628P Testing and referral patterns for germline testing of mismatch repair deficient (dMMR) endometrial cancer patients

Mismatch repair-deficient (dMMR) and microsatellite instability-high (MSI-H) colorectal cancers demonstrate exceptional responsiveness to immune checkpoint inhibitors; however, evidence for the efficacy of neoadjuvant immunotherapy remains limited. This review consolidates all prospective trials evaluating neoadjuvant immune checkpoint blockade in non-metastatic dMMR/MSI-H colorectal cancer. This systematic review followed the PRISMA guidelines and was registered with the PROSPERO database (CRD420251074066). A comprehensive search of PubMed, Embase, CENTRAL, and ClinicalTrials.gov was conducted until May 2025. Prospective interventional studies involving neoadjuvant immunotherapy in adults with stage II-III dMMR/MSI-H colorectal adenocarcinoma were included in this review. The primary outcomes were pathological complete response (pCR), major pathological response (MPR), and clinical complete response (cCR). The risk of bias was assessed using the Risk of Bias in Non-randomized Studies of Interventions tool. Eight prospective phase 2 trials encompassing 352 patients with stage II-III dMMR/MSI-H colorectal cancer were included. The pCR rates ranged from 41 to 90%, with the highest responses in patients with colon cancer receiving dual checkpoint blockade (nivolumab plus ipilimumab: 90% pCR, 95% MPR). In rectal cancer, 100% of patients receiving dostarlimab (n = 16) and 46% of those in the camrelizumab plus apatinib group (n = 24/52) achieved cCR with organ preservation. MPR was observed in 80-95% of the studies. Grade ≥ 3 adverse events occurred in 3-34% of patients, with no treatment-related deaths reported. At the median follow-up (8-26months), disease-free survival exceeded 98% in most cohorts. Watch-and-wait strategies are durable, with no local regrowth in patients with complete clinical response (cCR). Neoadjuvant immune checkpoint inhibition demonstrates high pathological and clinical response rates in dMMR/MSI-H colorectal cancer, with organ preservation achievable in selected rectal cancer patients. Neoadjuvant immunotherapy may become an alternative to surgery as the primary treatment for MSI-H/dMMR colorectal cancer if long-term quality of life is superior and toxicity and cost are competitive with standard surgical approaches. However, longer follow-up, predictive biomarkers, and randomized comparisons with upfront surgery are required before its routine clinical use.

This study assesses the accuracy of radiographic clinical staging by computed tomography (CT) of mismatch repair-deficient (dMMR) colon cancer, given emerging data for neoadjuvant immune checkpoint inhibitors (ICIs). Patients with stage I-III colon cancer treated with upfront surgical resection were retrospectively reviewed using the electronic medical record from a single institution from 2012 to 2023. We performed a cohort study of dMMR tumors with a stage-matched control cohort of mismatch repair-proficient (pMMR) tumors. The primary end point was the accuracy of clinical stage using preoperative CT compared with pathologic stage for dMMR colon cancer. Statistical analysis was performed using R. We identified 78 patients with dMMR colon cancer. For dMMR tumors, T-stage clinical radiologic staging matched pathologic stage in 51% of cases and the nodal stage was accurately matched in 55% of cases. For stage I and IIA (low-risk) tumors, the overstaging rate on CT was 41% and for T4 or N+ (high-risk), the understaging rate was 25%. When comparing the dMMR and pMMR cohorts, pMMR nodal status was more likely to be understaged (P < .001). There was moderate to substantial interrater reliability for overall stage, T stage, and N staging between radiologists (kappa = 0.64, 0.60, and 0.63, respectively). Radiographic tumor and nodal staging for dMMR colon tumors is unreliable with high rates of overstaging low-risk tumors where neoadjuvant treatment may not be indicated. The low accuracy of clinical staging demonstrates clear limitations to make systemic therapy decisions. Additional diagnostic modalities for lymph node status may be necessary to accurately clinically stage patients before neoadjuvant ICIs in patients with locally advanced disease.

Colorectal cancer (CRC) is considered to be a heterogeneous disease with different molecular subtypes based on the expression status of mismatch repair (MMR) e.g. It is well known that tumours with mismatch repair deficiency (dMMR) are associated with better prognosis, as well as a more effective response to immunotherapy. In this case report, a patient is diagnosed with three new dMMR tumors in the colon 3,5 years after successful treatment with immunotherapy for metastatic CRC. Until now, retreatment with immunotherapy has not been described in the literature, and this case report describes the advantages and disadvantages from this perspective.

