MSI-H/dMMR

P1, N=200, Recruiting, BeiGene | Active, not recruiting --> Recruiting | N=37 --> 200 | Trial completion date: May 2026 --> Dec 2026 | Trial primary completion date: May 2025 --> Dec 2026

During a limited 1.5-year follow-up period, neither a confirmed local recurrence nor a distant organ metastasis occurred in this case. We propose that BRAF fusion variations can occur in metastatic EOCC.

At the same time POLE-mutated endometrial carcinomas recur rarely and exhibit the excellent prognosis. Here we report the rare case of 65 y.o. female patient with endometrioid carcinoma sharing immunohistochemical and molecular features of TP53-aberrant, MMR deficient and POLE-mutated subtypes.

This review analyzes the current landscape of existing randomized clinical trials, highlighting the efficacy of immune checkpoint inhibitors (ICIs) like pembrolizumab, avelumab, and dostarlimab. These findings underscore the importance of tailoring treatments based on the molecular characteristics of each tumor and paving the way for future advancements in the field of gynecologic oncology. Despite promising results, this article acknowledges the necessity of further research to refine patient selection criteria and explore combination strategies that can overcome resistance mechanisms.

Furthermore, reduced MSI signal was observed in tumours with isolated MSH6 loss (p = 0.009 Ohio, p = 6.2 × 10-5 Manchester) and in both ECs and CRCs with germline defects, although this only reached significance in CRCs (p = 0.002). These results provide further evidence that ECs with MSH6 loss in particular and LS tumours in general have an attenuated MSI signal, providing support for current guidelines specifically recommending IHC for LS detection and immune checkpoint therapy assessment in EC.

Key to immunotherapy efficacy in EC is the tumor's mismatch repair status, with MMR-deficient tumors demonstrating a higher tumor mutational burden and increased PD-L1 expression, making them more susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab, durvalumab, and dostarlimab. To overcome resistance in cold tumors, novel therapies, including Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes are being explored, offering targeted immune-based strategies to enhance treatment efficacy. This review discusses the current understanding of immunotherapy in EC, emphasizing the prognostic and therapeutic implications of MMR status, TME composition, and emerging cell-based therapies.

In conclusion, the mutation and expression characteristics of PRGs in CRC were comprehensively analyzed and a prognostic PRG signature was constructed in the present study. This signature may predict immune cell infiltration and therapeutic response in CRC, providing new insights into the prognosis and treatment of CRC.

P2, N=80, Active, not recruiting, AIO-Studien-gGmbH | Recruiting --> Active, not recruiting | Trial completion date: Nov 2026 --> Apr 2027 | Trial primary completion date: Nov 2026 --> Apr 2027

P2, N=40, Recruiting, ImmunityBio, Inc. | Active, not recruiting --> Recruiting | N=147 --> 40

In our report we focused on the recent immune checkpoint inhibitor treatment of metastatic and locally advanced colorectal cancer, as a monotherapy, or combined with chemo- or radiotherapy. We summarize the studies with the most promising results.

The FGL1 antibody was more effective in treating MSI GC.The novel immunosuppressor FGL1 antibody exerts a good therapeutic influence on MSI GC. These findings provide a basis for the development of drugs targeting FGL1 for MSI GC treatment.

These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.

We attempted to elucidate the underlying causes and mechanisms behind this lack of response, and to provide new insights into treatment options for these patients. Mutations of key genes within tumor-related signaling pathways and the infiltration of CD8+T cells in the tumor microenvironment may influence the efficacy of immunotherapy for MSI-H solid tumors.

P2, N=320, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Nov 2025 --> Jun 2027 | Trial primary completion date: Oct 2025 --> Jun 2026

The TP53MUT-resistant line can tolerate aneuploidy or polyploidy and exhibits drug resistance. Our study explores the potential of an MPS1/TTK inhibitor, compound-9, as a targeted therapy in gastric cancer cells and investigates its mechanism of action.

P3, N=1147, Recruiting, Bristol-Myers Squibb | N=831 --> 1147 | Trial primary completion date: Jun 2025 --> Aug 2024

Higher CD8+ T cell density was a prognostic marker for disease-free survival in EC, including within NSMP (p<0.05). In summary, the four WHO molecular subtypes of EC exhibit distinct TIME subtypes, complementing molecular classification and providing insights for optimizing EC immunotherapy strategies.

In summary, the cellular MSI-H score reflects the MSI-H cell level within a tumor and demonstrates superior accuracy compared to molecular MSI-H status in predicting immunotherapy response and PFS. This underscores its potential as a more robust biomarker for guiding immunotherapy decisions.

