Microsatellite Instability Status In Patients Research Articles

PAIP 2020: Microsatellite instability prediction in colorectal cancer.

Microsatellite instability (MSI) refers to alterations in the length of simple repetitive genomic sequences. MSI status serves as a prognostic and predictive factor in colorectal cancer. The MSI-high status is a good prognostic factor in stage II/III cancer, and predicts a lack of benefit to adjuvant fluorouracil chemotherapy in stage II cancer but a good response to immunotherapy in stage IV cancer. Therefore, determining MSI status in patients with colorectal cancer is important for identifying the appropriate treatment protocol. In the Pathology Artificial Intelligence Platform (PAIP) 2020 challenge, artificial intelligence researchers were invited to predict MSI status based on colorectal cancer slide images. Participants were required to perform two tasks. The primary task was to classify a given slide image as belonging to either the MSI-high or the microsatellite-stable group. The second task was tumor area segmentation to avoid ties with the main task. A total of 210 of the 495 participants enrolled in the challenge downloaded the images, and 23 teams submitted their final results. Seven teams from the top 10 participants agreed to disclose their algorithms, most of which were convolutional neural network-based deep learning models, such as EfficientNet and UNet. The top-ranked system achieved the highest F1 score (0.9231). This paper summarizes the various methods used in the PAIP 2020 challenge. This paper supports the effectiveness of digital pathology for identifying the relationship between colorectal cancer and the MSI characteristics.

Prediction of Microsatellite Instability in Colorectal Cancer Using a Machine Learning Model Based on PET/CT Radiomics.

We investigated the feasibility of preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) radiomics with machine learning to predict microsatellite instability (MSI) status in colorectal cancer (CRC) patients. Altogether, 233 patients with CRC who underwent preoperative FDG PET/CT were enrolled and divided into training (n=139) and test (n=94) sets. A PET-based radiomics signature (rad_score) was established to predict the MSI status in patients with CRC. The predictive ability of the rad_score was evaluated using the area under the receiver operating characteristic curve (AUROC) in the test set. A logistic regression model was used to determine whether the rad_score was an independent predictor of MSI status in CRC. The predictive performance of rad_score was compared with conventional PET parameters. The incidence of MSI-high was 15 (10.8%) and 10 (10.6%) in the training and test sets, respectively. The rad_score was constructed based on the two radiomic features and showed similar AUROC values for predicting MSI status in the training and test sets (0.815 and 0.867, respectively; p=0.490). Logistic regression analysis revealed that the rad_score was an independent predictor of MSI status in the training set. The rad_score performed better than metabolic tumor volume when assessed using the AUROC (0.867 vs. 0.794, p=0.015). Our predictive model incorporating PET radiomic features successfully identified the MSI status of CRC, and it also showed better performance than the conventional PET image parameters.

Development and external validation of a multiparametric MRI-based radiomics model for preoperative prediction of microsatellite instability status in rectal cancer: a retrospective multicenter study.

To establish and validate a radiomics model based on multiparametric magnetic resonance imaging (MRI), and to predict microsatellite instability (MSI) status in rectal cancer patients. A total of 199 patients with pathologically confirmed rectal cancer were included. The MSI status was confirmed by immunohistochemistry (IHC) staining. Clinical factors and laboratory data associated with MSI status were analyzed. The imaging data of 100 patients from one of the hospitals were used as the training set. The remaining 99 patients from the other two hospitals were used as the external validation set. The regions of interest (ROIs) were delineated from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast-enhanced T1WI (CE-T1WI) sequence to extract the radiomics features. The Tree-based approach was used for feature selection. The models were constructed based on the four single sequences and a combination of the four sequences using the random forest (RF) algorithm. The external validation set was used to verify the generalization ability of each model. The receiver operating characteristic (ROC) curves and the area under the curve (AUC) were plotted to evaluate and compare the predictive performance of each model. In the four single-series models, the CE-T1WI model performed the best. The AUCs of the T1WI, T2WI, DWI, and CE-T1WI prediction models in the training set were 0.74, 0.71, 0.71, and 0.78, respectively, while in the external validation set, the corresponding AUCs were 0.67, 0.66, 0.70, and 0.77. The prediction and generalization performance of the combined model of multi-sequences was comparable to that of the CE-T1WI model and it was better than that of the remaining three single-series models, with AUC values of 0.78 and 0.78 in the training and validation sets, respectively. The established radiomics models based on CE-T1WI or multiparametric MRI have similar predictive performance. They have the potential to predict MSI status in rectal cancer patients. • A radiomics model for the prediction of MSI status in patients with rectal cancer was established and validated using external validation. • The models based on CE-T1WI or multiparametric MRI have better predictive performance than those based on single unenhanced sequence images. • The radiomics model has the potential to suggest MSI status in rectal cancer patients; however, it is not yet a substitute for histological confirmation.