Immune checkpoint inhibitor nivolumab induces durable response in microsatellite instability-high andDNA damage repair-deficient metastatic castration-resistant prostate cancer.

Immune checkpoint inhibitors for dMMR/MSI localized rectal cancer: A systematic review of treatment strategies.

ABSTRACT Immune checkpoint inhibitors (ICIs) can re-active the immune response and induce a complete response in mismatch repair-deficient and microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, most CRCs exhibit proficient mismatch repair and microsatellite stable (pMMR/MSS) phenotypes with limited immunotherapy response because of sparse intratumoral CD8+ T-lymphocyte infiltration. Cellular senescence has been reported to involve immune cell infiltration through a senescence-associated secretory phenotype (SASP). However, the relationship between CRC cellular senescence and CD8+ T-lymphocyte infiltration remains unclear. Through integrated analysis of clinical cohorts and transcriptomic data across mismatch repair (MMR) subtypes, we identified cellular senescence as a hallmark of dMMR tumors, accompanied by elevated expression of KDM4A (lysine demethylase 4A). Clinically, KDM4Ahigh CDKN2A/p16high expression correlated with improved CRC patient prognosis. Mechanistically, KDM4A upregulated AGT (angiotensinogen) expression through H3K9me3 demethylation and promoted CRC cellular senescence. Meanwhile, KDM4A-driven senescence suppressed tumor growth and enhanced intratumoral CD8+ T-lymphocyte infiltration via enhancing SASP-associated secretion. Furthermore, AGT disrupted PHB1 (prohibitin 1)-mediated basal mitophagy, triggering cytoplasmic mitochondrial DNA (mtDNA) accumulation that activated CGAS-STING1 signaling and enhanced SASP secretion. Crucially, KDM4A overexpression potentiated anti-PDCD1/PD1 efficacy in MSI-H CRC and reversed therapy resistance in MSS CRC. Conclusively, we established a KDM4A-AGT-PHB1 (KAP) grade system that robustly predicts immunotherapy responsiveness in pMMR CRC patients. Abbreviation: AGT: angiotensinogen; BafA: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRC: colorectal cancer; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CHX: cycloheximide; Co-IP: co-immunoprecipitation; dMMR: deficient mismatch repair; EdU: 5-ethynyl-2’-deoxyuridine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; IL6: interleukin 6; IL8: interleukin 8; IHC: immunohistochemical; KDM4A: lysine demethylase 4A; mtDNA: mitochondrial DNA; MS: mass spectrometry; NFKB/NF-κB: nuclear factor kappa B; PHB1: prohibitin 1; PHB2: prohibitin 2; PINK1: PTEN induced kinase 1; pMMR: proficient mismatch repair; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; SASP: senescence-associated secretory phenotype; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TRIM21: tripartite motif containing 21; TUBB/beta-tubulin: tubulin beta class I.

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform nonbinding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses durvalumab (Imfinzi) 50 mg/mL, concentrate for IV infusion. Indication: Durvalumab in combination with carboplatin and paclitaxel for the first-line treatment of adults with primary advanced or recurrent mismatch repair deficient (dMMR) endometrial cancer who are candidates for systemic therapy, followed by durvalumab as monotherapy.

Proposal of a novel model for identifying complete response and nonoperative management in DMMR colon cancer following neoadjuvant immunotherapy: a retrospective cohort study.

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

Neoadjuvant treatment of IBI310 plus sintilimab in locally advanced MSI-H/dMMR colon cancer: A randomized phase 1b study.