P2, N=14, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Dec 2025

KL-50-based compounds are a promising new strategy for the treatment of MGMT-deficient, MMR-deficient GBM that recurs after frontline TMZ.

Before routine use of immune checkpoint inhibitors, the patients with MSI-H, MMRd, and LS-associated PDACs displayed significantly better survival than the patients with MSS, MMR-proficient, non-LS-associated PDACs. It is expected that survival for this cohort will further improve with increased availability of immunotherapy.

Approximately 2% of all CRC cases in this study were CLDN18.2 positive and had unfavorable features (e.g., mucinous or poorly differentiated adenocarcinoma, T3-4 disease, lymphatic invasion, BRAF V600E mutation) and deficient MMR status. CLDN18.2 positivity did not have a significant impact on RFS or OS.

P1, N=327, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2030 --> May 2029 | Trial primary completion date: Jan 2030 --> May 2029

No abstract available

The most frequently observed pathogenic variant in both MSI-H and MSS cancer patients was BLM exon 7 c.1544delA. Our study covers not only colorectal cancer patients but also other solid tumor types, providing the first data from the Turkish population on the MSI-H/dMMR status and somatic mutation profile in the presence of this condition.

P1, N=48, Completed, Symphogen A/S | Active, not recruiting --> Completed

Correct interpretation of molecular results, accurate identification and classification are important for predicting prognosis and avoiding overtreatment. However, a small number of cases may have recurrence and metastasis, and therefore it is necessary to make a reasonable treatment plan based on the comprehensive judgment of other high risk factors.

For HER2-positive tumours, preoperative systemic therapy with trastuzumab may be considered as it demonstrates a significantly higher number of pathological complete remissions and offers the possibility of achiev-ing a higher R0 resection rate. In oligometastatic disease, surgical management of the primary tumour and metastases may be considered in individual cases in patients who respond to systemic therapy. However, an impact on overall survival has only been documented in patients with retroperitoneal involvement and no peritoneal metastases.

This case report supports the potential importance of immunotherapy in the treatment of resectable locally advanced MSI-H gastric cancer, which is currently being evaluated in clinical trials.

The INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as pre-operative treatment in dMMR/MSI GAC/GEJAC and the first available feasibility results of a NOM strategy in this disease setting, worth of further validation in larger cohorts.

P2, N=240, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

P1/2, N=139, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed

Furthermore, suppressing GDF15 can increase the sensitivity of MSI-H CRC cells to 5-fluorouracil (5-FU), which decreases cell viability and increases the apoptosis rate...Our research indicates that inhibiting GDF15 affects ferroptosis-related pathways, leading to ferroptosis and improving the MSI-H CRC response to 5-FU therapy. As a result, GDF15 could be a promising target for diagnosing and treating MSI-H CRC, potentially enhancing the overall effectiveness of therapy for patients with MSI-H CRC.

With >5 years of follow-up, responses to pembrolizumab remained durable. Median OS was over twice as long in patients treated with pembrolizumab versus chemotherapy in first line despite an effective crossover rate of 62%. Pembrolizumab remains a standard of care for MSI-H/dMMR mCRC.

These findings highlight the ongoing difficulties in demonstrating clear clinical utility of CGP tests in Japan, emphasizing the need for broad discussions on its future direction.

dMMR and MSI-high likely result in an increased rate of structurally altered proteins, i.e., neoantigens, and the efficacy of cancer immunotherapies is thus expected to be higher. We compared MMR IHC to MSI PCR in a large cohort of cancer patients to study how PCR test results correlate to MMR IHC. Our data imply that preanalytical factors strongly influence the results of MMR IHC and MSI PCR and may question the current dogma that dMMR phenotype and genetic MSI status are equivalent predictive markers for immunotherapies.

These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.

The formation of TLS may play a significant role in inhibiting lymph node metastasis, liver metastasis, and vascular tumor thrombus in colorectal cancer, and patients with mature TLS have a favorable clinical prognosis, which can provide a reference for the immunotherapy and prognostic assessment of colorectal cancer patients.

P1, N=26, Completed, Nykode Therapeutics ASA | Active, not recruiting --> Completed | N=60 --> 26

TAF1L is closely related to the occurrence and development of GC. Our results suggested that TAF1L is a significant biomarker for predicting prognosis of GC and may play an important role in immunotherapy and targeted therapy.

The model achieved a high NPV in detecting deficient mismatch repair colorectal cancers. This model might serve as an automatic screening tool.

The current efficacy evaluation was the partial response (PR), and the overall survival (OS) was more than 12 months. Considering the safety and efficacy of Envafolimab observed in our case, we believe that Envafolimab may be a promising drug for the treatment of MSS metastatic colon cancer.