dMMR Patients Research Articles

Intraoperative rapid immunohistochemistry of microsatellite instability using non-contact alternating current electric field mixing.

Tumors caused by failure of the DNA-mismatch repair system generally show microsatellite instability (MSI). High-frequency MSI cancers have been shown to be susceptible to immuno-oncology therapies. The aim of this study was to evaluate the clinical reliability of a rapid immunohistochemistry (IHC) technique for intraoperatively assessing molecular status through detection of tumoral deficiencies in the expression of mismatch repair proteins (dMMR; MLH1, MSH2, MSH6, and PMS2). The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within a minimum of 13min during surgery. Sixteen formalin-fixed paraffin-embedded (FFPE) tumor samples from 3 dMMR patients with Lynch syndrome and 6 FFPE samples from 6 dMMR-cancer patients were collected to establish an IHC protocol for MMR proteins. Next, 26 surgical patients treated and whose MSI status was determined using PCR-based tests were retrospectively analyzed. The concordance of dMMR diagnoses for thoracic tumors between the conventional (frozen section (FS)- and FFPE-IHCs) and rapid AC-mixing IHC with FSs were compared. A rapid IHC protocol using primary antibodies against four MMR proteins (mixed 5-10min) was established (entire process within 40min). The concordance rate for MMR-IHC between the conventional and rapid IHC was 100%. dMMR diagnoses including an MSI-high pulmonary sarcoma patient entirely matched between FS- and FFPE-IHC. Rapid MMR-IHC could potentially serve as a clinical tool for intraoperative determination of tumor MSI/dMMR status. AC-mixing technology will contribute to improving pathological diagnostic capability through the development of an original and innovative rapid IHC.

Ipilimumab with nivolumab in molecularly selected patients with castration-resistant prostate cancer: primary analysis of the phase II INSPIRE trial

Metastatic castration-resistant prostate cancer (mCRPC) typically exhibits resistance to immune checkpoint inhibitors (ICIs). However, a subset of mCRPC patients displays a more immunogenic profile. This study examines efficacy and safety of dual ICI therapy in molecularly selected mCRPC. This single-arm, phase II trial included 69 molecularly selected mCRPC patients with mismatch repair deficiency (dMMR), non-synonymous tumour mutational burden ≥7.1 muts/Mb (hTMB), a BRCA2 mutation (BRCAm), or biallelic CDK12 inactivation (CDK12i). Efficacy was assessed in ICI-naïve patients (cohort A) with RECIST 1.1 (A1) and Prostate Cancer Working Group 3 (A2) measurable disease. Safety was evaluated in cohorts A and B (prior ICI monotherapy). Treatment included nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for four cycles, followed by nivolumab 480 mg every 4 weeks for up to 1 year. The primary endpoint was disease control rate beyond 6 months (DCR > 6), aiming to surpass a DCR > 6 of 22%. Patients initiated treatment between January 2021 and February 2024. Cohort A included 65 patients. Of these, 21 had dMMR (32%), 8 had hTMB (12%), 20 had BRCAm (31%), and 16 had CDK12i (25%). DCR > 6 was achieved in 38% of patients [95% confidence interval (CI) 27% to 51%], and was highest in dMMR (81%), followed by hTMB (25%), CDK12i (19%), and BRCAm (15%). Objective response rate in cohort A was 38% (95% CI 22% to 55%) and 47% (95% CI 34% to 60%) exhibited a 50% decline in prostate-specific antigen levels. Median progression-free survival (PFS) was 4.0 months (95% CI 3.5-12.0 months) in cohort A, and 32.7 months (95% CI 21.8 months-not reached) in dMMR patients. Treatment-related adverse events (TRAEs) led to permanent discontinuation in 14 of 69 patients (20%). Grade ≥3 TRAEs occurred in 48% of patients, with diarrhoea and elevated transaminases each in 10%. There was one treatment-related death due to a bowel perforation and a second following euthanasia after grade 4 toxicity. This trial of dual ICIs in molecularly selected mCRPC met its primary endpoint, showing DCR > 6 in 38% of patients. Dual ICIs exhibited modest responses in the hTMB, BRCAm, and CDK12i subgroups, but demonstrated exceptional efficacy in dMMR.

The Clinicopathological Features and Prognoses of Lower Uterine Segment Cancer: A Retrospective, Single-Center Cohort Study.

