MSI-H/dMMR

P1/2, N=188, Recruiting, Cancer Research UK | N=114 --> 188 | Trial completion date: Sep 2025 --> Jun 2027 | Trial primary completion date: Sep 2025 --> Jun 2027

ICIs combined with platinum-based chemotherapy significantly prolonged PFS and OS in patients with advanced or recurrent EC. Patients with dMMR status, Caucasians, endometrioid histology, and positive PD-L1 status showed significant PFS benefits, emphasizing the need for personalized treatment approaches to improve outcomes.

The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer.

Assessing MSI in patients with gastrointestinal tract (GI) cancers is useful to exclude Lynch syndrome, but also to predict benefit for ICI. Following review of the relevant literature, this review article aims to outline the clinicopathologic spectrum of MSI and mismatch repair deficiency (dMMR) in the GI tract, hepatobiliary system and pancreas and discuss the therapeutic consideration in this disease.

Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than MLH1 methylation analysis; however, it may be useful for ruling out MLH1 methylation cases due to its high sensitivity. Further studies are needed to determine whether EPM2AIP1 IHC can predict pembrolizumab efficacy.

Our findings suggest that ENO2 serves as a novel prognostic biomarker and is associated with the progression of MSI-H CRC.

Mismatch repair deficiency was significantly associated with shorter survival (P=0.004). Immunotherapy trials need to progress, and patients with mismatch repair-deficient pediatric high-grade gliomas are the most suitable candidates for such studies.

The protective associations of undergoing lower endoscopy (hazard ratios [HR] 0.43, 95% confidence interval (CI) 0.37, 0.49 for aggressive versus HR 0.61, 95% CI 0.56, 0.67 for non-aggressive) and regular use of aspirin (HR 0.70, 95% CI 0.61, 0.81 versus HR 0.84, 95% CI 0.77, 0.92) were stronger for aggressive than non-aggressive CRC (pHeterogeneity <0.05)...Similar results were observed for fatal CRC and advanced tumor stages at diagnosis. These findings provide initial evidence for the role of pre-diagnostic risk factors in the pathogenesis of aggressive CRC and suggest research priorities for preventive interventions.

A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.

No abstract available

This cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.

KMT2A mutations (hazard ratio &lsqb;HR], 4.47; 95% confidence interval &lsqb;CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.

P2, N=154, Not yet recruiting, Ibrahim Halil Sahin | Trial completion date: Aug 2028 --> Apr 2029 | Initiation date: Aug 2023 --> May 2024 | Trial primary completion date: Aug 2025 --> Apr 2026

The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced endometrial cancer.

In endometrial cancer, co-mutation of FAT3 and LRP1B not only leads to activation of the immune state, but also represents a subgroup with an improved prognosis, particularly in the MSI-H subtype.

P1/2, N=206, Recruiting, C4 Therapeutics, Inc. | N=102 --> 206

P1, N=29, Terminated, Elevar Therapeutics | Phase classification: P1b/2 --> P1 | Completed --> Terminated; Phase 2 portion of the study was not performed due to redirection of the rivoceranib development plan by the Sponsor.

P1/2, N=53, Recruiting, University of Chicago | Trial completion date: Apr 2024 --> Aug 2025 | Trial primary completion date: Apr 2024 --> Aug 2025

This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H.

Envafolimab yielded promising surgical outcomes and safety in dMMR/MSI-H locally advanced colon cancer, representing a promising treatment modality for this population.

The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a 'watch-and-wait" strategy could be used for cases in which ICI is effective.

In this population-based study using the NCDB, immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer, but not in those with MSI-L/MSS metastatic colorectal cancer. Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer.

We report a case of luminal-type breast cancer with bone metastases and MSI-High, which was treated with PEM and showed a rapid therapeutic response.

Results The 64 patients with colorectal cancer were at a male-to-female ratio of 1.21∶1,with the mean age of (56.59±13.27) years.The tumors were located in the colon in 46(71.88%) patients and in the rectum in 18(28.12%) patients.Sixty(93.75%) patients presented adenocarcinoma,and 4(6.25%) patients presented other types of tumors.The patients in T1/T2 and T3/T4 phases accounted for 17.19%(n=11) and 82.81%(n=53),respectively.Lymph node metastasis occurred in 24(37.50%) patients.The immunohistochemical staining results showed partially down-regulated or absent expression of SMARCA4 in 1(1.56%) patient,positive BRAF expression in 4(6.25%) patients,and mutant expression of P53 in 35(54.69%) patients.The PD-1-expressing tumor associated immune cell was proportion score<10% in 45(70.31%) patients and≥10% in 19(29.69%) patients.The PD-L1 combined positive score was<10 in 52(81.25%) patients and≥10 in 12(18.75%) patients.The gene fusion of NTRK1,NTRK2,and NTRK3 was negative in all the patients,and BRAF V600E gene mutation was positive in 4(6.25%) patients.The SMARCA4 gene alteration was not detected in the patient with partial expression missing of SMARCA4.The PD-L1 combine positive score was correlated with the deficient mismatch repair(dMMR)/microsatellite instability-high (MSI-H) and the PD-1 expression (χ2=10.223,P=0.001;χ2=11.979,P=0.001). Conclusions The down-regulated or absent SMARCA4 expression and NTRK gene fusion are rare in the patients with colorectal cancer in Tibet.A few patients present BRAF V600E gene mutations,and Pan-TRK and BRAF expression can be used for the primary screening of NTRK gene fusion and BRAF gene mutation.The patients with dMMR/MSI-H are prone to high expression of PD-L1 and expected to benefit from immunotherapy.No significant correlation exists between P53 mutation and PD-L1 expression.The high expression of PD-1 is positively correlated with the high expression of PD-L1.

