MSI (Microsatellite instability)

P1/2, N=480, Recruiting, Parabilis Medicines, Inc. | N=245 --> 480

They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms...For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.

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.

Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

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.

Synthesizing evidence from diverse studies, this review provides insights into the prognostic and predictive landscape of CRC, highlighting the potential clinical implications of identified determinants. Understanding the multifaceted nature of prognostic and predictive factors in CRC is imperative for the advancement of personalized treatment strategies and improvement of patient outcomes.

These findings underscore the critical role of CD19 within the tumor microenvironment, suggesting its potential as a biomarker and a therapeutic target in specific types of cancer.

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

P1/2, N=97, Active, not recruiting, NextCure, Inc. | Recruiting --> Active, not recruiting | N=209 --> 97

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

The responsiveness of gastrointestinal stromal tumors to imatinib requires validation via molecular testing. Patients diagnosed with pancreatic cancer may see enhanced survival rates by targeted therapy addressing microsatellite instability and BRCA mutations. In bile duct malignancies, especially intrahepatic cholangiocarcinoma of the small duct variant, the analysis of IDH1 mutations and FGFR2 fusions presents new treatment prospects.

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.

RPS27A overexpression in HCC cells promoted the proliferation, migration, and invasion of cancer cells, and accelerated M2 polarization of macrophage. RPS27A had the potential to be a biomarker for diagnosis, prognosis and immunotherapy response in pan-cancer, and targeting RPS27A may provide new ideas for cancer immunotherapy.

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

In summary, our study found that DHX34 is highly expressed in pan-cancer and has diagnostic and prognostic value. Targeting DHX34 may improve the therapeutic efficacy of immunotherapy and chemotherapy in a multitude of tumors.

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.

In addition, NGS-based MSI detection exhibited higher levels of repeatability and applicability compared with other MSI-NGS-based methods, such as MSISensor2 and MANTIS. Collectively, the results of the present study highlighted that the combination of MSIPeak and NGS exhibits potential in the detection of cancer.

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

While the MMRd/MSI carcinoma was recognized early and showed complete pathologic response after pembrolizumab treatment, the MMRp/MSS adenocarcinoma was underrecognized and poorly responsive to treatment. A second patient, with a pathogenic PMS2 variant, also developed a MMRp CRC. These cases highlight the complex biological pathways in CRC development and the impact of molecular classification on treatment.

Furthermore, the NGFR gene was shown to be more significantly expressed in various pancreatic cancer cells. Bioinformatics analysis was used to create a validated prognostic model of pancreatic cancer, which explored the critical mechanisms of neural-tumor interactions and revealed the potential of cancer-neural crosstalk-related genes as prognostic biomarkers and anti-tumor therapy targets.

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

P2, N=28, Not yet recruiting, Shanghai Zhongshan Hospital

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.

The existing challenges are also pointed out, such as the tumor heterogeneity, the inconstant nature of TIME, nonuniformed thresholds and standardization approaches. The review concludes by emphasizing the importance of biomarker research in realizing the potential of personalized immunotherapy, with the goal of improving patient selection, treatment strategies, and overall outcomes in cancer treatment.

The prognostic model comprising ARPC1B, BATF, CCL2, and COTL1 can effectively identify high-risk EC patients and predict their response to immunotherapy, demonstrating significant clinical potential. These genes are implicated in EC development and immune infiltration, with BATF emerging as a potential therapeutic target for EC.

No abstract available

MeC is a pathological subtype with an active immune response and is a promising group for ICB therapy. This heightened immune response was not limited to the patient's microsatellite status.

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.

The rare diagnosis of intramucosal colorectal carcinoma aids in identifying patients at increased colorectal cancer risk, notably those with hereditary syndromes. Standardizing this diagnosis is critical to prevent overdiagnosis and unnecessary treatment.

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.

No abstract available

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.

In gallbladder and biliary tract cancers, we are mainly looking for IDH1 and IDH2 mutations, FGFR2 gene fusions and mutations, HER2 amplifications or mutations, as well as mutations of BRAF or BRCA1/2. All results should be discussed within the molecular tumor board.

The microstructural heterogeneity assessment of ZOOMit DKI allowed for characterizing MSI status in EC. Within the current universal MSI testing paradigm, DKI may provide added value as a potential noninvasive imaging biomarker for preoperative assessment of MSI tumors, thereby facilitating clinical decision-making.

Although current first- and second-line therapies stratify for KRAS/NRAS/BRAF mutations, microsatellite instability, tumour location and co-morbidities, the therapeutic mainstay for the first- and second-line treatment of the majority of patients consists of 5-fluorouracil (5-FU)-based chemo-immunotherapy. By exchanging the chemotherapeutic combination partner from oxaliplatin to irinotecan or vice versa, plus the additive anti-epidermal growth factor receptor/anti-vascular endothelial growth factor antibody, the negative factor of non-response to first-line therapy could not be overcome by second-line treatment in this study population. These findings must be confirmed in larger studies, but indicate the need for novel treatment options, especially for patients not responding to first-line 5-FU-based chemo-immunotherapy.