This study used single-center data to analyze the clinicopathological features of site-specific endometrial cancer. Patients with endometrial carcinoma who had undergone surgery at Peking Union Medical College Hospital, China, between March 2016 and January 2022 were enrolled. Clinical information and pathological characteristics were summarized, and microsatellite status was analyzed using the immunohistochemical method. Patient prognoses were measured in terms of the rates of overall survival and progression-free survival. The mean patient age was 49 years (ranging: from 25 to 76 years old), and there was no difference in clinicopathological features between endometrioid and type II endometrial carcinoma in LUSC. The ER and PR expression ratios were 80.4% and 64.3%, respectively, in this LUSC cohort, and the MMR deficiency ratio was 33.9%, including 39.6% in endometrioid carcinoma and 15.4% in type II endometrial carcinoma. Combined MSH2&MSH6 loss was more common than combined MLH1&PMS2 being unexpressed (16.1% vs 12.5%), and dMMR patients differed significantly from the pMMR group in terms of vascular invasion (P=0.003). The combination of chemotherapy and radiotherapy did not provide a statistically significant improvement in prognosis compared to chemotherapy alone. The results of this study showed that LUSC patients tended to be younger and their tumors had less expression of hormone markers. The biological behavior of both endometrioid cancer and type II EC may be similar when EC occurs in this area. Furthermore, this type of tumor also showed a higher incidence of vascular invasion, and the combination of chemotherapy and radiotherapy did not provide significant improvement. Thus, successful treatment of LUSC tumors requires aggressive surgical intervention and a more effective postoperative treatment approach.

The relationship between mismatch repair (MMR) proteins status and the response to conventional neoadjuvant therapy in colorectal cancer (CRC).

e15627 Background: MMR proteins status is not routinely detected in CRC patients. Neoadjuvant use of immune checkpoint inhibitors (ICIs) in deficient mismatch repair (dMMR) CRC patients can achieve a pathological complete response (pCR) rate of 60-100%. Conversely, dMMR/MSI-H patients may exhibit a poor response to conventional neoadjuvant therapy, although supporting evidence is limited. Methods: We retrospectively collected clinical data from patients who underwent neoadjuvant chemoradiotherapy or chemotherapy at Fudan University Shanghai Cancer Center from 2008 to 2021, excluding those who received neoadjuvant ICIs. MMR proteins were detected using immunohistochemistry on surgical samples or preoperative colonoscopy biopsy samples, and some patients underwent genetic testing to evaluate their microsatellite status. This study included M0 CRC patients with complete tumor regression grading (TRG) assessment and MMR/MSI status. Responses were assessed using TRG evaluation (AJCC-TRG system) on the primary tumor. Results: Among 1005 patients, the median age was 57 years (range: 19-95), with 643 males (64.0%) and 362 females (36.0%). Seventy-two (7.2%) had right colon cancer, 80 (8.0%) had left colon cancer, and 853 (84.9%) had rectal cancer. Fifty-five (5.5%) had dMMR, and 950 (94.5%) had proficient mismatch repair (pMMR). In dMMR patients, defective proteins included hMLH1 and PMS2 combined in 22 patients, hMSH6 in 14 patients, PMS2 in 9 patients, hMSH6 and hMSH2 combined in 6 patients, hMLH1 in 2 patients, hMLH1 and hMSH6 combined in 1 patient, and hMSH6, PMS2, and hMSH2 combined in 1 patient. Compared to pMMR patients, dMMR patients showed either no response or poor response to conventional neoadjuvant therapy, with no patients exhibiting TRG = 0/1. One hundred and eleven (11.7%) pMMR patients showed a good response (TRG = 0/1). There was no statistically significant difference in overall survival between the two groups of patients (HR, 1.547; 95% CI: 0.9221-2.596; P = 0.172). Conclusions: Although our study is retrospective and some patients with pCR lacked MMR expression information, we can still conclude that dMMR patients have a poor response to conventional neoadjuvant therapy, and neoadjuvant ICIs treatment may be a better choice for dMMR patients. We recommend routine immunohistochemistry of MMR proteins in preoperative colonoscopies to guide the development of neoadjuvant strategies. [Table: see text]

Factors associated with the efficacy of first-line nivolumab plus chemotherapy in advanced gastric cancer patients with deficient mismatch repair.