P2, N=0, Withdrawn, Genmab | N=80 --> 0 | Initiation date: Apr 2024 --> Oct 2023 | Not yet recruiting --> Withdrawn

P2, N=1609, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Oct 2026 --> May 2027 | Trial primary completion date: Oct 2026 --> May 2027

P2, N=70, Recruiting, Inspirna, Inc. | N=50 --> 70

P1, N=60, Active, not recruiting, Nykode Therapeutics ASA | Recruiting --> Active, not recruiting

Patients with the genetic characteristics of MSI-H cancer showed higher expression levels of ICMs than those in patients with MSS cancer, and predominantly, two or more ICMs were concurrently expressed. Our findings highlight the potential efficacy of the dual-blockade approach in immunotherapy, particularly in patients with MSI-H CRC.

The findings of our study will be published in a peer-reviewed journal. CRD42023494276.

MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.

Of them, 85 received pembrolizumab, 10 received sintilimab, 8 received tislelizumab, 4 received camrelizumab, 2 received toripalimab, and 1 received pabocizumab. The adjuvant chemotherapy regimens used among the chemotherapy alone group includes SOX regimen (132 cases), XELOX (102 cases), S-1 monotherapy (44 cases), and other regimens (15 cases)...Subgroup analysis showed that stage IIIC (HR=0.416, 95%CI: 0.184~0.940), aged ≥60 years (HR=0.336, 95%CI: 0.121~0.934) and extranodal invasion (HR=0.378, 95%CI: 0.170~0.839) were associated with benefit from the combined immune adjuvant chemotherapy, while no association was observed for MMR, HER-2 or EBER status. Stage III gastric/esophagogastric junction cancer patients may benefite from postoperative immune checkpoint inhibitor combined with adjuvant chemotherapy in real-world settings.

Finally, the medication choices of immunotherapy, the treatment regimen, and the follow-up strategy are further discussed. We hope that neoadjuvant immunotherapy could be appropriately applied in MSI-H/dMMR colorectal cancer so that more patients can achieve organ preservation.

HRD showed a positive correlation with tumor mutational burden, which might serve as indirect evidence supporting the potential of HRD as a biomarker for GC. These findings highlighted GC's high heterogeneity and complexity and provided valuable insights into the somatic mutations that affect early genetic progression and immune microenvironment.

The assay was evaluated using two different patient cohorts and evaluation included several DNA extraction methodologies, two different PCR platforms, and an inter-laboratory ring study. The MicroSight® MSI assay showed a high repeatability regardless of DNA extraction method and PCR platform, and a 100% agreement of the MSI status with PCR fragment analysis methods applied as clinical comparator.

The majority of the recruited EC patients in this study showed advanced age and a high percentage of d-MMR status.

Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

The distribution of the molecular subclasses in stage IV endometrial cancer patients differed substantially from the distribution in stage I-III endometrial cancer patients, with the unfavorable subclasses being more frequently present. Although the molecular classification was not prognostic in stage IV endometrial cancer, it could guide adjuvant treatment decisions.

Our data suggest that molecular classification does not seem useful to tailor the need of nodal dissection in apparent early-stage endometrial cancer. p53 abnormality predicts the risk of having advanced disease at presentation. Further external validation is needed.

The compound was well tolerated in mice and led to robust tumour regression in multiple MSI-H colorectal cancer cell lines and patient-derived xenograft models. Our work shows an allosteric approach for inhibition of WRN function that circumvents competition from an endogenous ATP cofactor in cancer cells, and designates VVD-133214 as a promising drug candidate for patients with MSI-H cancers.

Evolving research on pembrolizumab allows a deeper clinical understanding, despite challenges as variable patient responses. Pembrolizumab has emerged as a pivotal breakthrough in cancer treatment, improving patient outcomes and safety.