecular profile (NSMP). In historical cohorts, age- and/or family history-directed screening was performed with MMR IHC. Statistical analysis was performed using a t-test for continuous variables and chi-square or Fisher's exact test for categorical variables. In the NGS cohort, 38 subjects (27%) had MSI-H EC, 100 (71%) had microsatellite stable EC, and two (1%) had an indeterminate result. LS was diagnosed in two subjects (1%), and all but five patients completed genetic screening (96%). Molecular subtypes were ascertained: eight had POLE-ultramutated EC, 28 had TP53-mutated EC (20%), and 66 (47%) had NSMP. MSI-H and TP53-mutated EC had worse prognostic features compared with NSMP EC. Comparison with historical cohorts demonstrated a significant increase in follow-up testing after an initial positive genetic screen in the MSI NGS cohort (56% v 89%; P = .001). MSI by NGS allowed for simultaneous screening for LS and categorization of EC into molecular subtypes with prognostic and therapeutic implications.

Real-world study on microsatellite instability and mismatch repair deficiency testing patterns among patients with metastatic colorectal cancer in Spain

PurposeClinical practice guidelines recommend that all patients with metastatic colorectal cancer (mCRC) should be tested for mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). We aimed to describe the dMMR/MSI-H testing practice in patients with mCRC in Spanish centers.MethodsMulticenter, observational retrospective study that included patients newly diagnosed with mCRC or who progressed to a metastatic stage from early/localized stages.ResultsThree hundred patients were included in the study from May 2020 through May 2021, with a median age of 68 years, and two hundred twenty-five (75%) had stage IV disease at initial diagnosis; two hundred eighty-four patients received first-line treatment, and dMMR/MSI-H testing was performed in two hundred fifty-one (84%) patients. The results of the dMMR/MSI-H tests were available in 61 (24%) of 251 patients before the diagnosis of metastatic disease and in 191 (81%) of 236 evaluable patients for this outcome before the initiation of first-line treatment. Among the 244 patients who were tested for dMMR/MSI-H with IHC or PCR, 14 (6%) were MMR deficient. The most frequent type of first-line treatment was the combination of chemotherapy and biological agent, that was received by 71% and 50% of patients with MMR proficient and deficient tumors, respectively, followed by chemotherapy alone, received in over 20% of patients in each subgroup. Only 29% of dMMR/MSI-H tumors received first-line immunotherapy.ConclusionOur study suggests that a high proportion of patients with mCRC are currently tested for dMMR/MSI-H in tertiary hospitals across Spain. However, there is still room for improvement until universal testing is achieved.Trial registration: Not applicable.

Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement.

Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.

Assessing the Genomic Landscape of Cervical Cancers: Clinical Opportunities and Therapeutic Targets.

Tumor genomic profiling is increasingly used to guide treatment strategy in patients with cancer. We integrated tumor genomic, clinical demographic, and treatment response data to assess how prospective tumor-normal sequencing impacted treatment selection in patients with cervical cancer. Cervical cancers were prospectively analyzed using the MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing panel. Clinical data, including histology, stage at diagnosis, treatment history, clinical trial enrollment and outcomes, date of last follow-up, and survival status were obtained from medical records. A total of 177 patients with cervical cancer (squamous, 69; endocervical adenocarcinoma, 50; gastric type, 22; adenosquamous, 21; and other, 15) underwent MSK-IMPACT testing. The most prevalent genomic alterations were somatic mutations or amplifications in PIK3CA (25%), ERBB2 (12%), KMT2C (10%), and KMT2D (9%). Furthermore, 13% of patients had high tumor mutational burden (TMB >10 mut/Mb), 3 of which were also microsatellite instability-high (MSI-H). Thirty-seven percent of cases had at least one potentially actionable alteration designated as a level 3B mutational event according to the FDA-recognized OncoKB tumor mutation database and treatment classification system. A total of 30 patients (17%) were enrolled on a therapeutic clinical trial, including 18 (10%) who were matched with a study based on their MSK-IMPACT results. Twenty patients (11%) participated in an immune checkpoint inhibition study for metastatic disease; 2 remain progression free at >5 years follow-up. Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer.

Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification. We aimed to assess the utility of immunohistochemistry (IHC) staining for MMR protein expression and polymerase chain reaction (PCR)-based MSI assays in EC and the correlation between MMR/MSI status and various clinicopathological parameters. We reviewed the clinical and pathological information of 333 patients with EC. MMR protein expression was assessed as retained or lost to determine MMR status by IHC staining, and MSI status was identified by PCR capillary electrophoresis (PCR-CE) testing with a National Cancer Institute (NCI) panel. The correlation of MMR/MSI status with clinicopathological features was determined by statistical analysis. Discrepant results were further analyzed using an alternative PCR-CE MSI (Promega panel) method, MLH1 promoter methylation assays, and next-generation sequencing (NGS). Among the EC patients, the overall percentage of dMMR was 25.2%, and the overall percentage of MSI-H was 24%. Among the dMMR patients, 50 (59.5%) showed loss of MLH1 and PMS2 expression, 19 (22.6%) loss of MSH2 and MSH6 expression, and seven (8.3%) and eight (9.5%) loss of PMS2 and MSH6 expression, respectively. The dMMR subgroup was significantly younger than the pMMR subgroup, especially for <60-years-old patients (p=0.038). In addition, we identified a strong correlation between MMR/MSI status and high-grade endometrioid or nonendometrioid components (p=0.004 or p=0.003). IHC staining and PCR-CE assay results showed a high level of overall concordance (98.8%, Cohen's κ=0.98). Four patients were found to have dMRR/MSS in both examinations. We reanalyzed them with additional methods. One case showed MLH1 promotor methylation, and the other three cases harbored MSH6 germline pathogenic variations. One of the cases with MSH6 deficiency was reanalyzed as MSI-H by alternative PCR-CE assay or NGS testing. This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.

Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers.

Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including B2M and JAK1/2 mutations, TMB, WNT pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases.

Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials

The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR)= 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR= 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR= 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

Frameshift mutations of immunomodulatory BTN2A1, BTN2A2, and BTNL3 genes in colon cancers

The butyrophilin family genes are immunoregulatory genes with either immune stimulatory or inhibitory functions. In the present study, we analyzed three butyrophilin genes, BTN2A1 (immune-stimulatory), BTN2A2 (inhibitory), and BTNL3 (stimulatory) genes in sporadic colon cancers (CCs). By the mutation analysis, we identified the frameshift mutations of BTN2A1, BTN2A2, and BTNL3 genes in 2, 4, and 8 CCs in microsatellite instability-high (MSI-H) CCs (2.1–8.4% of MSI-H), respectively, but not the microsatellite stable (MSS) CCs. Four of 16 MSI-H CCs (25%) exhibited regional heterogeneous mutations (RHM) of BTN2A1, BTN2A2, and BTNL3 genes. In immunohistochemistry, BTNL3 expression was lost in approximately 30% of CCs, and BTN2A2 loss was minimal in CCs (around 3%) irrespective of the MSI status. Our study revered that butyrophilin family genes BTN2A1, BTN2A2, and BTNL3 harbored multiple levels of gene alterations at frameshift mutations, RHMs, and expression losses in CCs, suggesting that butyrophilin family genes could contribute to CC pathogenesis by altering immune responses.

Histopathology and levels of proteins in plasma associate with survival after colorectal cancer diagnosis

BackgroundThe TNM system is used to assess prognosis after colorectal cancer (CRC) diagnosis. Other prognostic factors reported include histopathological assessments of the tumour, tumour mutations and proteins in the blood. As some of these factors are strongly correlated, it is important to evaluate the independent effects they may have on survival.MethodsTumour samples from 2162 CRC patients were visually assessed for amount of tumour stroma, severity of lymphocytic infiltrate at the tumour margins and the presence of lymphoid follicles. Somatic mutations in the tumour were assessed for 2134 individuals. Pre-surgical levels of 4963 plasma proteins were measured in 128 individuals. The associations between these features and prognosis were inspected by a Cox Proportional Hazards Model (CPH).ResultsLevels of stroma, lymphocytic infiltration and presence of lymphoid follicles all associate with prognosis, along with high tumour mutation burden, high microsatellite instability and TP53 and BRAF mutations. The somatic mutations are correlated with the histopathology and none of the somatic mutations associate with survival in a multivariate analysis. Amount of stroma and lymphocytic infiltration associate with local invasion of tumours. Elevated levels of two plasma proteins, CA-125 and PPP1R1A, associate with a worse prognosis.ConclusionsTumour stroma and lymphocytic infiltration variables are strongly associated with prognosis of CRC and capture the prognostic effects of tumour mutation status. CA-125 and PPP1R1A may be useful prognostic biomarkers in CRC.