BackgroundMismatch repair deficiency (dMMR) is observed in 12–15% of sporadic colon carcinomas. dMMR tumors have unique genetic characteristics, with mutation rates 10 to 100 times higher than those of tumors with intact mismatch repair functions. Approximately 15% of colon cancer cases exhibit mismatch repair deficiency. Moreover, the status of DNA mismatch repair deficiency holds prognostic and predictive significance in both non-metastatic and metastatic colon cancer. Therefore, we aim to comprehensively conduct a bibliometric analysis of research on mismatch repair-deficient colon cancer studies to identify research trends and potential future directions.MethodsA total of 1428 relevant articles from January 1, 1995 to July 1, 2024 were obtained from the Web of Science Core Collection. Knowledge graphs were analyzed and visualized using VOSviewer, CiteSpace, and Scimago Graphica software as bibliometric tools to extract or calculate evaluation metrics. Publications were categorized by country, institution, author, journal, highly cited article, and keyword. These variables were compared in terms of publication and academic impact, including citation count, citation impact, H-index, and journal impact factor.ResultsA total of 1428 publications related to mismatch repair-deficient colon cancer were retrieved from 351 countries and 6953 research institutions. The United States and China led the way in terms of the number of publications and impact; the most prolific institution was Sun Yat-sen University, followed by the Mayo Clinic; Cancers was the journal with the most publications, while Cancer Research was the most cited journal; André, Thierry was the most prolific author, and Thibodeau, Stephen N. had the highest H-index of all authors; the five most cutting-edge keywords identified were colorectal cancer, microsatellite instability, immunotherapy, Lynch syndrome, and mismatch repair. Among these, topics such as Nivolumab, PD-1 blockade, open label, mismatch repair deficient, immune checkpoint inhibitors, and metastatic colorectal cancer remain the hot topics in this field.ConclusionResearch on mismatch repair-deficient colon cancer is poised to enter a golden age in the coming years. This study not only provides insights into the directions and frontiers of mismatch repair-deficient colon cancer research but also highlights that the treatment of mismatch repair-deficient colon cancer benefits from a multidisciplinary approach. The comparison of different immune-assisted therapies will contribute to a more comprehensive understanding of the therapeutic landscape. Ultimately, large-scale and well-designed clinical trials are required to establish a recognized standard that can benefit more patients with mismatch repair-deficient colon cancer.

BackgroundColorectal cancer (CRC) is a common malignancy, with mismatch repair deficient (dMMR) CRC comprising approximately 15% of non-metastatic cases. dMMR tumors generate neoantigens making them highly responsive to immune checkpoint inhibitors, this became the first-line treatment for metastatic dMMR CRC. Aim of this study is to evaluate the efficacy of single-agent Pembrolizumab for patients with locally advanced unresectable dMMR intestinal cancers.MethodsWe retrospectively reviewed patients with locally advanced unresectable dMMR/MSI-H CRC or small intestinal adenocarcinoma (SIA) who received PD-1 inhibitors between January 2022 and December 2023 at 1 University Medical Center and 3 regional hospitals and analyzed the treatment efficacy and survival outcomes.ResultsResponse rate was 78% after at least one cycle of Pembrolizumab with conversion to resection in nearly 40%. Patients who underwent primary tumor resection had a two-year overall survival (OS) of 100%, whereas those without resection had significantly lower OS (42%), progression-free survival (PFS; 36%), and cancer-specific survival (CSS; 71%) at two years. In total, 22% of the patients discontinued the treatment due to toxicity.DiscussionAlthough the observed response rates of Pembrolizumab are high, there is still room for improvement. Dual immune checkpoint inhibitors might be needed for these patients to improve outcomes.Clinical Trial RegistrationA selection of patients included in this study were part of the ATAPEMBRO study, a single-centre, open label, phase 1-2 study (NCT04014530).

Neoadjuvant PD-1 blockade with toripalimab with or without celecoxib for patients with mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): long-term outcomes of a single-centre, parallel-group, non-comparative, randomised phase 2 trial

Real World Multi-centre UK Review of Nivolumab Monotherapy in Metastatic Endometrial Cancer With Mismatch Repair Deficiency During COVID-19.

A phase II study of induction PD-1 blockade (nivolumab) in patients with surgically completely resectable mismatch repair deficient endometrial cancer (NIVEC)

1116P A phase II study of induction PD-1 blockade (nivolumab) in patients with surgically completely resectable mismatch repair deficient endometrial cancer (NIVEC)

The DNA mismatch repair protein, MSH6 is a novel regulator of PD-L1 expression.

Real-world efficacy of immune checkpoint inhibitors in microsatellite unstable/mismatch repair-deficient biliary tract cancer: An AGEO study.

1149P Chromosome 1q gain defines a genomic subset of mismatch repair-deficient endometrial cancer deriving limited benefit from immune checkpoint blockade