We aimed to investigate clinicopathologic factors leading to different clinical outcomes in patients with deficient mismatch repair protein (d-MMR) gastric cancer (GC) treated with nivolumab plus chemotherapy (nivolumab chemotherapy). This retrospective study included 28 patients with d-MMR advanced GC treated with first-line nivolumab chemotherapy. As a control group, 68 treated with first-line chemotherapy alone were included. Clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and PD-L1 combined positive score (CPS), were analyzed with regards to the efficacy outcomes. Progression-free survival (PFS) was longer (median PFS; not reached [NR] vs. 5.2months, hazard ratio [HR] 0.28, P < 0.001), and overall survival (OS) tended to be longer (median OS; NR vs. 17.9months, HR 0.43, P = 0.057) in patients treated with nivolumab chemotherapy than those treated with chemotherapy. The PFS benefit of nivolumab chemotherapy over chemotherapy was pronounced in the subgroup with a lower NLR (< 3.80 [median NLR]) (HR 0.10), whereas it was less prominent in patients with a high NLR (≥ 3.80) (HR 0.58). Among patients treated with nivolumab chemotherapy, PFS was worse in patients with a higher NLR (≥ 3.80) than in those with a lower NLR (< 3.80), and survival outcomes were similar between those with PD-L1 CPS ≥ 5 and < 5. Nivolumab chemotherapy was associated with better efficacy outcomes than chemotherapy alone among patients with d-MMR GC, but survival outcomes were poor even with nivolumab chemotherapy for those with a high NLR. Survival outcomes were not different according to PD-L1 CPS among d-MMR patients treated with nivolumab chemotherapy.

Old Issues and New Perspectives on Endometrial Cancer Therapy: How Molecular Characteristics Are Changing the Therapeutic Pathway.

The Cancer Genome Atlas (TCGA) has radically changed the history of endometrial cancer by outlining a new classification, based on its molecular characteristics. In the field of oncology, we are approaching the new era of molecular biology, particularly regarding endometrial cancer, with the increasing importance of targeted therapy. This paper is a review of phase III randomized controlled trials published in English between January 2019 and December 2023, comparing drugs of interest with standard adjuvant treatment and molecular subtypes in endometrial cancer. The use of immunotherapy alone or in combination with chemotherapy as therapy in patients with recurrent or advanced primary or metastatic endometrial cancer significantly improves the prognosis of these patients. The results show greater efficacy of all proposed treatments for mismatch repair deficiency (dMMR/MSI-H) patients compared to mismatch repair proficiency (pMMR) patients. Progression-free survival (PFS) and overall survival (OS) are better in dMMR patients in all studies analysed. Immunotherapy has the potential to revolutionize the gynaecological cancer treatment landscape, offering a new pathway and new hope for endometrial cancer patients, improving their outcomes in the future. Given the exciting results obtained in dMMR/MSI-H patients, MMR status should be investigated in every patient with advanced endometrial cancer at the time of diagnosis.

Prognosis and immunotherapy efficacy in dMMR&MSS colorectal cancer patients and an MSI status predicting model.

The inconsistency between mismatch repair (MMR) protein immunohistochemistry (IHC) and microsatellite instability PCR (MSI-PCR) methods has been widely reported. We aim to investigate the prognosis and the effect of immunotherapy in dMMR by IHC but MSS by MSI-PCR (dMMR&MSS) colorectal cancer (CRC) patients. A microsatellite instability (MSI) predicting model was established to help find dMMR&MSS patients. MMR and MSI states were detected by the IHC and MSI-PCR in 1622 CRC patients (ZS6Y-1 cohort). Logistic regression analysis was used to screen clinical features to construct an MSI-predicting nomogram. We propose a new nomogram-based assay to find patients with dMMR&MSS, in which the MSI-PCR assay only detects dMMR patients with MSS predictive results. We applied the new strategy to a random cohort of 248 CRC patients (ZS6Y-2 cohort). The consistency of MMR IHC and MSI-PCR in the ZS6Y-1 cohort was 95.7% (1553/1622). Both pMMR&MSS and dMMR&MSS groups experienced significantly shorter overall survival (OS) than those in dMMR by IHC and MSI-H by MSI-PCR (dMMR&MSI-H) group (hazard ratio [HR] = 2.429, 95% confidence interval [CI]: 1.89-3.116, p < .01; HR = 21.96, 95% CI: 7.24-66.61, p < .01). The dMMR&MSS group experienced shorter OS than the pMMR&MSS group, but the difference did not reach significance (log rank test, p = .0686). In the immunotherapy group, the progression-free survival of dMMR&MSS patients was significantly shorter than that of dMMR&MSI-H patients (HR = 13.83, 95% CI: 1.508-126.8, p < .05). The ZS6Y-MSI-Pre nomogram (C-index = 0.816, 95% CI: 0.792-0.841, already online) found 66% (2/3) dMMR&MSS patients in the ZS6Y-2 cohort. There are significant differences in OS and immunotherapy effect between dMMR&MSI-H and dMMR&MSS patients. Our prediction model provides an economical way to screen dMMR&MSS patients.