Non-invasive prediction of microsatellite instability in colorectal cancer by a genetic algorithm-enhanced artificial neural network-based CT radiomics signature.

The stratification of microsatellite instability (MSI) status assists clinicians in making treatment decisions for colorectal cancer (CRC) patients. This study aimed to establish a CT-based radiomics signature to predict MSI status in patients with CRC. A total of 837 CRC patients who underwent preoperative enhanced CT and had available MSI status data were recruited from two hospitals. Radiomics features were extracted from segmented tumours, and a series of data balancing and feature selection strategies were used to select MSI-related features. Finally, an MSI-related radiomics signature was constructed using a genetic algorithm-enhanced artificial neural network model. Combined and clinical models were constructed using multivariate logistic regression analyses by integrating the clinical factors with or without the signature. A Kaplan-Meier survival analysis was conducted to explore the prognostic information of the signature in patients with CRC. Ten features were selected to construct a signature which showed robust performance in both the internal and external validation cohorts, with areas under the curves (AUC) of 0.788 and 0.775, respectively. The performance of the signature was comparable to that of the combined model (AUCs of 0.777 and 0.767, respectively) and it outperformed the clinical model constituting age and tumour location (AUCs of 0.768 and 0.623, respectively). Survival analysis demonstrated that the signature could stratify patients with stage II CRC according to prognosis (HR: 0.402, p = 0.029). This study built a robust radiomics signature for identifying the MSI status of CRC patients, which may assist individualised treatment decisions. • Our well-designed modelling strategies helped overcome the problem of data imbalance caused by the low incidence of MSI. • Genetic algorithm-enhanced artificial neural network-based CT radiomics signature can effectively distinguish the MSI status of CRC patients. • Kaplan-Meier survival analysis demonstrated that our signature could significantly stratify stage II CRC patients into high- and low-risk groups.

Magnetic resonance imaging downstaging, pathological response, and microsatellite instability status in patients with signet-ring cell carcinoma rectum undergoing preoperative long-course chemoradiation

Aim and Objective: To assess the magnetic resonance imaging (MRI) downstaging, pathological response, and the relationship between microsatellite instability (MSI) and radiotherapy response in signet-ring cell carcinoma rectum. Materials and Methods: Twenty two patients were recruited prospectively and retrospectively in this observational study. Six weeks following radiotherapy, the response was assessed using an MRI pelvis, and patients who were operable underwent total mesorectal excision followed by adjuvant chemotherapy. The outcome of radiotherapy was correlated with post radiation MRI downstaging, pathological response, and MSI status. Results: The post radiotherapy response assessment MRI showed tumor regression grading (TRG) 5 in 5 patients. TRG 4 seen in 12, TRG 3 in 3, and TRG 2 in 1 patient. Fifteen patients were operable and post-operativ histopathology showed that 40% had pathological complete response (pCR) and 26.7% had near-complete response. Even those who had no response in MRI had pCR. MSI done 17 patients were stable. Of the 6 patients who had complete pathological response, two were MRI TRG 5, three were MRI TRG 4, and one was MRI TRG 3. The median survival was 23 months. The 2-year and 3-year disease-free survival was 46% and 38%, respectively. Conclusion: The predictive value of MRI downstaging in these tumors following neoadjuvant long-course chemoradiation therapy is not often in concurrence with the histopathological response and needs to be interpreted carefully. Even though the pCR rate seen in this cohort is encouraging, this needs to be evaluated in studies with large cohorts.