Subclonal accumulation of immune escape mechanisms in microsatellite instability-high colorectal cancers.

Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.

An immunogenic cell death-related signature predicts prognosis and immunotherapy response in stomach adenocarcinoma.

The immunogenic cell death (ICD) is a specific type of regulatory cell death (RCD), which induces adaptive immunity against antigens of dead cells. ICDs have received increasing attention for their potential role in tumor microenvironment reprogramming and immunotherapy. However, the relationship between ICD-related features and stomach adenocarcinoma (STAD) prognosis, immune cell infiltration and immunotherapy remains unclear. Patients were divided into different ICD-related subtypes by consensus clustering. The differences in prognosis, Tumor microenvironment (TME), and immune checkpoint expression between different ICD-related subtypes were systematically assessed. Additionally, we constructed an ICD-related gene risk score (ICDRS). We systematically analyzed the correlation between ICDRS and prognosis, TME, immunotherapy response and drug sensitivity of gastric cancer. In addition, we explored the role of TGM2 in promoting gastric cancer progression through in vitro experiments. We identified three ICD-associated subtypes by consensus clustering. The ICD gene was highly expressed in Cluster B. Compared with the other two subtypes, Cluster B had better prognosis, higher immune response signaling activity, massive immune cell infiltration and lower tumor purity. Immune checkpoint (ICP) and human leukocyte antigen (HLA) related genes were also highly expressed in Cluster B. In addition, we found that ICDRS is an effective indicator for predicting the prognosis and immune efficacy of STAD. The low ICDRS group has the characteristics of good prognosis, high tumor mutation burden (TMB), high microsatellite instability (MSI), and sensitivity to immunotherapy, while the high ICDRS group is prone to immune escape and immunotherapy resistance. In addition, we found that down-regulating TGM2 gene can inhibit the proliferation and migration of gastric cancer cells through in vitro experiments. Our study found that the model based on ICD features is helpful to clarify the TME characteristics of STAD, and has important clinical significance for evaluating the prognosis and immunotherapy response of STAD patients. TGM2 plays an important role in the progression of STAD, suggesting that TGM2 can be used as a new target for the treatment of STAD.

Validity and utility of blood tumor mutational burden (bTMB) is dependent on circulating tumor DNA (ctDNA) shed: SCRUM-Japan MONSTAR-SCREEN

BackgroundThe tumor mutational burden (TMB) is a genomic biomarker associated with the benefits from immune checkpoint inhibitors (ICIs) cancer therapy. An elevated blood TMB (bTMB) in circulating tumor DNA (ctDNA) represents a compelling non-invasive diagnostic approach; however, the validity and utility of this emerging biomarker across cancer types have not been examined. Patient and methodsThe blood and tissue TMB was measured in a large pan-tumor clinical cohort and the MONSTAR-SCREEN observational study (UMIN000036749) using the FoundationOne Liquid CDx and FoundationOne CDx assays. A subset of the MONSTAR-SCREEN cohort was used to evaluate the association between the bTMB and the efficacy of ICIs therapy. ResultsThe majority of cancer types showed similar prevalence of TMB≥10 mutations/megabase and bTMB≥10. There was high concordance between bTMB and TMB in blood and tissue biopsy from the same patient when the plasma tumor fraction (TF) was at least 1% (Spearman's coefficient 0.74 and > 80% sensitivity to detect TMB-high). High microsatellite instability (MSI-H) was detected by ctDNA with 79% sensitivity when TF was at least 1%, but only 6% sensitivity when TF was <1%. Among patients with bTMB≥14 and elevated TF≥10% treated with ICIs, there was a trend toward a longer progression-free survival and overall survival compared with patients with bTMB<14 and elevated TF≥10% (HR, 0.62 [95%CI, 0.39–0.98]; p = 0.04 and HR, 0.60 [95%CI, 0.34-1.1]; p = 0.05). ConclusionsOur findings suggest that an elevated bTMB is correlated with elevated TMB and represents a pragmatic biomarker for assessing ICIs benefits. The utility of this biomarker is likely to be associated with high TF levels, informing future prospective investigations.

Neutrophil extracellular traps-related signature predicts the prognosis and immune infiltration in gastric cancer.

Gastric cancer (GC) is the fifth most prevalent cancer globally, with the third highest case fatality rate. Neutrophil extracellular traps (NETs) are a reticulated structure of DNA, histones, and antimicrobial peptides produced by active neutrophils that trap pathogens. Even though NETs are associated with poorer recurrence-free survival (RFS) and overall survival (OS), the specifics of this interaction between NETs and cancer cells are yet unknown. The keywords "neutrophil extracellular traps and gastric cancer" were used in the GEO database for retrieval, and the GSE188741 dataset was selected to obtain the NETs-related gene. 27 NETs-related genes were screened by univariate Cox regression analysis (p < 0.05). 27 NETs-related genes were employed to identify and categorize NETs-subgroups of GC patients under the Consensus clustering analysis. 808 GC patients in TCGA-STAD combined with GES84437 were randomly divided into a training group (n = 403) and a test group (n = 403) at a ratio of 1:1 to validate the NETs-related signature. Based on Multivariate Cox regression and LASSO regression analysis to develop a NETs-related prognosis model. We developed a very specific nomogram to improve the NETs-clinical score's usefulness. Similarly, we also performed a great result in pan-cancer study with NETs-score. Low NETs scores were linked to higher MSI-H (microsatellite instability-high), mutation load, and immune activity. The cancer stem cell (CSC) index and chemotherapeutic treatment sensitivity were also connected to the NET score. Our comprehensive analysis of NETs in GC suggests that NETs have a role in the tumor microenvironment, clinicopathological features, and prognosis. The NETs-score risk model provides a basis for better prognosis and therapy outcomes in GC patients.

T-cell priming transcriptomic markers: implications of immunome heterogeneity for precision immunotherapy

Immune checkpoint blockade is effective for only a subset of cancers. Targeting T-cell priming markers (TPMs) may enhance activity, but proper application of these agents in the clinic is challenging due to immune complexity and heterogeneity. We interrogated transcriptomics of 15 TPMs (CD137, CD27, CD28, CD80, CD86, CD40, CD40LG, GITR, ICOS, ICOSLG, OX40, OX40LG, GZMB, IFNG, and TBX21) in a pan-cancer cohort (N = 514 patients, 30 types of cancer). TPM expression was analyzed for correlation with histological type, microsatellite instability high (MSI-H), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression. Among 514 patients, the most common histological types were colorectal (27%), pancreatic (11%), and breast cancer (10%). No statistically significant association between histological type and TPM expression was seen. In contrast, expression of GZMB (granzyme B, a serine protease stored in activated T and NK cells that induces cancer cell apoptosis) and IFNG (activates cytotoxic T cells) were significantly higher in tumors with MSI-H, TMB ≥ 10 mutations/mb and PD-L1 ≥ 1%. PD-L1 ≥ 1% was also associated with significantly higher CD137, GITR, and ICOS expression. Patients’ tumors were classified into “Hot”, “Mixed”, or “Cold” clusters based on TPM expression using hierarchical clustering. The cold cluster showed a significantly lower proportion of tumors with PD-L1 ≥ 1%. Overall, 502 patients (98%) had individually distinct patterns of TPM expression. Diverse expression patterns of TPMs independent of histological type but correlating with other immunotherapy biomarkers (PD-L1 ≥ 1%, MSI-H and TMB ≥ 10 mutations/mb) were observed. Individualized selection of patients based on TPM immunomic profiles may potentially help with immunotherapy optimization.

Efficacy of Immune Checkpoint Inhibition and Cytotoxic Chemotherapy in Mismatch Repair-Deficient and Microsatellite Instability-High Pancreatic Cancer: Mayo Clinic Experience.

Pancreatic cancer (PC) carries a poor prognosis with high rates of unresectable/metastatic disease at diagnosis, recurrence after resection, and few systemic therapy options. Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) PCs demonstrated uncharacteristically poor outcomes in KEYNOTE-158, evaluating pembrolizumab in MSI-H solid tumors. Our study aggregates the Mayo Clinic experience with dMMR/MSI-H PCs, characterizing the clinical, molecular, and treatment response patterns with a focus on response to immune checkpoint inhibitors (ICIs). Retrospective data were collected from the electronic medical record from December 2009 to February 2023. Patients were included if they had a pathologically confirmed pancreatic malignancy and had (1) deficient expression of mismatch repair (MMR) proteins by tumor immunohistochemistry, (2) pathogenic mutation of MMR genes on genomic sequencing, and/or (3) MSI-H by polymerase chain reaction. Thirty-two patients were identified for inclusion, with all stages of disease represented. Sixteen of these patients underwent surgery or chemoradiotherapy. Of these patients, uncharacteristically favorable responses were seen, with a recurrence rate of only 19% (n = 3) despite a median follow-up of 25 months. In the palliative setting, excellent responses to ICI were seen, with overall response rate (ORR) of 75% (20% complete response). Median time to disease progression was not reached. Response rates to cytotoxic chemotherapy in the palliative setting were poor, with 30% ORR and median time to progression of 4 months. We observed a high rate of discrepancy between MMR and MSI testing methods, representing 19% of the entire cohort and 26% of evaluable cases. Our data argue for the preferential use of ICI over cytotoxic chemotherapy in any patient with dMMR/MSI-H PC requiring systemic therapy, including in the metastatic and adjuvant/neoadjuvant settings.

Molecular subtypes of endometrial cancer: Implications for adjuvant treatment strategies.

When determining adjuvant treatment for endometrial cancer, the decision typically relies on factors such as cancer stage, histologic grade, subtype, and a few histopathologic markers. The Cancer Genome Atlas revealed molecular subtyping of endometrial cancer, which can provide more accurate prognostic information and guide personalized treatment plans. To summarize the expression and molecular basis of the main biomarkers of endometrial cancer. PubMed was searched from January 2000 to March 2023. Studies evaluating molecular subtypes of endometrial cancer and implications for adjuvant treatment strategies. Three authors independently performed a comprehensive literature search, collected and extracted data, and assessed the methodological quality of the included studies. We summarized the molecular subtyping of endometrial cancer, including mismatch repair deficient, high microsatellite instability, polymerase epsilon (POLE) exonuclease domain mutated, TP53 gene mutation, and non-specific molecular spectrum. We also summarized planned and ongoing clinical trials and common therapy methods in endometrial cancer. POLE mutated endometrial cancer consistently exhibits favorable patient outcomes, regardless of adjuvant therapy. Genomic similarities between p53 abnormality endometrial cancer and high-grade serous ovarian cancer suggested possible overlapping treatment strategies. High levels of immune checkpoint molecules, such as programmed cell death 1 and programmed cell death 1 ligand 1 can counterbalance mismatch repair deficient endometrial cancer immune phenotype. Hormonal treatment is an appealing option for high-risk non-specific molecular spectrum endometrial cancers, which are typically endometrioid and hormone receptor positive. Combining clinical and pathologic characteristics to guide treatment decisions for patients, including concurrent radiochemotherapy, chemotherapy, inhibitor therapy, endocrine therapy, and immunotherapy, might improve the management of endometrial cancer and provide more effective treatment options for patients. We have characterized the molecular subtypes of endometrial cancer and discuss their value in terms of a patient-tailored therapy in order to prevent significant under- or overtreatment.

Neoadjuvant Immunotherapy for Patients with dMMR/MSI-High Gastrointestinal Cancers: A Changing Paradigm.

Immune checkpoint inhibitors have revolutionized the management of mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) gastrointestinal cancers, particularly colorectal cancer. Cancers with the MMR-D/MSI-H genotype often carry a higher tumor mutation burden with frameshift alterations, leading to increased mutation-associated neoantigen (MANA) generation. The dramatic response seen with immune checkpoint inhibitors (ICIs), which are orchestrated by MANA-primed effector T cells, resulted in the rapid development of these novel therapeutics within the landscape of MSI-H gastrointestinal cancers. Recently, several clinical trials have utilized ICIs as potential neoadjuvant therapies for MSI-H gastrointestinal cancers and demonstrated deep clinical and pathological responses, creating opportunities for organ preservation. However, there are potential challenges to the neoadjuvant use of ICIs for certain disease types due to the clinical risk of overtreatment for a disease that can be cured through a surgery-only approach. In this review article, we discuss neoadjuvant management approaches with ICI therapy for patients with MSI-H gastrointestinal cancers, including those with oligometastatic disease. We also elaborate on potential challenges and opportunities for the neoadjuvant utilization of ICIs and provide further insight into the changing treatment paradigm of MMR-D/MSI-H gastrointestinal cancers.