Unveiling prognosis and traits of dMMR/MSI-H gastric and colorectal cancer after curative surgery: A large-scale, multi-center, retrospective study in China.

729 Background: This study conducted a large-scale multi-center analysis using real-world data from China to comprehensively investigate the clinical characteristics and prognosis of patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) gastric and colorectal cancer undergoing curative surgery. Additionally, we analyzed postoperative adjuvant treatment effects and recurrence/metastasis patterns. Methods: We retrospectively analyzed 1800 gastric and colorectal cancer patients with dMMR and/or MSI-H confirmed by immunohistochemistry (IHC) and PCR after radical resection from 19 hospitals in China. We compared clinical characteristics among positive patients identified by both testing methods and evaluated their relationship with disease-free survival (DFS) and overall survival (OS). Results: The cohort included 1702 dMMR patients (regardless of MSI status), 667 MSI-H patients (regardless of MMR status), and 46 cases with inconsistent MMR and MSI statuses. No significant differences in overall clinical-pathological characteristics were observed between IHC-dMMR and PCR-MSI-H patients, highlighting the clinical utility of both approaches. Predominantly, MMR protein defects involved MLH1/PMS2 loss (&gt;70%). We found a positive correlation between lymph node metastasis and MLH1/PMS2 protein deficiency (P&lt;0.01) and an inverse correlation trend in cases of MSH2/MSH6 deficiency (P&lt;0.1). Additionally, poorer prognosis was linked to alcohol consumption (DFS, P&lt;0.001), lymph node metastasis (DFS, P&lt;0.001; OS, P&lt;0.001), vascular cancer emboli (OS, P&lt;0.001), and neural invasion (OS, P&lt;0.001). In the dMMR/MSI-H colorectal subgroup, colon cancer patients exhibited superior DFS compared to rectal cancer (P=0.025) and improved DFS with right colon tumors (P=0.01). Patients with MLH2/MSH6 deficiency showed a trend towards better survival, even within the subgroup receiving adjuvant chemotherapy (P=0.067), compared to MLH1/PMS2 and other deficiency disorders. Notably, patients with dMMR and/or MSI-H exhibited a shorter DFS following adjuvant therapy (P&lt;0.001), while OS did not achieve a significant difference, potentially due to the insufficient follow-up duration. Conclusions: This study provides valuable insights into the correlation between MSI-H/dMMR status and clinical characteristics in Chinese patients with gastric and colorectal cancer after radical resection. The findings also illuminate prognostic factors impacting DFS and OS, as well as the intricate relationship between MMR/MSI status and tumor metastasis patterns. It highlights the feasibility of utilizing both MMR-IHC and MSI-PCR for patient selection and enhances our understanding of the clinical management and outcomes of patients with dMMR/MSI-H gastric and colorectal cancer.

Streamlining the diagnostic pathway for Lynch syndrome in colorectal cancer patients: a 10-year experience in a single Italian Cancer Center.

Universal screening of colorectal cancer (CRC) patients for Lynch syndrome (LS) through MisMatch Repair (MMR) testing is recommended. BRAF V600E mutation and/or MLH1 promoter methylation (Reflex Testing, RefT)generally rule out LS in MLH1-deficient (dMLH1) patients. We estimated the impact of RefTon genetic counseling (GC) and on the diagnostic yield of genetic testing (GT). Overall, 3199 CRC patients were referred to our center between 2011 and 2021. Patients referred until January 2019 (n=2536) underwent universal MMR testing and were termed 'Cohort A'; among patients after February 2019 (n=663), 'Cohort B', RefT was also performed in dMLH1 patients. Overall, 401/3199 patients (12.5%) were MMR-deficient (dMMR); 312 (77.8%) in cohort A and 89 (22.2%) inB; 346/401 were dMLH1 (86.3%), 262/312 (83.9%) in cohort A and 84/89 (94.3%) in B. In Cohort A, 91/312 (29.1%) dMMR patients were referred to GC, 69/91 (75.8%) were in the dMLH1 group; 57/69 (82.6%) dMLH1 patients underwent GT and 1/57 (1.7%) had LS. In Cohort B, 3/84 dMLH1 patients did not undergo BRAF testing. Three BRAF wt and not hypermethylated of the remaining 81 dMLH1 patients were referred to GC and GT, and one had LS. This diagnostic pathway reduced GC referrals by 96% (78/81) in Cohort B and increased the diagnostic yield of GT by about 20 times. Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.