Pre-treatment CT-based radiomics nomogram for predicting microsatellite instability status in colorectal cancer.

Stratification of microsatellite instability (MSI) status in patients with colorectal cancer (CRC) improves clinical decision-making for cancer treatment. The present study aimed to develop a radiomics nomogram to predict the pre-treatment MSI status in patients with CRC. A total of 762 patients with CRC confirmed by surgical pathology and MSI status determined with polymerase chain reaction (PCR) method were retrospectively recruited between January 2013 and May 2019. Radiomics features were extracted from routine pre-treatment abdominal pelvic computed tomography (CT) scans acquired as part of the patients' clinical care. A radiomics nomogram was constructed using multivariate logistic regression. The performance of the nomogram was evaluated using discrimination, calibration, and decision curves. The radiomics nomogram incorporating radiomics signatures, tumor location, patient age, high-density lipoprotein expression, and platelet counts showed good discrimination between patients with non-MSI-H and MSI-H, with an area under the curve (AUC) of 0.74 [95% CI, 0.68-0.80] in the training cohort and 0.77 [95% CI, 0.68-0.85] in the validation cohort. Favorable clinical application was observed using decision curve analysis. The addition of pathological characteristics to the nomogram failed to show incremental prognostic value. We developed a radiomics nomogram incorporating radiomics signatures and clinical indicators, which could potentially be used to facilitate the individualized prediction of MSI status in patients with CRC. • There is an unmet need to non-invasively determine MSI status prior to treatment. However, the traditional radiological evaluation of CT is limited for evaluating MSI status. • Our non-invasive CT imaging-based radiomics method could efficiently distinguish patients with high MSI disease from those with low MSI disease. • Our radiomics approach demonstrated promising diagnostic efficiency for MSI status, similar to the commonly used IHC method.

P-293 Overall survival according to mutation frequency of BRAF, NRAS genes, and MSI status in patients with wild-type KRAS metastatic colorectal cancer treated with cetuximab

The treatment of colorectal cancer (CRC) has been progressively based on its molecular profile. This study was justified by the prognostic relevance of BRAF and NRAS genes and microsatellite instability (MSI) status in CRC, and the small number of studies evaluating the mutation frequency of these genes as well as the status of MSI in colorectal tumors in Brazil. In addition, it is one of the first studies in the Brazilian population that aimed to confirm previous findings regarding the efficacy of cetuximab in the treatment of advanced CRC in an enriched population of refractory poly-treated patients.

Prognostic significance of PD-L1 expression and evaluation of microsatellite instability status in patients with retroperitoneal leiomyosarcomas

