Incidence Of Microsatellite Instability Research Articles

Low incidence of microsatellite instability in gastric cancers and its association with the clinicopathological characteristics: a comparative study

Gastric cancer is a complex heterogeneous disease with different molecular subtypes that have clinical implications. It is characterized by high mortality rates and limited effective therapies. Microsatellite instability (MSI) has been recognized as a subgroup with a good prognosis based on TCGA and ACRG categorizations. Besides its prognostic and predictive value, gastric cancers with high MSI exhibit different clinical behaviors. The prevalence of high MSI has been assessed in gastric cancer worldwide, especially in East Asia, but there is a lack of such information in the Middle East. Therefore, this study aimed to investigate the incidence and status of MSI in Iranian gastric cancer patients using 53 samples collected from 2015 to 2020 at Taleghani Hospital Medical Center. DNA from tumoral and normal tissues were extracted and assessed through multiplex-PCR based on five mononucleotide repeats panel. Clinicopathological variables, including age, sex, Lauren classification, lymph node involvement, TNM stage, differentiation, localization, and tumor size, were also analyzed. With 2 males and 2 females, high microsatellite instability represented a small subgroup of almost 7.5% of the samples with a median age of 60.5 years. High microsatellite instability phenotypes were significantly associated with patients aged 68 years and older (p‑value of 0.0015) and lower lymph node involvement (p‑value of 0.0004). Microsatellite instability was also more frequent in females, with distal gastric location, bigger tumor size, and in the intestinal type of gastric cancer rather than the diffuse type.

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.

Incidence of Microsatellite Instability, Mutational Burden, and Actionable Alterations in Genes of Patients with Metastatic Colorectal Carcinoma: A Study from a Tertiary Care Hospital in India

Background and objective: Tumor mutational burden (TMB) and microsatellite instability (MSI) are predictive clinical markers of responses to immunotherapy in a wide range of advanced cancers, including colorectal cancers. The data about TMB and MSI in Indian patients is scarce. Hence, assessed the incidence of MSI, TMB, and actionable alterations in genes of patients with metastatic colorectal carcinoma. Methods: A single centre, observational, prospective study in newly diagnosed patients (n=60) with colorectal carcinoma were assessed for MSI incidence, mutational burden, and actionable alterations in genes. Results: The TMB ranged between 5.08 and 2391 mutations per megabase, and 12 (20%) had low TMB, 12 (20%) intermediate TMB and 36 (60%) high TMB. The TMB was high in right-sided than left-sided cancer (100% vs. 47%). Three or more two, and one genomic alteration were observed in 26 (44%), 20 (33%), and (20%) patients, respectively. Gene fusion was absent in all 60 patients. Gene mutations were predominant in the left-sided than right-sided but statistically insignificant (p=0.7). APC, TP53, and BRCA2 gene mutations were evident in 46, 28, and 22 patients, respectively. Wild KRAS/NRAS gene alterations were evident in all metastatic cancers (n=22) presented at baseline. There was no significant correlation between the genomic alterations and age, sex, histology, or tumor differentiation. Conclusion: This study highlights the importance of detecting genomic mutations at the earliest. Genomic mutations should form the basis for customizing and exploring newer targeted therapy against the most common genomic alteration like APC, TP53, and RAS mutations to improve outcomes.

Microsatellite Instability Analysis and Its Prognostic Value in Invasive Nonampullary Duodenal Adenocarcinoma

Purpose: Nonampullary duodenal adenocarcinoma (NADA) is a rare disease. Although several prognostic factors have been reported for this disease, they remain controversial due to their rarity. In this study, we retrospectively analyzed 54 cases of invasive NADA, focusing on the microsatellite instability (MSI) phenotype, programmed cell death-ligand 1 (PD-L1) expression, and prognostic factors. Methods: Expression of the PD-L1 protein and cell differentiation markers in tumors was detected by immunohistochemistry. Microsatellite markers (NR-21, NR-22, NR-24, BAT-25, and BAT-26) were amplified for MSI assessment by PCR. Results: The incidence of MSI in invasive NADA was 35.2%. No significant correlation between the MSI phenotype and clinicopathological factors was observed. Positive expression of PD-L1 by immune cells was common in advanced-stage disease (p = 0.054), and positive expression of PD-L1 in cancer cells correlated significantly with the histologically undifferentiated type (p = 0.016). Kaplan-Meier survival analysis demonstrated a significantly better overall survival (OS) in patients with MSI (p = 0.013) and at early-stage disease (p = 0.000) than in those with microsatellite-stable or at late tumor stages. Univariate and multivariate analyses showed that MSI (hazard ratio [HR]: 0.282, 95% confidence interval [CI]: 0.106–0.751, p = 0.011) and early tumor stage (stage I-II) (HR: 8.81, 95% CI: 2.545–30.500, p = 0.001) were independent better prognostic factors of OS. Conclusions: MSI and early tumor stage (stage I-II) were independent better prognostic factors of OS. A high proportion of MSI phenotypes and positive PD-L1 expression may be helpful for identifying immune checkpoint inhibitors as a novel therapeutic strategy.

Microsatellite instability and chemosensitivity in solid tumours.

The use of biomarkers that influence a targeted choice in cancer treatments is the future of medical oncology. Within this scenario, in recent years, an important role has been played by knowledge of microsatellite instability (MSI), a molecular fingerprint that identifies defects in the mismatch repair system. This knowledge has changed clinical practice in the adjuvant setting of colon cancer, and its role in the neoadjuvant setting in gastric tumours is becoming increasingly interesting, as well as in endometrial cancers in both early and advanced diseases. Furthermore, it has undoubtedly conditioned the first lines of treatment in the metastatic setting in different types of cancers. The incidence of MSI is different in different cancer types, as well as in early cancers versus metastatic disease. Knowing the incidence of MSI in the various histologies can provide insight into the potential use of this biomarker considering its prognostic value, especially in the early stages, and its predictive role with respect to treatment response. In particular, MSI can guide the choice of chemotherapy treatments in the adjuvant setting of colon and perioperative setting in gastric tumours, which could lead to immunotherapy treatments in these patients in both the early stages of the disease and the metastatic setting where the response to immunotherapy drugs in diseases with MSI is now well established. In this review, we focus on colon, gastric and endometrial cancers, and we briefly discuss other cancer types where MSI could have a potential role in oncological treatment decisions.

Evaluation of Microsatellite Instability in Neuroendocrine Pancreatic Tumors

Introduction: Microsatellite instability (MSI), as an acquired feature of malignant tumors, is a predictive and prognostic marker. The less aggressive nature of MSI-positive tumors has been associated with high immunogenicity. In the present study, MSI was assessed in pancreatic NET samples. Methods: The sample included 50 patients with a diagnosis of pancreatic NET (G1-G3). MSI was analyzed by fragment analysis of five microsatellite loci (Bat25, Bat26, NR21, NR24, NR27). The level of MLH1 methylation was detected by pyrosequencing. Results: MSI was noted in 13.3% cases of the NET of the pancreas. In the case of pancreatic NET, only MSI low level was identified (instability at 1/5 loci), most cases were classified as MSI high level. The incidence of MSI of pancreatic NET was consistent with literature data for small intestinal NET (14%) , unlike MSI NET and BRAF V600 mutated adenocarcinomas of colon, MSI-positive pancreatic NET were not associated with hypermethylation of the MLH1 promoter. MSI was more often detected in women over 60 years old, at stages of the tumor process without distant metastases (p = 0.49). The sample size did not allow us to determine significant differences in the studied clinical and pathological groups of NETs, however, we note that in all cases of an unfavorable course of the disease (progression, death), was noted MSS status of tumors. Conclusion: MSI-positive pancreatic NETs resemble the NET of the small intestine Keywords: Microsatellite instability pancreatic neuroendocrine tumors.

Microsatellite Instability in Sporadic Colorectal Malignancy: A Pilot Study from Northern India.

Background:Three molecular pathways are described as the genetic basis of colorectal tumorigenesis. Among these, microsatellite instability (MSI) has shown greatest promise in serving as a biomarker to determine disease aggression by tumour biology, recurrence, and response to chemotherapy. Methodology:This prospective observational pilot study included patients of colorectal cancers, in a population subset coming to a tertiary care hospital in northern India, who were operated with curative or palliative intent over a period of one year and followed up for a maximum of 55 months. The post-operative pathological assessment was done for MSI status using PCR technique, and an attempt was made to evaluate its correlation with conventional clinical and histological parameters, early recurrences, disease-free survival and overall survival in comparison to MSS type tumours in sporadic cases of colorectal malignancies. Results:Out of 38 patients of colorectal cancer, 26 were included in the study. Male to female ratio was 7:6 (n=14:12). Mean age of presentation was 48±14.2 years. Incidence of MSI was n=4 (15.4%). On subgroup analysis, age of presentation (p=0.044) and evidence of perineural invasion (p=0.017) was found to have significant statistical association with MSI tumour biology. Recurrence was seen in seven of the seventeen patients who previously had no synchronous or metastatic disease (41.2%). The mean disease-free survival for MSS was 21.32 months and was 25.25 months for MSI group which was statistically insignificant (p = 0.277). Out of four MSI tumour biology patients one was alive and without recurrence at 47 months. While the other two were alive and without recurrence till 27 months of follow-up. Conclusion:Age and perineural invasion showed statistically significant association with MSI tumour biology. Due to the small sample size statistical significance was not established with site, recurrence rate, DFS and OS.

Study of microsatellite instability in neuroendocrine tumors of pancreas and colon.

e16196 Background: Microsatellite instability (MSI), as an acquired feature of malignant tumors, is a predictive and prognostic marker. The less aggressive nature of MSI-positive tumors has been associated with high immunogenicity. In the present study, MSI was assessed in NET samples of different localizations. Methods: The sample included 50 patients with a diagnosis of pancreatic NET (G1-G3) and NET of colon (G2-G3). MSI was analyzed by fragment analysis of five microsatellite loci (Bat25, Bat26, NR21, NR24, NR27). The level of MLH1 methylation was detected by pyrosequencing. Results: MSI was noted in 25.8% cases of the NET of colon and in 13.3% cases of the NET of the pancreas. In the case of pancreatic NET, only MSI low level was identified (instability at 1/5 loci), while in the case of NET of colon, most cases were classified as MSI high level. The incidence of MSI of pancreatic NET was consistent with literature data for small intestinal NET (14%), unlike MSI NET and BRAF V600 mutated adenocarcinomas of colon, MSI-positive pancreatic NET were not associated with hypermethylation of the MLH1 promoter. MSI was more often detected in women over 60 years old, at stages of the tumor process without distant metastases (p = 0.49). The sample size did not allow us to determine significant differences in the studied clinical and pathological groups of NETs, however, we note that in all cases of an unfavorable course of the disease (progression, death), was noted MSS status of tumors. Conclusions: Thus, MSI-positive NET of colon resembles MSI-positive adenocarcinomas of colon in frequency and pathogenetic mechanisms, while in terms of the identified frequency of MSI in pancreatic NET resembles the NET of the small intestine.

Sequential filtering for clinically relevant variants as a method for clinical interpretation of whole exome sequencing findings in glioma

BackgroundIn the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings.MethodsThe analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas.ResultsThe median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14–33) variants per patient was reported. There was a median of 6 (0–590) reported somatic short variants per tumor. A median of 19 (0–94) broad SCNAs and a median of 6 (0–12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%).ConclusionsWe demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.

Microsatellite Instability Incidence in Recurrent Colon Cancer Stage II and III

Objective: To evaluate the incidence of Microsatellite Instability (MSI) in patients with Colon Cancer in stage II & III in the Mexican population. Methods: This is a descriptive, retrospective and cross-sectional study performed through a review of 30 clinical charts of patients with the diagnosis of Colorectal Cancer and evaluation of Microsatellite Instability in surgical pathology specimens. Results: Males with 53.3% had a higher incidence than females. The most frequent site was the left colon (53%), followed by the right colon (16.6%), higher rectum (10%), mid rectum (10%), and lower rectum (10%). The majority of the patient were classified as moderately differentiated (86.7%), with 6.7% being poorly differentiated and the rest 6.7% well differentiated. For the presence of MSI in repair genes (MLH1, MSH2, PMS2), this was positive in 33% of the population studied. The clinical-stage most frequently affected was IIA with 36.7% of the positive cases followed by stage IIB with 20%, stage IIIA 20%, and finally, stage IIC and IIIB with 13% and 10% respectively. Among histologic subtypes, adenocarcinoma was found in 90% of the cases, mucinous carcinoma in 6.7%, and signet ring cell carcinoma in 3.3%. In regards to treatment, 50 % of patients underwent only surgery while the other 50% were treated with surgery followed by adjuvant chemotherapy. Clean surgical margins were achieved in 93.7% after initial surgery and the rest were taken back to surgery for a wider resection. The predominant tumor size was T2 (50%), T3 (33%), and T4a (16.7%). The most commonly found lymph node involvement was N1a with 63.3% of the cases followed by N1b with 16.7%. In terms of recurrent metastatic disease, M1a was the most frequent, found in 73.3% of the cases. Conclusion: In our study population in contrast with current literature from the rest of the world we found a higher presence of microsatellite instability (33% vs 15%) and a higher incidence in the left colon with a definitive impact in the survival of patients.

Remnant gastric cancer: a neglected group with high potential for immunotherapy.

The importance of targeted therapy and interest in the study of predictive markers in gastric cancer (GC) have increased in recent years with the use of anti-HER2 therapy and immunotherapy with anti-PD1/PD-L1 for microsatellite instability (MSI) and PD-L1 + tumors. However, the behavior of remnant GC (RGC) in this scenario is poorly reported. Thus, this study aims to evaluate the clinicopathological characteristics and prognosis of RGC and its association with the expression of current markers for targeted therapy. All RGC resections performed in a single center from 2009 to 2019 were retrospectively reviewed. As a comparison group, 53 primary proximal GC (PGC) who underwent total D2-gastrectomy were selected. HER2, MSI status and PD-L1 expression were analyzed by immunohistochemistry. Combined Positive Score (CPS) was used to determine PD-L1 positivity. A total of 40 RGC were included. RGC patients were older (p = 0.001), had lower BMI (p = 0.001) and number of resected lymph nodes (p < 0.001) compared to the PGC. Regarding markers expression, MSI was higher in RGC than PGC (27.5% vs 9.4%, p = 0.022). The frequency of CPS-positive was 32.5% and 26.4% in RGC and PGC, respectively (p = 0.522). HER2 positivity was 17.5% and 22.6% for RGC and PGC, respectively (p = 0.543). In survival analysis, DFS was better for RGC CPS-positive than RGC CPS-negative (p = 0.039) patients. There was no difference in survival considering MSI status. RGC had higher incidence of MSI than PGC, and CPS-positive RGC was associated with better survival. The immunological profile of RGC patients suggests that they would be good candidates for immunotherapy.

MICROSATELLITE INSTABILITY AND GASTRIC CARCINOMA. REVIEW OF THELITERATURE

Carcinoma of the stomach is wide spread malignancy with the poor prognosis. Recent investigations of the genome features let to consider this tumor as heterogeneous lesion, presenting different biological subtypes. Each of those subtypes has its own definitive characteristics including difference in prognosis. Microsatellite instability (MSI) – epigenetic molecular abnormality known in many tumors. The role of MSI in the carcinoma of stomach, prognostic as well predictive, is still not clear. High incidence (10 up to 22 %) of MSI in carcinoma of stomach requires performing more extensive studying of this malignancy. The present review is dedicated to recent data of the literature, concerning clinical, morphological, prognostic and predictive features of MSI in the carcinoma of stomach.

A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability–High Cases in 67,000 Patient Samples

Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.

Molecular alterations and PD-L1 expression in non-ampullary duodenal adenocarcinoma: Associations among clinicopathological, immunophenotypic and molecular features

Non-ampullary duodenal adenocarcinoma (NADC) is extremely rare. Little is known about its clinicopathological and molecular features or its management. Herein we retrospectively analyzed the cases of 32 NADC patients, focusing on microsatellite instability (MSI), genetic mutations, CpG island methylator phenotype (CIMP), and immunostaining including mucin phenotype and PD-L1 expression. The incidence of MSI, KRAS/BRAF/GNAS mutations and CIMP was 51.6%, 34.4%/3.1%/6.5% and 28.1%, respectively. PD-L1 expression was seen in 34.4% of patients. No significant associations between clinicopathological features and KRAS/BRAF/GNAS genetic mutations or CIMP were found. Histologically non-well-differentiated-type NADCs and those in the 1st portion of the duodenum were significantly associated with later stages (stages III–IV) (P = 0.006 and P = 0.003, respectively). Gastric-phenotype NADCs were frequently observed in the 1st portion and in late-stage patients; their cancer cells more frequently expressed PD-L1. Histologically, the non-well-differentiated type was an independent predictor of PD-L1 expression in cancer cells (OR 25.05, P = 0.04) and immune cells (OR 44.14, P = 0.02). Only late-stage disease (HR 12.23, P = 0.01) was a prognostic factor for worse overall survival in a Cox proportional hazards regression model. Our observation of high proportions of MSI and PD-L1 expression may prompt the consideration of immune checkpoint inhibitors as a new treatment option for NADCs.

A pilot study on clinicopathological features and intestinal microflora changes in colorectal cancer patients born over a nine-year period encompassing three years before and after the Great Chinese famine

BackgroundExposure to energy restriction during childhood is associated with a lower risk of developing colorectal cancer (CRC). To date, the association between this critical period of growth and prognosis of CRC has rarely been investigated. Changes in microbiota and epigenetic dysregulation may be key underlying mechanisms. MethodologyTissues collected from patients born between 1956 and 1964 were grouped based on time-period. The differences in overall survival among patients from the three time-periods were examined via univariate analysis. The 16S rRNA gene sequencing approach was to determine differences in microbiota among the groups. Samples were randomly selected to detect BRAF mutations, microsatellite instability (MSI) and promoter CpG island methylator phenotype (CIMP) status. The chi-square test was to assess the relationship between alterations in these molecules and microbiota differences. ResultsPatients from the three groups differed in terms of location of CRC (P = 0.034) and carcinoembryonic antigen (CEA) level (P = 0.036). A survival advantage was observed in the famine group compared with the other two groups. Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were more abundant in the two comparing groups. Abundance of B. fragilis was associated with BRAF mutations, microsatellite instability (MSI) and abundance of E. coli. Moreover, the incidence of CIMP and MSI was higher in patients with greater abundance of F. nucleatum. ConclusionsLimitation of energy intake during childhood may affect the composition of gut microbiota, resulting in persistent epigenetic changes that subsequently influence the prognosis of patients with CRC.

Abstract 2610: Consequences of a high incidence of microsatellite instability (non-Lynch) and BRAF mutated tumors in a population based cohort of metastatic colorectal cancer

Abstract Background: Clinical trials in metastatic colorectal cancer (mCRC) have shown few patients with microsatellite instable high (MSI-H) tumors and BRAF mutations (mutBRAF). Recent data show that patients with MSI-H tumors benefit from immunotherapy and there are promising data of adding BRAF inhibitors to standard treatment in patients with mutBRAF. It is therefore important to know the frequency of these molecular changes and their importance for outcome in unselected populations of mCRC. Methods: A prospectively collected population-based cohort of 798 mCRC patients from three geographic areas in Scandinavia was studied. Gene analysis was available for 446 cases for BRAF and KRAS analysis, MSI analysis was done for mutBRAF only. Immunohistochemistry was performed for BRAF and MMR in 611 patients. Kaplan-Meier method, logistic regression and Cox proportional hazards models were used for statistical analyses. Results: Totally 8 % (46/589 patients) were MSI-H and 20 % (119/586 patients) were mutBRAF. MSI-H tumours harboured mutBRAF in 76 % of cases and 29 % of mutBRAF was MSI-H. MSI-H correlated to female sex, age &amp;gt;75 years, right-sided tumor, mutBRAF, lymph node metastasis and less often lung and liver metastasis. Patients with MSI-H received less often chemotherapy compared to MSS patients; 46 % vs. 64 % received 1st line, 13 % vs. 38 % received 2nd line and 2 % vs. 17 % received 3rd line chemotherapy, respectively. Patients with MSI-H had poorer prognosis, however only significant in BRAF wildtype (wtBRAF) patients, and the negative prognostic potential of mutBRAF was only valid in MSS tumors. Median overall survival (OS) was 4 months in MSI-H vs. 11 months in MSS tumors (p &amp;lt; 0.001). After multivariate analysis of OS in patients given 1st line chemotherapy MSI-H and mutBRAF was independent poor prognostic factors with HR 2.2 (95 % CI: 1.09, 4.60, p = 0.028) and HR 1.9 (95 % CI: 1.24, 2.97, P = 0.004) respectively. Median progression-free survival (PFS) during 1st line chemotherapy was 4 months for MSI-H vs. 8 months for MSS tumors (p = 0.087), and multivariate analysis of PFS showed HR 2.21 (95 % CI: 1.10, 4.44, p = 0.027). MSI-H and wtBRAF patients (n=10) had the worst prognosis with median OS of 1 month (p &amp;lt;0.001) and median PFS after 1st line chemotherapy of 2 months (p = 0.015). Conclusion: In unselected patients with mCRC, MSI-H and mutBRAF are more common than previously reported, and consequently more patients could benefit from immunotherapy and BRAF inhibitor treatments. Most MSI-H patients harbored mutBRAF (non-Lynch) in contrast to patients in recent mCRC immunotherapy trials, and further studies are needed to evaluate the effect of immunotherapy in this subgroup. Chemotherapy had minimal effect in MSI-H patients and fewer received 2-line palliative chemotherapy indicating that these patients could be considered for immunotherapy as 1st line treatment. Citation Format: Kristine Aasebø, Anca Dragomir, Magnus Sundström, Per Pfeiffer, Per-Henrik Edqvist, Geir Eide, Fredrik Ponten, Camilla Qvortrup, Bengt Glimelius, Halfdan Sørbye. Consequences of a high incidence of microsatellite instability (non-Lynch) and BRAF mutated tumors in a population based cohort of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2610.

Abstract PD6-03: Distribution of microsatellite instability, tumor mutational load, and PD-L1 status in molecularly profiled invasive breast cancer

Abstract Background: Recent data indicate a promising response to immune check point blockade (ICB) in patients with breast cancer. Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1) receptor and one of several ICB agents in development, was given an FDA approval for all MSI (microsatellite instability)-high solid tumors. MSI incidence in breast cancer is not fully elucidated. Other biomarkers being explored in possible relationship to ICB activity include PD-1 ligand (PD-L1) status and tumor mutational load (TML). In this study, we aimed to explore the incidence of these biomarkers in invasive breast cancers. Methods: A retrospective data analysis of patients profiled by commercial next-generation sequencing (NGS) at Caris Life Sciences was performed. MSI results were either high, stable, or equivocal. MSI was calculated by comparing repeat-insertions or deletions across over 7,000 microsatellite sequences in the patient sample to the hg19 reference genome. Samples with repeat variances in more than 45 microsatellites were classified as MSI-High PD-L1 expression was evaluated using immunohistochemical analysis (IHC), with clone SP-142 (Roche Diagnostics). A sample was considered positive if there was &amp;gt;5% membranous staining of tumor cells. Tumor mutational load was calculated as a total number of non-synonymous somatic mutations identified per megabase of the genome coding area with high being greater than or equal to 17. Results: A total of 9,627 breast cancer cases were queried from the Caris Life Sciences database. The mean age (±SD) was 56.8 ± 12.4 years (range 20-90). The tumor distribution was 60.7% hormone receptor (HR) positive (ER and/or PR) and HER2 negative, 9.5% HER2 positive (with HR negative or positive), and 29.8% triple negative (negative for ER, PR and HER2). Of all cases, there were 5,203 tested for PD-L1 status, 354 (6.8%, 95% CI 6.2-7.5%) were positive. Of 1,440 tumors tested for MSI status, 15 (1.04%, 95% CI 0.58-1.71%) were either high (8) or equivocal (7), the rest were MSI-low. Tumor mutational load (TML) was available on 1,766 tumors, of which 55 (3.1%, 95% CI 2.4-4.0%) were high. Seven out of the 8 MSI-high tumors were also TML-high. Four out of the 8 MSI-high breast cancers were triple negative. Conclusion: In this large dataset of molecularly profiled breast cancer, MSI was observed in about 1% of the breast tumors tested. Overall, modest positivity of TML, PD-L1, and MSI of all invasive breast cancers was observed. The percentage of patients that had at least one of these biomarkers that may confer responsiveness to ICB is planned and will be further stratified by subtype. MSI-high breast cancers mostly overlapped with those that were TML-high. Future research is needed to show the clinical utility of these biomarkers in response to ICB. Updated data will be presented. Citation Format: Obeid E, Ellerbrock A, Handorf E, Goldstein L, Gatalica Z, Arguello D, Swain SM, Isaacs C, Vacirca J, Tan A, Schwartzberg L. Distribution of microsatellite instability, tumor mutational load, and PD-L1 status in molecularly profiled invasive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-03.

Trial in progress: A multicenter phase II study of pembrolizumab in patients with advanced small bowel adenocarcinomas.

TPS535 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, possibly because of the high rate of immunosurveillance in baseline small bowel function, and is frequently diagnosed in late stages. Due to these factors, there is no consistent standard of care for metastatic disease beyond first-line where several prospective studies have confirmed activity of FOLFOX/CAPOX. Historically, second-line treatment of SBA has been extrapolated from colon/gastric cancer. Recent studies suggest that SBA has a distinct genomic profile, including higher incidence of microsatellite instability, compared to gastric and colon cancers. Additionally, the tumor microenvironment reflects a greater degree of PD-L1 expression and infiltration by lymphocytes. Immune checkpoint inhibitors have not previously been tested in SBA unselected for MSI status. Methods: The study is a phase 2, multicenter, single-arm clinical trial of pembrolizumab (200 mg IV every 3 weeks) for patients with unresectable or metastatic SBA refractory to first-line chemotherapy. Forty patients with any tumor mismatch repair status will be enrolled at 8 US sites as part of the ACCRU network and International Rare Cancer Initiative (IRCI) with a primary objective to assess the confirmed response rate (H0 p &lt; 10%, HA: p &gt; 30%) to pembrolizumab. Secondary endpoints include PFS, OS, and adverse events. Correlative aims include assessing blood and tissue biomarkers (i.e. PD-L1, MSI-H/MSS status, cfDNA, mutation burden, etc.) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 18 patients become evaluable. The study is open with 16 patients enrolled at time of submission. Clinical trial information: NCT02949219.

Treatment of Elderly Patients with Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. As society ages, the number of elderly patients with CRC will increase. The percentage of patients with right-sided colon cancer and the incidence of microsatellite instability are higher in elderly than in younger patients with CRC. Moreover, the higher incidence of comorbid diseases in elderly patients indicates the need for less invasive treatment strategies. For example, care should be taken in performing additional surgery after endoscopic submucosal dissection for elderly patients with high-risk T1 CRC. Minimally invasive surgery, such as laparoscopic colectomy, would be preferable for elderly patients with CRC. Chemotherapy for elderly patients requires careful monitoring for adverse events. The aim of this review is to summarize the clinicopathological features of CRC in elderly patients, optical surgical strategies, including endoscopic and laparoscopic resection, and chemotherapeutic strategies, including postoperative adjuvant chemotherapy and systemic chemotherapy for unresectable CRC.

Abstract IA05: Epidemiologic, environmental, and molecular disparities in gastrointestinal cancer among Hispanics

Abstract IA05: Epidemiologic, environmental, and molecular disparities in gastrointestinal cancer among Hispanics