Identification of Comprehensive Biomarkers in Patients With Mismatch Repair-Deficient Colon Adenocarcinoma Based on Parallel Multiomics

Immunocheckpoint inhibitors have shown impressive efficacy in patients with colon cancer and other types of solid tumor that are mismatch repair-deficient (dMMR). Currently, PCR-capillary electrophoresis is one of the mainstream detection methods for dMMR, but its accuracy is still limited by germline mismatch repair (MMR) mutations, the functional redundancy of the MMR system, and abnormal methylation of MutL Homolog 1 promoter. Therefore, this study aimed to develop new biomarkers for dMMR based on artificial intelligence (AI) and pathologic images, which may help to improve the detection accuracy. To screen for the differential expression genes (DEGs) in dMMR patients and validate their diagnostic and prognostic efficiency, we used the expression profile data from the Cancer Genome Atlas (TCGA). The results showed that the expression of Immunoglobulin Lambda Joining 3 in dMMR patients was significantly downregulated and negatively correlated with the prognosis. Meanwhile, our diagnostic models based on pathologic image features showed good performance with area under the curves (AUCs) of 0.73, 0.86, and 0.81 in the training, test, and external validation sets (Jiangsu Traditional Chinese Medicine Hospital cohort). Based on gene expression and pathologic characteristics, we developed an effective prognosis model for dMMR patients through multiple Cox regression analysis (with AUC values of 0.88, 0.89, and 0.88 at 1-, 3-, and 5-year intervals, respectively). In conclusion, our results showed that Immunoglobulin Lambda Joining 3 and nucleus shape–related parameters (such as nuclear texture, nuclear eccentricity, nuclear size, and nuclear pixel intensity) were independent diagnostic and prognostic factors, suggesting that they could be used as new biomarkers for dMMR patients.

DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial.

The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. The PRODIGY trial showed the survival benefit of adding preoperative docetaxel, oxaliplatin, and S-1 (DOS) to surgery plus postoperative S-1 for LAGC patients. In this sub-analysis, we evaluated the benefit of preoperative DOS according to MMR status. Among patients enrolled in the PRODIGY trial treated with either preoperative DOS followed by surgery and postoperative S-1 (CSC arm), or surgery and postoperative S-1 (SC arm) at Asan Medical Center (n = 249), those in the full analysis set with available tissue to assess MMR status were included in the present analysis. A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included (median age, 58years [range, 27-75]), and 21 patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had D-MMR tumors. Progression-free survival and overall survival tended to be superior in the CSC arm than in the SC arm among D-MMR patients (HR 0.48 [95% CI 0.09-2.50]; log-rank P = 0.37 and HR 0.55 [95% CI 0.11-2.86]; log-rank P = 0.46, respectively), as well as among proficient MMR (P-MMR) patients (HR 0.68 [95% CI 0.46-1.03]; log-rank P = 0.07 and HR 0.75 [95% CI 0.49-1.14]; log-rank P = 0.17, respectively). Preoperative DOS followed by surgery and postoperative S-1 may be considered a treatment option for LAGC patients regardless of MMR status.

Mismatch Repair Deficiency Is a Prognostic Factor Predicting Good Survival of Opisthorchis viverrini-Associated Cholangiocarcinoma at Early Cancer Stage.

The mismatch repair (MMR) system prevents DNA mutation; therefore, deficient MMR protein (dMMR) expression causes genetic alterations and microsatellite instability (MSI). dMMR is correlated with a good outcome and treatment response in various cancers; however, the situation remains ambiguous in cholangiocarcinoma (CCA). This study aims to evaluate the prevalence of dMMR and investigate the correlation with clinicopathological features and the survival of CCA patients after resection. Serum and tissues were collected from CCA patients who underwent resection from January 2005 to December 2017. Serum OV IgG was examined using ELISA. The expression of MMR proteins MLH1, MSH2, MSH6 and PMS2 was investigated by immunohistochemistry; subsequently, MMR assessment was evaluated as either proficient or as deficient by pathologists. The clinicopathological features and MMR status were compared using the Chi-square test. Univariate and multivariate analyses were conducted to identify prognostic factors. Among the 102 CCA patients, dMMR was detected in 22.5%. Survival analysis revealed that dMMR patients had better survival than pMMR (HR = 0.50, p = 0.008). In multivariate analysis, dMMR was an independent factor for a good prognosis in CCA patients (HR = 0.58, p = 0.041), especially at an early stage (HR = 0.18, p = 0.027). Moreover, subgroup analysis showed dMMR patients who received adjuvant chemotherapy had better survival than surgery alone (HR = 0.28, p = 0.012). This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.

Mismatch Repair Status is an Effective Prognostic Factor for Early-Stage Endometrial Carcinoma

This study is to evaluate the impact of mismatch repair (MMR) status on prognosis among patients with stage I to II (FIGO 2009) endometrial carcinoma (EC) treated with hysterectomy and adjuvant RT. Between Oct. 2017 and Dec. 2020, patients with stage I to II (FIGO 2009) EC who had undergone hysterectomy followed by adjuvant RT in our institution were retrospectively reviewed. Clinical characteristics were compared between patients with proficient and deficient mismatch repair (pMMR and dMMR) using Pearson Chi-Square test for categorical variables. Kaplan-Meier method and log-rank test were used to compared overall survival (OS), disease-free survival (DFS), local-regional recurrence free survival (LRFS) and distant metastasis free survival (DMFS). Statistically significant difference was set as p<0.05. Totally 276 stage I to II EC patients with known MMR status were included in this study. Among them, 211 patients were classified as pMMR while 65 patients were classified as dMMR. When compared to pMMR, patients with dMMR were more likely to have grade 3 and non-endometrioid type(37.8% vs. 20.8%, p = 0.014), lympho-vascular invasion (36.7% vs. 16.3%, p = 0.000), young age (<60) (28.6% vs. 17.2%, p = 0.027), HIR to HR classification(30.9% vs. 16.1%, p = 0.004). Of all the 276 patients, the median follow-up time was 31 months. Two-year DMFS was superior for pMMR compared to dMMR patients (96.3% vs. 95.0%, p = 0.048). Two-year DFS tended to be better for pMMR than dMMR patients with survival curves not crossed over each other (93.0% vs. 86.8%, p = 0.074). Two-year OS (98.9% vs. 98.4%, p = 0.716) and LRFS (96.3% vs. 95.0%, p = 0.815) were not different between pMMR/dMMR patients. For HIR to HR group, we reached the similar conclusion while for LR to IR group, survival statistics were not different between pMMR/dMMR patients. As to failure pattern, dMMR were more likely to have distant failure while local and regional failure were not different between the two groups. For stage I to II EC, patients with dMMR have poorer DMFS and DFS compared to pMMR patients especially in HIR to HR risk classification. The combination of MMR status and other clinical and pathological factors may establish a new prognostic model and form a new risk stratification system.

Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

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.

Efficacy and Safety of PD-1/PD-L1 Inhibitor as Single-Agent Immunotherapy in Endometrial Cancer: A Systematic Review and Meta-Analysis.

The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway plays a crucial role in the immune escape mechanism and growth of cancer cells in endometrial cancer (EC). Clinical trials investigating PD-1/PD-L1 inhibitor have shown promising results in other cancers, but their efficacy in EC still remains uncertain. Therefore, this meta-analysis aims to provide an updated and robust analysis of the effectiveness and safety of PD-1/PDL1 inhibitor as single-agent immunotherapy in EC, focusing on the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). This meta-analysis utilized STATA version 17 and RevMan version 5.4 software to pool the results of relevant studies. Five studies conducted between 2017 and 2022, comprising a total of 480 EC patients enrolled for PD-1/PD-L1 inhibitor immunotherapy met the inclusion criteria. The pooled proportion of EC patients who achieved ORR through PD-1/PD-L1 inhibitor treatment was 26.0% (95% CI: 16.0-36.0%; p < 0.05). Subgroup analysis based on mismatch repair (MMR) status showed an ORR of 44.0% (95% CI: 38.0-50.0%; p = 0.32) for the deficient mismatch repair (dMMR) group and 8.0% (95% CI: 0.0-16.0%; p = 0.07) for the proficient mismatch repair (pMMR) group. Pooled proportion analysis by DCR demonstrated an odds ratio (OR) of 41.0% (95% CI: 36.0-46.0%, p = 0.83) for patients undergoing PD-1/PD-L1 inhibitor treatment. Subgroup analysis based on MMR status revealed DCR of 54.0% (95% CI: 47.0-62.0%; p = 0.83) for the dMMR group, and 31.0% (95% CI: 25.0-39.0%; p = 0.14) for the pMMR group. The efficacy of PD-1/PD-L1 inhibitors was significantly higher in the dMMR group compared to the pMMR group, in terms of both ORR (OR = 6.30; 95% CI = 3.60-11.03; p < 0.05) and DCR (OR = 2.57; 95% CI = 1.66-3.99; p < 0.05). In terms of safety issues, the pooled proportion of patients experiencing at least one adverse event was 69.0% (95% CI: 65.0-73.0%; p > 0.05), with grade three or higher AEs occurring in 16.0% of cases (95% CI: 12.0-19.0%; p > 0.05). Based on the subgroup analysis of MMR status, PD-1/PD-L1 inhibitor immunotherapy showed significantly better efficacy among dMMR patients. These findings suggest that patients with dMMR status may be more suitable for this treatment approach. However, further research on PD-1/PD-L1 inhibitor immunotherapy strategies is needed to fully explore their potential and improve treatment outcomes in EC.

Mismatch Repair system protein deficiency as a factor of resistance to chemo-radiotherapy treatment in patients with locally advanced rectal adenocarcinoma and its influence on disease-free survival.

3615 Background: Available data on Mismatch Repair system deficit and microsatellite instability are conflicting and are generally derived from a small number of patients due to the rarity of this condition in rectal cancer. Our study aimed to evaluate the frequency and therapeutic implications of Mismatch Repair proteins (MMR) status in patients with locally advanced rectal cancer (LARC). Methods: We retrospectively collected data from 318 patients affected by LARC adenocarcinoma (cT3-4 +/- N1-2) treated at the Medical Oncology Unit of the University Hospital of Cagliari, Italy, the Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and at the Medical Oncology Unit, AOU Ospedali Riuniti, Ancona. Italy. All patients included in the study underwent neoadjuvant concurrent capecitabine and long-course radiotherapy (RT) (total dose of Gy 50.4), afterwards a total mesorectal excision (TME) was performed. MMR expression was evaluated through immunohistochemistry. The primary objective was major TRG (0-1 Ryan’s score) while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). Results: 160 patients (148 pMMR and 12 dMMR) were included in exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in validation cohort. A major TRG has been shown in 64/148 (42,6%) and 63/146 (43,1%) patients with pMMR in exploratory cohort and validation cohort, respectively; while no major TRG have been shown in dMMR patients in exploratory cohort nor in validation cohort. Both exploratory and validation cohorts showed a statistically significant higher median DFS in pMMR patients compared to dMMR ones: NR vs 14 months in exploratory cohort ( p = 0,003) and NR vs 17 months in validation cohort ( p = 0,02). Conclusions: Our retrospective study indicated an association between dMMR and poor or no response to preoperative chemoradiotherapy. These results are consistent with the role of MMR as a predictor of poor-response to chemoradiotherapy and represent a hypothesis-generating study for the selection of these patients for immunotherapy in the neoadjuvant setting, in which the available data are immature.

Universal screening for Lynch syndrome in operated colorectal cancer by immunohistochemistry: a cohort of patients in Liaoning province, China.

Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome worldwide. Due to the decreasing family size in Liaoning province. The Bethesda and Amsterdam II criteria have lower sensitivity and specificity and are not suitable for the local population. Immunohistochemistry screening for mutations in DNA mismatch repair (MMR) in newly diagnosed colorectal cancer can improve the detection rate of LS. All newly diagnosed colorectal cancer patients who underwent surgery between January 2018 and June 2020 at Cancer Hospital of China Medical University and Shengjing Hospital of China Medical University from Liaoning China were included retrospectively, and the ratio of universal LS screening by immunohistochemistry, MMR protein deficiency (dMMR) ratio, MLH1 loss, MSH2 loss, MSH6 loss, and PMS2 loss was analyzed. The clinicopathological characteristics of patients with pMMR and dMMR were analyzed. A total of 7019 colorectal cancer patients underwent surgery and 4802 (68.41%) patients were screened by immunohistochemistry for MMR, 258 (5.37%) cases were reported to have a loss of MMR expression. In the dMMR group, a higher number of patients were under 50 years old, more tumors were located at the right colon, less patients have lymph node metastasis, more tumors were stage II, and histological types of mucinous carcinoma or signet ring carcinoma were more common, compared with the pMMR group. Only 2.71% dMMR patients meet Amsterdam criteria II, 2.71% of patients meet Revised Bethesda guidelines, and 17.83% meet Chinese LS criteria. Twenty-five dMMR patients were confirmed by next-generation sequencing and five families were confirmed as Lynch family. These data imply that universal screening for LS by immunohistochemistry may be effective in Liaoning province.

DNA ploidy and stroma predicted the risk of recurrence in low-risk stage III colorectal cancer.

For clinically low-risk stage III colorectal cancer, the decision on cycles of adjuvant chemotherapy after surgery is disputed. The present study investigates the use of additional biomarkers of ploidy and stroma-ratio(PS) to stratify patients with low-risk stage III colorectal cancer, providing a basis for individualized treatment in the future. This study retrospectively enrolled 198 patients with clinical-low-risk stage III colorectal cancer (T1-3N1M0) and analyzed the DNA ploidy and stroma ratio of FFPE tumor tissues. The patients were divided into PS-low-risk group (Diploidy or Low-stroma) and PS-high-risk group (Non-diploid and High-stroma). For survival analyses, Kaplan-Meier and Cox regression models were used. The results showed that the 5-year DFS of the PS-high-risk group was significantly lower than that in the PS-low-risk group (78.6 vs. 91.2%, HR = 2.606 [95% CI: 1.011-6.717], P = 0.039). Besides, in the PS-low-risk group, the 5year OS (98.2 vs. 86.7%, P = 0.022; HR = 5.762 [95% CI: 1.281-25.920]) and DFS (95.6, vs 79.9%, P = 0.019; HR = 3.7 [95% CI: 1.24-11.04]) of patients received adjuvant chemotherapy for > 3months were significantly higher than those received adjuvant chemotherapy for < 3months. We also found that the PS could stratify the prognosis of patients with dMMR tumors. The 5-year OS (96.3 vs 71.4%, P = 0.037) and DFS (92.6 vs 57.1%, P = 0.015) were higher in the PS-low-risk dMMR patients than those in the PS-high-risk dMMR patients. In this study, we found that PS can predict the prognosis of patients with stage III low-risk CRC. Besides, it may guide the decision on postoperative adjuvant chemotherapy.

597P Endometrial carcinoma and mismatch repair deficiency: Clinical association and universal screening for Lynch syndrome

Endometrial carcinoma (EC) is characterised by a high rate of DNA Mismatch Repair deficiency (dMMR). Testing for dMMR might have implications for EC prognosis and is part of Universal Screening (US) for Lynch syndrome (LS) diagnosis. However, this is not widely implemented yet, and LS is still underdiagnosed. For these reasons, we aimed to evaluate dMMR prevalence, its association with clinicopathological variables and its role for LS diagnosis for EC patients. This is a monocentric retrospective study on 368 consecutive EC cases (stages I-IV). From 2013 to 2020 they underwent surgery and immunohistochemistry (IHC) analysis for dMMR. We collected age, date of surgery, tumor histotype, grading, FIGO stage at diagnosis, lymphovascular invasion (LVSI), and survival status. We then assessed the proportion of dMMR patients on the entire cohort. Major outcome were OS and RFS in the dMMR patients compared to MMR proficient cases (pMMR). Among the dMMR cases, we reported those who underwent genetic testing and had LS. dMMR was found in 91/368 EC patients (25%). 84 had endometroid histotype, 7 other histotypes (92% vs 8% p= 0.010), 50 had G2 nuclear grading vs 19 G1 and 22 G3 (55% vs 21% vs 24%; p=0.005). As compared to pMMR at a 4-year follow-up an unfavorable trend in OS and RFS was observed for patients with dMMR (4 y OS 82% vs 74% p=0.115, 4 y RFS 70% vs 54% p-value=0.153). In multivariate analysis, age (p<0.001), histotype and grade (p<0.001), stage (p=0.003) and LVSI (p=0.010) were independently associated to OS. dMMR only showed a trend in worse OS (p=0.10). Among the 91 patients with dMMR, only 5 underwent genetic counseling (GC)(6.6%): LS was diagnosed in 1 patient (20%) with loss of MSH2/MSH6 expression. This is the largest Italian cohort of US for LS. dMMR prevalence was 25%, mainly associated with endometrioid type, G2 grading and a worse 4 y OS, as compared to pMMR cases, consistent with the literature. Unfortunately, oncologists' compliance with US for LS is still very poor, with a 6.6% GC referral. This should be implemented according to international guidelines, to increase LS diagnosis, reduce mortality in relatives and incidence of second cancers in survived patients.