Background. Leiomyosarcoma is one of the most common types of soft tissue sarcomas. Radical surgical resection with subsequent adjuvant chemotherapy remain the most effective treatment approach. Immunotherapy based on inhibition of PD-L1 (programmed death ligand 1) or its receptor PD1 (programmed death 1) is considered a promising treatment option. Level of PD-L1 expression in tumor cells and presence of microsatellite instability (МSI) could be considered prognostic and predictive markers of disease progression and effectiveness of immunotherapy.The study objective is to determine PD-L1 expression level and МSI status in patients with retroperitoneal leiomyosarcomas and evaluate their effect on overall and recurrence-free survival.Materials and methods. The study included 57 patients with retroperitoneal leiomyosarcomas who underwent surgical or combination treatment. Analysis of clinical and morphological characteristics was performed; results of surgical treatment were researched. Evaluation of PD-L1 expression and MSI status was performed using immunohistochemical and molecular genetic analysis.Results. PD-L1 expression and MSI status were evaluated in 41 patients of 57. In 10 (24 %) of 41 cases, positive PD-L1 expression was observed (expression level 3–50 %). In 1 (2.4 %) patient, the primary tumor and metastatic lesion had low MSI level (MSI-low, MSI-L). Median follow-up was 31 months. In patients with positive PD-L1 expression, higher Ki-67 proliferative index was observed compared to patients with PD-L1 negative tumors (58.8 and 47.8 % respectively; р = 0.02), as well as significantly lower median overall survival for grade II tumors (30 and 105 months; p = 0.043). In grade III leiomyosarcomas, a trend towards lower median overall survival in patients with PD-L1‑negative tumors (31.0 months) compared to patients with PD-L1 expression (61.2 months) (р = 0.11) was observed.Conclusion. Among patients with retroperitoneal leiomyosarcomas, positive expression of PD-L1 was observed in 24 % (10 / 41) of cases and MSI-low status was found in 2.4 % (1 / 41) of cases. In patients with grade 2 tumors, positive PD-L1 expression is associated with significantly lower overall survival. PD-L1 expression in patients with retroperitoneal leiomyosarcomas could be considered a prognostic marker and a potential therapeutic target.

Predicting the Efficacy of 5-Fluorouracil-Based Adjuvant Chemotherapy in Gastric Cancer by Microsatellite Instability: A Meta-Analysis.

Microsatellite instability (MSI) implies the deletion of mismatch repair genes caused by DNA methylation or gene mutation. MSI is a good predictor for efficacy of 5-fluorouracil (FU)-based chemotherapy in the treatment of colorectal cancer. Some gastric cancer studies have reported that MSI has no apparent impact on prognosis after patients receive 5-FU-based adjuvant chemotherapy. However, other studies suggest that high-frequency MSI (MSI-H) status reduced survival in patients receiving 5-FU-based adjuvant chemotherapy. Thus, the correlation between MSI status and efficacy of 5-FU-based adjuvant chemotherapy for gastric cancer remains controversial. We performed a PubMed, Embase, and Cochrane search to retrieve studies that explore the correlation between MSI status and 5-FU-based adjuvant chemotherapy efficacy in gastric cancer. After extracting 65 potentially eligible studies, four were ultimately included in this meta-analysis using Stata software (ver. 12.0). For each study, we estimated the hazard ratio (HR) value for overall survival (OS), and HR was extracted per the survival curve in the studies. Heterogeneity was estimated using the random-effects model. Overall, 1174 patients after operation were included: 84 patients were classed as MSI-H and 1090 as microsatellite stable (MSS)/low-frequency MSI (MSI-L). For the four studies, the overall estimate of HR for OS between MSI-H and MSS/MSI-L groups was 1.90 (95% confidence interval: 0.91-3.93; p = 0.08). We found no correlation to exist between MSI status and efficacy of 5-FU-based adjuvant chemotherapy for gastric cancer. Although MSI can effectively predict efficacy of 5-FU-based chemotherapy in patients with colorectal cancer, the correlation between MSI status and efficacy of 5-FU-based adjuvant chemotherapy for gastric cancer remains controversial. This meta-analysis suggests that MSI status is unrelated to efficacy of 5-FU-based adjuvant chemotherapy in gastric cancer, and more prospective clinical studies are needed to further investigate predictive value of MSI status in patients with gastric cancer who, after operation, receive 5-FU-based adjuvant chemotherapy.

Utility of the quasi-monomorphic variation range in unresectable metastatic colorectal cancer patients.

Microsatellite Instability (MSI) status is an established predictive biomarker for the treatment of the anti‐programmed death 1 (PD‐1) antibody. The current approach to determine the MSI status in tumours requires matched normal DNA. Some mononucleotide microsatellite markers are known to have few variant alleles in both Caucasians and Asians. Therefore, the length of these microsatellite makers is almost confined within the quasi‐monomorphic variation range (QMVR). Considering the application of MSI testing for various types of cancers, a simple, sensitive and inexpensive method is desired. This study assessed the clinical utility of the QMVR for determining the MSI status in patients with unresectable metastatic colorectal cancer (mCRC). The study enrolled 435 patients with mCRC. The concordance of the MSI status in mCRC between the standard method using tumour DNA plus matched normal DNA and the testing method using only tumour DNA was evaluated. Eleven (2.5%) MSI‐high cases were detected by both the standard and testing methods. The sensitivity and specificity of the testing method were both 100%, indicating complete concordance between the methods. Among the mononucleotide markers, three and two patients showed discordance for NR‐21 and BAT‐25, respectively. Results from MSI testing with normal tissue indicated that four of five patients had rare germline variants outside the QMVR. For BAT‐26, NR‐24 and MONO‐27, all patients showed complete concordance. Using the QMVR, the MSI status of mCRC can be determined without matched normal DNA.

Familial aggregation of gastric cancer with microsatellite instability*

Background: Microsatellite instability (MSI) is currently a new molecular subtype of gastric cancer (GC). About 90% of GC cases appear sporadically. MSI seems to be responsible for both sporadic and familial GC. The aim of this study was to analyze the frequency of MSI in GC with familial history of GC.Methods: The MSI analysis was conducted using five quasi-monomorphic mononucleotide repeats: BAT-26, BAT-25, NR-24, NR-21 and NR-27. From our database, we analyzed 457 patients in terms of cancer history across family members, particularly focusing on GC.Results: MSI status in patients without familial history of GC was present in 22.1% of the cases, whereas in the patients with familial history of GC it was present in 28% of the cases (p = 0.220). For 1st or 2nd degree family members with GC, MSI was observed in 27.6% and in 30.8%, respectively (p = 0.812). MSI was observed in hereditary gastric cancer (HGC) in 33.3% and in familial gastric cancer (FGC) in 30%. No difference in survival rates was observed between the analyzed groups.Conclusions: In our publication, we could not find any link between familial background and the MSI status in GC patients. More detailed molecular and genetic analysis of subgroups of these patients is required.

Prognostic Value of the Microsatellite Instability Status in Patients With Stage II/III Rectal Cancer Following Upfront Surgery

BackgroundWe investigated whether the microsatellite instability (MSI) status affects the survival outcomes in patients with stage II/III rectal cancer who have undergone an upfront curative resection. Patients and MethodsA total of 1103 patients with curatively resected stage II/III rectal cancer who had available polymerase chain reaction-based MSI results were included in the final analysis. ResultsTwenty-four (2.2%) patients in the total cohort were found to be MSI-high (MSI-H). In univariate analysis, neither disease-free survival (DFS) nor overall survival (OS) demonstrated significant differences between patients with MSI-H tumors and those with MSI-low (MSI-L) or microsatellite stable (MSS) tumors. The 5-year DFS rate was 78.0% in MSI-H patients and 69.9% in MSI-L/MSS patients (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.35-2.02; P = .689). The 5-year OS rates for MSI-H and MSI-L/MSS patients were 84.0% and 83.1%, respectively (HR, 0.86; 95% CI, 0.27-2.69; P = .790). By multivariate analysis, the MSI status did not affect either the DFS (HR, 1.00; 95% CI, 0.40-2.47; P = .994) or OS (HR, 0.85; 95% CI, 0.26-2.73; P = .778). ConclusionsMSI-H tumors are rarely observed in rectal adenocarcinoma, and the MSI status may not affect the survival outcome in patients with a resected rectal cancer.

Predictive and Prognostic Implications of Mutation Profiling and Microsatellite Instability Status in Patients with Metastatic Colorectal Carcinoma.

To investigate whether mutation profiling and microsatellite instability (MSI) status were associated with clinicopathological features and the prognosis in metastatic colorectal cancer (mCRC), mutations in RAS (including KRAS, NRAS, and HRAS) and BRAF were determined by Sanger sequencing. Tumor mismatch repair proteins and MSI status were examined using immunohistochemistry and polymerase chain reaction, respectively. The clinical value of these abnormalities was statistically analyzed, and prognostic value of different treatment regimens was also evaluated. Among 461 mCRC patients, mutations in RAS, BRAF, and MSI-high (MSI-H) status were observed in 45.3% (209/461), 5.6% (26/461), and 6.5% (30/461) of cases, respectively. Brain metastasis and high carcinoembryonic antigen level were highly correlated with KRAS mutation (P = 0.011 and P < 0.001), and tumors from females or located in the right colon tended to harbor BRAF mutation (P = 0.039 and P = 0.001). RAS/BRAF mutations may predict brain and/or lung metastases. Although neither clinical nor prognostic importance of MSI status was identified in our study, KRAS and BRAF mutations were demonstrated to be independent prognostic factors for overall survival and progression-free survival. Besides, in wild-type group, patients treated with chemotherapy plus targeted therapy exhibited the most favorable prognosis. Therefore, RAS/BRAF mutations may serve as indicators for prognosis and treatment options in mCRC.

Exploring the Prognostic Role of Microsatellite Instability in Patients With Stage II Colorectal Cancer: A Systematic Review and Meta-Analysis

BackgroundMany studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little evidence supports their role in the decision-making of adjuvant therapy for patients with stage II disease. Materials and MethodsThe aim of this systematic review was to evaluate the prognostic and/or predictive role of MSI status in patients with stage II colorectal cancer on disease-free survival and overall survival. MEDLINE, EMBASE, and Cochrane libraries were searched to identify eligible studies. ResultsOnly 2 of 389 articles identified fulfilled the eligibility criteria. In both treated and untreated patients, high-level MSI improved disease-free survival compared with low-level MSI, suggesting a prognostic role but not supporting the hypothesis of a predictive effect of MSI. ConclusionsFurther studies are needed to explore the predictive role of MSI/mismatch repair proteins, because available data do not allow definitive conclusions.

Prognostic and predictive significance of MSI in stages II/III colon cancer.

In colon cancer, classic disease staging remains the key prognosis and treatment determinant. Although adjuvant chemotherapy has an established role in stage III colon cancer patients, in stage II it is still a subject of controversy due to its restriction to a small subgroup of patients with high-risk histopathologic features. Patients with stage II tumors form a highly heterogeneous group, with five-year relative overall survival rates ranging from 87.5% (IIA) to 58.4% (IIC). Identifying those for whom adjuvant chemotherapy would be appropriate and necessary has been challenging, and prognostic markers which could serve in the selection of patients more likely to recur or benefit from adjuvant chemotherapy are eagerly needed. The stronger candidate in this category seems to be microsatellite instability (MSI). The recently reported European Society for Medical Oncology guidelines suggest that MSI should be evaluated in stage II colorectal cancer patients in order to contribute in treatment decision-making regarding chemotherapy administration. The hypothetical predictive role of MSI regarding its response to 5-fluorouracil-based adjuvant chemotherapy has proven a much more difficult issue to address. Almost every possible relation between MSI and chemotherapy outcome has been described in the adjuvant colon cancer setting in the international literature, and the matter is far from being settled. In this current report we critically evaluate the prognostic and predictive impact of MSI status in patients with stage II and stage III colon cancer patients.

Prognostic Value of Mucinous Histology Depends on Microsatellite Instability Status in Patients with Stage III Colon Cancer Treated with Adjuvant FOLFOX Chemotherapy: A Retrospective Cohort Study

The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer. This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models were used. The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2%) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9%; log-rank, P=0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95% confidence interval 1.03-3.23, P=0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P=0.732). Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy.