Microsatellite Instability In Patients Research Articles

Failure of immune checkpoint inhibitors for microsatellite instability-positive pancreatic adenocarcinoma with atypical pattern of short tandem repeat mutation.

Microsatellite instability (MSI) is an important biomarker in cancer. While routine methods can detect MSI in certain tumor types, in other tumor types the results may be incorrect due to differences in the MSI loci pattern. Here, we report the case of a patient with pancreatic adenocarcinoma, with confirmed MSI by two independent next-generation sequencing tests, but not by routine methods, who had progression on pembrolizumab. Comparison of the patient's MSI loci patterns with MSI+ colorectal adenocarcinoma samples showed a lower fraction of unstable loci, low resolution of a second peak in the repeat length spectrum of unstable short tandem repeats in the patient's sample, and a lower length of indels (3.7 vs 4.5 base pairs, p<0.01).

Predictive value of intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT in distinguishing microsatellite instability status of colorectal carcinoma.

Microsatellite instability (MSI) status is a significant biomarker for the response to immune checkpoint inhibitors, response to 5-fluorouracil-based adjuvant chemotherapy, and prognosis in colorectal carcinoma (CRC). This study investigated the predictive value of intratumoral-metabolic heterogeneity (IMH) and conventional metabolic parameters derived from 18F-FDG PET/CT for MSI in patients with stage I-III CRC. This study was a retrospective analysis of 152 CRC patients with pathologically proven MSI who underwent 18F-FDG PET/CT examination from January 2016 to May 2022. Intratumoral-metabolic heterogeneity (including heterogeneity index [HI] and heterogeneity factor [HF]) and conventional metabolic parameters (standardized uptake value [SUV], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) of the primary lesions were determined. MTV and SUVmean were calculated on the basis of the percentage threshold of SUVs at 30%-70%. TLG, HI, and HF were obtained on the basis of the above corresponding thresholds. MSI was determined by immunohistochemical evaluation. Differences in clinicopathologic and various metabolic parameters between MSI-High (MSI-H) and microsatellite stability (MSS) groups were assessed. Potential risk factors for MSI were assessed by logistic regression analyses and used for construction of the mathematical model. Area under the curve (AUC) were used to evaluate the predictive ability of factors for MSI. This study included 88 patients with CRC in stages I-III, including 19 (21.6%) patients with MSI-H and 69 (78.4%) patients with MSS. Poor differentiation, mucinous component, and various metabolic parameters including MTV30%, MTV40%, MTV50%, and MTV60%, as well as HI50%, HI60%, HI70%, and HF in the MSI-H group were significantly higher than those in the MSS group (all P < 0.05). In multivariate logistic regression analyses, post-standardized HI60% by Z-score (P = 0.037, OR: 2.107) and mucinous component (P < 0.001, OR:11.394) were independently correlated with MSI. AUC of HI60% and our model of the HI60% + mucinous component was 0.685 and 0.850, respectively (P = 0.019), and the AUC of HI30% in predicting the mucinous component was 0.663. Intratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT was higher in MSI-H CRC and predicted MSI in stage I-III CRC patients preoperatively. HI60% and mucinous component were independent risk factors for MSI. These findings provide new methods to predict the MSI and mucinous component for patients with CRC.

Noninvasive detection of microsatellite instability in patients with endometrial cancer.

The analysis of mismatch repair proteins in solid tissue is the standard of care (SoC) for the microsatellite instability (MSI) characterization in endometrial cancer (EC). Uterine aspirates (UAs) or circulating-DNA (cfDNA) samples capture the intratumor heterogeneity and provide a more comprehensive and dynamic molecular diagnosis. Thus, MSI analysis by droplet-digital PCR (ddPCR) in UAs and cfDNA can provide a reliable tool to characterize and follow-up the disease. The UAs, paraffin-embedded tumor tissue (FFPE) and longitudinal plasma samples from a cohort of 90 EC patients were analyzed using ddPCR panel and compared to the SoC. A high concordance (96.67%) was obtained between the analysis of MSI markers in UAs and the SoC. Three discordant cases were validated as unstable by ddPCR on FFPE samples. Besides, a good overall concordance (70.27%) was obtained when comparing the performance of the ddPCR assay on UAs and cfDNA in high-risk tumors. Importantly, our results also evidenced the value of MSI analysis to monitor the disease evolution. MSI evaluation in minimally invasive samples shows great accuracy and sensitivity and provides a valuable tool for the molecular characterization and follow-up of endometrial tumors, opening new opportunities for personalized management of EC.

A multicenter comparative study of endoscopic ultrasound-guided fine-needle biopsy using a Franseen needle versus conventional endoscopic ultrasound-guided fine-needle aspiration to evaluate microsatellite instability in patients with unresectable pancreatic cancer.

Immune checkpoint blockade has recently been reported to be effective in treating microsatellite instability (MSI)-high tumors. Therefore, sufficient sampling of histological specimens is necessary in cases of unresectable pancreatic cancer (UR-PC). This multicenter study investigated the efficacy of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) using a Franseen needle for MSI evaluation in patients with UR-PC. A total of 89 patients with UR-PC who underwent endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or EUS-FNB using 22-G needles at three hospitals in Japan (2018-2021) were enrolled. Fifty-six of these patients (FNB 23 and FNA 33) were followed up or evaluated for MSI. Patient characteristics, UR-PC data, and procedural outcomes were compared between patients who underwent EUS-FNB and those who underwent EUS-FNA. No significant difference in terms of sufficient tissue acquisition for histology was observed between patients who underwent EUS-FNB and those who underwent EUS-FNA. MSI evaluation was possible significantly more with tissue samples obtained using EUS-FNB than with tissue samples obtained using EUS-FNA (82.6% [19/23] vs. 45.5% [15/33], respectively; p<0.01). In the multivariate analysis, EUS-FNB was the only significant factor influencing the possibility of MSI evaluation. EUS-FNB using a Franseen needle is desirable for ensuring sufficient tissue acquisition for MSI evaluation.

Molecular Typing and Clinical Characteristics of Synchronous Multiple Primary Colorectal Cancer

Synchronous multiple primary colorectal cancer (sMPCC) is clinically rare, but its incidence has increased over the past decade. However, little is known about the molecular and clinical features of sMPCC, which may differ from those of single primary colorectal cancer (SPCRC). To evaluate the clinical characteristics and pathogenic variations in lesions and the molecular typing of sMPCC. From November 2012 to April 2021, patients with colorectal cancer (CRC) treated at the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this cohort study. Follow-up ended on January 31, 2022. The primary outcome was mismatch repair (MMR) status of each lesion in all patients examined using immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutation burden (TMB) were also calculated. A total of 13 276 patients with CRC were enrolled, and 239 patients with sMPCC (mean [SD] age, 63.3 [12.2] years; 173 men [72.4%]) with available clinical data were evaluated. Seventy-eight patients with sMPCC and 94 with SPCRC also underwent next-generation sequencing (NGS)-based molecular testing. The deficient MMR (dMMR)/MSI-H frequencies in sMPCC were significantly higher than those in SPCRC, which was confirmed by both IHC (50 of 239 patients vs 872 of 13 037 patients) and NGS (17 of 78 patients vs 5 of 94 patients). According to the MMR/MSI status of different lesions in patients with sMPCC, they were further divided into 3 subgroups: all dMMR/MSI-H, dMMR/MSI-H and proficient MMR (pMMR)/microsatellite stability (MSS), and all pMMR/MSS. The EGFR and PIK3CA variants were more common, whereas TP53 variants were less prevalent in patients with sMPCC than in those with SPCRC. Moreover, higher tumor mutation burden was associated with higher MSI in patients with sMPCC rather than in those with SPCRC. In this cohort study of sMPCC, the incidence of dMMR/MSI-H in patients with sMPCC was significantly higher than that in patients with SPCRC. These findings suggest that sMPCC can be classified into 3 subgroups according to the MMR/MSI status of each lesion, which might be applied to guide personalized therapies for better disease management.

Clinicopathological outcomes of microsatellite instability in colorectal cancer.

This study aims to evaluate the histopathological features and prognostic parameters of tumors with microsatellite instability (MSI) compared with those without MSI in patients who underwent surgery for colorectal cancer (CRC). Follow-up for CRC at Istanbul Sultan 2. Abdulhamid Han Training and Research Hospital was retrospectively evaluated between March 2017 and March 2021. The patients were divided into two groups: those with and without MSI. Groups were compared in survival parameters. As a secondary result, groups were compared in pathological parameters such as stage, tumor diameter, degree of differentiation, and lymphovascular, and perineural invasion. Survival calculations were performed using the Kaplan-Meier analysis method. The effects of various prognostic factors related to tumor and patient characteristics on disease-free and overall survival (OS) were investigated by log-rank test. Two hundred fourteen patients were analyzed. The median age of the patients was 66 (30-89), and 59.3% (n = 127) were male. There were 25 patients in the MSI group and 189 patients in the non-MSI group. We found that MSI tumors had a significantly higher differentiation degree than non-MSI tumors and larger tumor diameters. MSI tumors frequently settled in the proximal colon, and more lymph nodes were removed in the resection material. MSI tumors had longer disease-free survival, cancer-specific survival, and overall survival. By diagnosing microsatellite instability, CRCs can be divided into two groups. The histopathological features of the tumor and the prognosis of the disease differ between these groups. MSI can be a predictive marker in the patient's follow-up and treatment.

Microsatellite instability in patients with hepato-biliary-pancreatic malignancies in clinical practice (KHBO 1903).

This study aimed to determine the prevalence of microsatellite instability (MSI)-high status in hepato-biliary-pancreatic malignancies in clinical practice and the clinical characteristics of and therapeutic results of pembrolizumab on patients with MSI-high cancers. The subjects were 283 patients who had undergone MSI tests for unresectable, metastatic hepato-biliary-pancreatic malignancies at seven hospitals. The tests were polymerase chain reaction fragment analyses using the microsatellite markers consisting of BAT25, BAT26, NR21, NR24, and MONO27. Formalin-fixed, paraffin-embedded blocks, prepared according to the guidelines of the Japan Society of Pathology were used within 4years after sampling. There were 13 patients with cancers high in MSI, including eight patients receiving pembrolizumab treatment. The clinical characteristics of these patients and therapeutic outcomes of their pembrolizumab treatment were investigated. MSI-high was detected in 13 (4.6%) of the 283 patients with hepato-biliary-pancreatic malignancies. None of these 13 patients had been diagnosed with Lynch syndrome. Of the Eight patients receiving pembrolizumab, a complete response was observed in three patients, a partial response in one patient, and stable disease in three patients. The objective response rate was 50% and the disease control rate was 87.5%. MSI-high was detected in 4.6% of patients with hepato-biliary-pancreatic malignancies. There was a 50% objective response rate to pembrolizumab treatment for MSI-high cancers. The evaluation of MSI status by the current method using appropriately prepared tissue samples was to be a reliable and accurate approach to both the determination of MSI status and estimation of the effectiveness of pembrolizumab.

Incorporation of immunohistochemistry in the assessment of survival and prognosis of endometrial cancers: Are we ready for the change?

Objectives: The aim of the study was to determine the mismatch repair (MMR) proteins and p53 expression by immunohistochemistry in operable endometrial carcinoma (EC) patients. The study aimed to analyze and correlate clinicopathological factors and survival with MMR and p53 immunohistochemistry markers. Material and Methods: A retrospective cohort study of 115 cases of carcinoma endometrium who underwent primary surgery in our hospital from July 1, 2013, to December 31, 2020, with a minimum follow-up of 1 year. Available tissue blocks were stained for IHC expression of MMR and p53 proteins. Patients were stratified into Type I and Type II on basis of histopathology. Clinicopathological factors, overall survival (OS), and disease-free survival (DFS) were then compared on the basis of MMR deficiency and p53 status. Results: The mean age of study population was 58.9 years with a mean body mass index of 31.61 kg/m2. The mean follow-up was 41.29 months. Ninety-seven patients underwent IHC staining for MMR and p53 proteins. Among these 97 patients, 79 patients belonged to Type I histopathology and 18 patients belonged to Type II histopathology. The 79 patients of Type I histopathology were further divided into MSS or microsatellite stable group and MSI or microsatellite instable group. MMR deficit status was seen in 17 (21.5%) patients and 62 (78.5%) patients were MSS. For the 18 cases of Type II ECs, 5 (27.8%) patients were p53 positive whereas 13 (72.2%) patients were p53 negative. For patients with Type I histopathology; the clinicopathological factors such as stage, age, grade of the tumor, lymph-vascular space involvement, lymph node status, and myometrial invasion were compared between the MSI and MSS groups. Patients with microsatellite instability were more likely to present with a higher grade, a positive lymph node status, and with lymph-vascular space invasion. The OS and DFS are not significantly affected in patients with loss of MMR proteins. Due to a smaller number of cases in p53 group, clinicopathological features and survival could not be compared. Conclusion: Analyzing of immunohistochemistry status for evaluating the microsatellite instability in patients with Type I endometrioid adenocarcinomas is an alternative and efficient tool in predicting the prognosis for these patients. Further studies with more sample size can help us in studying the impact of MSI and p53 on OS and DFS and for guiding in the management of the same.

American Gastroenterological Association Institute and College of American Pathologists Quality Measure Development for Detection of Mismatch Repair Deficiency and Lynch Syndrome Management

American Gastroenterological Association Institute and College of American Pathologists Quality Measure Development for Detection of Mismatch Repair Deficiency and Lynch Syndrome Management

Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment.

Background and AimImmune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability‐high (MSI‐H) by using tumor samples from advanced HCC patients eligible for systemic therapy.MethodsMSI‐H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD‐L1, CD8, VEGF, and HLA‐class1 was evaluated by immunohistochemistry. Whole‐exome sequencing was performed for MSI‐H tumor samples.ResultsOf 50 patients, one (2.0%) was confirmed with MSI‐H. In the MSI‐H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8+ lymphocytes, and low expression of VEGF were identified. Although PD‐L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR‐21 and miR‐155 overexpression and hypermethylation of the MSH2 gene.ConclusionWe identified a very small number of MSI‐H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI‐H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI‐H in HCC and to analyze tumor microenvironments.

Predictive Value of Metabolic Parameters Derived From 18F-FDG PET/CT for Microsatellite Instability in Patients With Colorectal Carcinoma.

BackgroundMicrosatellite instability (MSI) is one of the important factors that determine the effectiveness of immunotherapy in colorectal cancer (CRC) and serves as a prognostic biomarker for its clinical outcomes.PurposeTo investigate whether the metabolic parameters derived from18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can predict MSI status in patients with CRC.Materials and MethodsA retrospective analysis was performed on CRC patients who underwent 18F-FDG PET/CT examination before surgery between January 2015 and April 2021. The metabolic 18F-FDG PET/CT parameters of the primary CRC lesion were calculated and recorded with different thresholds, including the maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean), as well as the metabolic tumor volume (MTV) and the total lesion glycolysis (TLG). The status of MSI was determined by immunohistochemical assessment. The difference of quantitative parameters between MSI and microsatellite stability (MSS) groups was assessed, and the receiver operating characteristic (ROC) analyses with area under ROC curves (AUC) was used to evaluate the predictive performance of metabolic parameters.ResultsA total of 44 patients (24 men and 20 women; mean ± standard deviation age: 71.1 ± 14.2 years) were included. There were 14 patients in the MSI group while there were 30 in the MSS group. MTV30%, MTV40%, MTV50%, and MTV60%, as well as TLG50% and TLG60% showed significant difference between two groups (all p-values <0.05), among which MTV50% demonstrated the highest performance in the prediction of MSI, with an AUC of 0.805 [95% confidence interval (CI): 0.657–0.909], a sensitivity of 92.9% (95% CI: 0.661–0.998), and a specificity of 66.7% (95% CI: 0.472–0.827). Patients’ age and MTV50% were significant predictive indicators of MSI in multivariate logistic regression.ConclusionThe metabolic parameters derived from18F-FDG PET/CT were able to preoperatively predict the MSI status in CRC, with MTV50% demonstrating the highest predictive performance. PET/CT imaging could serve as a noninvasive tool in the guidance of immunotherapy and individualized treatment in CRC patients.

Microsatellite Instability in Patients With Stage III Colon Cancer Receiving Fluoropyrimidine With or Without Oxaliplatin: An ACCENT Pooled Analysis of 12 Adjuvant Trials.

In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain. Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors. MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses. Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Unexpected tumor response to palliative pelvic radiotherapy in mismatch repair-deficient advanced prostate cancer: a case report

BackgroundMismatch-repair-deficiency resulting in microsatellite instability (MSI) may confer increased radiosensitivity in locally advanced/metastatic tumors and thus radiotherapy (RT) potentially might have a changing role in treating this subset of patients, alone or in combination with checkpoint inhibitors.Case presentationWe report a 76 year-old Italian male patient presenting with locally advanced undifferentiated prostate cancer (LAPC), infiltrating bladder and rectum. Molecular analysis revealed high-MSI with an altered expression of MSH2 and MSH6 at immunohistochemistry. Two months after 6 chemotherapy cycles with Docetaxel associated to an LHRH analogue, a computed tomography scan showed stable disease. After palliative RT (30 Gy/10 fractions) directed to the tumor mass with a 3D-conformal setup, a follow-up computed tomography scan at 8 weeks revealed an impressive response that remained stable at computed tomography after 9 months, with sustained biochemical response. To our knowledge, this is the first case of such a sustained response to low dose RT alone in high-MSI LAPC.ConclusionsRoutine evaluation of MSI in patients with locally problematic advanced tumors might change treatment strategy and treatment aim in this setting, from a purely palliative approach to a quasi-curative paradigm.

Single-nucleotide variants, tumour mutational burden and microsatellite instability in patients with metastatic colorectal cancer: Next-generation sequencing results of the FIRE-3 trial

BackgroundMolecular biomarkers and primary tumour sidedness guide treatment decisions in metastatic colorectal cancer. Comprehensive molecular profiling aims to identify targetable alterations and measure tumour mutational burden (TMB) to enable precision oncology. Material and methodsFoundationOne® next-generation sequencing identified single-nucleotide variants (SNVs), copy number alterations, high TMB (TMB-H) and high-grade microsatellite instability (MSI-H) in patients treated in the FIRE-3 trial. Data were correlated with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). ResultsThree hundred seventy-three (49.6%) of 752 patients provided material for this analysis. Frequent SNVs included TP53, APC, KRAS, PIK3CA, BRAF, SMAD4 and FBXW7. KRAS, BRAF V600E and SMAD4 mutations were confirmed as prognostic biomarkers by logistic penalised regression for ORR. OS was significantly longer in patients with SMAD4 wild-type (WT) tumours than in those with SMAD4-mutated tumours (hazard ratio = 0.59 [95% confidence interval {CI} = 0.34–1.01], p = 0.05), with a higher probability of ORR [odds ratio, SMAD4 SNV versus WT = 0.32 [95% CI = 0.10–0.98], p = 0.05] when treated with cetuximab. MSI-H (30.0%, p = 0.03) and TMB-H (17.3%, p = 0.003) tumours were enriched by FBXW7 mutations. Numerically lower ORR, OS and PFS were observed in MSI-H tumours. ConclusionsRAS, BRAF V600E and SMAD4 mutations were identified as poor prognostic biomarkers in patients of the FIRE-3 trial, whereas improved outcome was observed for BRAF non-V600E mutation. SMAD4 mutation might provide predictive relevance for cetuximab efficacy. MSI-H tumours showed numerically lower ORR, OS and PFS.

P-363 Clinical-pathological correlation of the presence of microsatellite instability in patients diagnosed with locally advanced gastric adenocarcinoma from Costa Rica

In Costa Rica gastric adenocarcinoma is the second leading cause of cancer-related death. The development of this malignancy is a complex multistep process involving numerous genetic alterations. Gastric cancer development proceeds through three different molecular pathways: the chromosomal instability (CIN) pathway, the mutator phenotype (or microsatellite instability pathway, MSI) pathway and the CpG island methylator phenotype (CIMP) pathway. The mutator phenotype pathway is characterized by frequent mutations in regions of the DNA containing microsatellite sequences.

Correlation between TMB and MSI in patients with solid tumors.

e15169 Background: Both oftumor mutational burden (TMB) and microsatellite instability (MSI) are promising predictive biomarkers for immunotherapy in cancer treatment. However, the association between TMB and MSI with solid tumors was not well investigated especially in East Asian patients. Herein, the relationships for characterizing TMB and MSI in major cancer types were made. Methods: TMB and MSI were measured by 539 genes panel via NGS in tumor tissues. The TMB were calculated as the numbers of synonymous and nonsynonymous mutations, and InDels per megabase in coding regions. MSI was the gain or loss of nucleotides from repetitive DNA and the criteria of MSI-H were defined as above 10% positive of the 195 tested microsatellites sites, and this method was totally consistent with conventional MSI-PCR testing in Research and development sample verification. The relationships between TMB and MSI of 874 patients with solid tumors including 174 patients with liver cancer, 32 patients with bile duct cancer, 54 patients with gastric cancer, 119 patients with colorectal cancer, 27 patients with pancreatic cancer, 32 patients with melanoma, 25 patients with glioma and 411 patients with lung cancer cases were performed by Spearman rank correlation analysis via SPSS v22.0. Results: There was no significant correlation between TMB and MSI in total patients with solid tumors (r = 0.061, p = 0.073). Significantly correlations were observed in patients with colorectal cancer (r = 0.248, p = 0.006) and pancreatic cancer (r = 0.397, p = 0.040). Meanwhile, no significant correlations between TMB and MSI were identified in patients with liver cancer (r = -0.016, p = 0.830), bile duct cancer (r = 0.325, p = 0.070), gastric cancer (r = 0.209, p = 0.130), melanoma (r = -0.057, p = 0.757), glioma (r = 0.009, p = 0.967) and lung cancer (r = 0.015, p = 0.758). Interestingly, total eleven cases were confirmed as MSI high in patients with colorectal cancer, glioma and lung cancer all presented phenotypes of TMB high. Conclusions: We demonstrated the presence of tumor-specific properties correlations between TMB and MSI and provided new insights to use them as biomarkers in immunotherapy. As a retrospective study with a relatively small population, the conclusions of this study needed to be verified with a larger sample.

Patient-reported Symptom Outcomes and Microsatellite Instability in Patients With Metastatic Colorectal Cancer

BackgroundThe survival of patients with metastatic colorectal cancer (mCRC) is influenced by the genetic and epigenetic changes that might influence the patient experience of symptom burden. Understanding the association of molecular changes with the symptom burden could help clinicians gain insight into the molecular basis of symptom burden and improve treatment tolerance. To date, no studies have compared the patient-reported symptom burden with these molecular subsets among patients with mCRC. Patients and MethodsWe recruited patients with mCRC that was refractory to ≥ 1 line of therapy who had been enrolled in the Assessment of Targeted Therapies Against Colorectal Cancer trial at The University of Texas MD Anderson Cancer Center. All patients completed a baseline gastrointestinal symptom inventory (MD Anderson Symptom Inventory, gastrointestinal). The symptom burden across key demographic variables and molecular changes, including CRC-associated mutations, microsatellite instability (MSI) status, and the CpG island methylator phenotype (CIMP) were compared using χ2 tests. Association of the symptom burden with overall survival was examined using Cox regression models. ResultsPatients with an MSI-high (MSI-H) phenotype reported greater pain (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.61-5.84), fatigue (OR, 2.78; 95% CI, 1.41-5.49), sleep (OR, 2.52; 95% CI, 1.32-4.08); and drowsiness (OR, 2.51; 95% CI, 1.32-4.78) compared with microsatellite stable patients. Patients with an MSI-H phenotype also had greater odds of overall symptom burden (OR, 2.48; 95% CI, 1.29-4.74) compared with microsatellite stable patients. The CIMP-high patients experienced greater odds of pain compared with the CIMP-negative patients (OR, 1.72; 95% CI, 1.06-2.80). A greater overall symptom burden was associated with poor overall survival (hazard ratio, 1.42; 95% CI, 0.98-2.06]), although the difference was not significant (P = .06). ConclusionCorrelation of MSI-H–associated tumor features with the symptom burden could help provide a better understanding of underlying mechanisms associated with our findings.

EP1.03-02 Frequency of Microsatellite Instability in Patients with Primary Non Small Lung Cancer in a Single Institution from Colombia

EP1.03-02 Frequency of Microsatellite Instability in Patients with Primary Non Small Lung Cancer in a Single Institution from Colombia

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer.

Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti-PD-1 therapy in cases of peritoneal or ovarian metastasis.

Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability As a Biomarker in Gastric Cancer.

In the CLASSIC and MAGIC trials, microsatellite instability (MSI)-high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value. We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI. MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P < .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse.