scholarly journals Pan-cancer analysis of CD274 (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression

2021 ◽  
Vol 9 (6) ◽  
pp. e002558
Author(s):  
Richard S.P. Huang ◽  
Brennan Decker ◽  
Karthikeyan Murugesan ◽  
Matthew Hiemenz ◽  
Douglas A. Mata ◽  
...  
Keyword(s):  
Protein Expression ◽  
Checkpoint Inhibitors ◽  
Endometrial Adenocarcinoma ◽  
Primary Melanoma ◽  
B Cell Lymphoma ◽  
Unknown Primary ◽  
Future Research ◽  
Tumor Type ◽  
Missense Mutations ◽  
L1 Protein

BackgroundThe effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1.MethodsCGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS).ResultsOverall, the prevalence of CD274 SV mutations was low (0.3%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p<0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049)ConclusionsWe defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.

Pan-cancer analysis of CD274 (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2605-2605
Author(s):  
Richard S.P. Huang ◽  
Brennan Decker ◽  
Karthikeyan Murugesan ◽  
Matthew Hiemenz ◽  
Douglas A. Mata ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Cutaneous Melanoma ◽  
Endometrial Adenocarcinoma ◽  
Primary Melanoma ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Unknown Primary ◽  
L1 Protein

2605 Background: The effects of non-amplification short variant (SV) mutations in CD274 (PD-L1) on PD-L1 protein expression and immune checkpoint inhibitor (ICPI) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. Methods: FoundationOne CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n = 213) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Results: Overall, the prevalence of CD274 SV mutations was low (0.3%, 1,081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n = 51), R260C (n = 18), R125Q (n = 12), C272fs*13 (n = 11), R86W (n = 10), and R113H (n = 10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Ultraviolet exposure was likely a mechanism for CD274 SV mutations in cutaneous tumors with high frequencies of ultraviolet mutational signatures (cutaneous squamous cell carcinoma [84.6%, 11/13], cutaneous melanoma [93.8%, 30/32], and unknown primary melanoma [100%, 32/32]), and microsatellite instability (MSI) was likely a mechanism for development of CD274 mutations in non-serous endometrial adenocarcinoma. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. This difference in protein expression of these two mutations was significantly different (p = 0.036). It was notable that nearly all samples (88.9%, 16/18) with a clonal truncating variant (nonsense or frame shift indel) and PD-L1 testing showed a PD-L1 TPS score ≤1, whereas three of four samples with sub-clonal truncating variants had TPS scores ≥5. Conclusions: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.

scholarly journals Pan-cancer landscape of CD274 (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression

2021 ◽  
Vol 9 (5) ◽  
pp. e002680
Author(s):  
Richard S.P. Huang ◽  
Karthikeyan Murugesan ◽  
Meagan Montesion ◽  
Dean C. Pavlick ◽  
Douglas A. Mata ◽  
...  
Keyword(s):  
Protein Expression ◽  
Solid Tumor ◽  
Copy Number ◽  
Endometrial Adenocarcinoma ◽  
Gastroesophageal Junction ◽  
Large Cohort ◽  
Tumor Type ◽  
Potential Biomarker ◽  
Tumor Types ◽  
L1 Protein

IntroductionSeveral studies have shown clinical outcomes data that support the use of CD274 (PD-L1) copy-number (CN) gains and/or losses as a biomarker for immune checkpoint inhibitor (ICPI). Here, we present the landscape of CD274 CN changes across a large cohort of solid tumor cases and correlate these with PD-L1 protein expression by immunohistochemistry.MethodsWe analyzed all cases that underwent comprehensive genomic profiling (CGP) testing at Foundation Medicine between August 2014 and June 2020. CD274 CN changes were correlated with PD-L1 expression in tumor types where there were Food and Drug Administration approved companion diagnostic (CDx) claims and the CDx assay was used to assess PD-L1 expression.ResultsIn all, 244 584 samples representing 290 solid tumor types were included in the study. Overall, 17.6% (42 983/244 584) had CD274 CN gains (>specimen ploidy), 44.6% (108 970/244 584) were CD274 CN neutral, and 37.9% (92 631/244 584) had CD274 CN loss. Using different CN cut offs to define CD274 positivity resulted in different prevalence estimates: ploidy +1, 17.4% (42 636/244 584); ploidy +2, 6.2% (15 183/244 584); ploidy +3, 2.2% (5375/244 584); ploidy +4, 1.1% (2712/244 584); and ploidy +8, 0.2% (434/244 584). The prevalence of CN changes and CN positivity varied based on tumor type. CD274 CN gains were significantly associated with PD-L1 positivity in NSCLC, urothelial carcinoma, breast carcinoma, cervical carcinoma, esophagus squamous cell carcinoma (SCC) and head and neck SCC (ORs 3.3, 3.0, 2.0, 4.5. 3.8, 8.4, 1.4, respectively; p<0.05) and with microsatellite instability status in only clinically relevant tumor types (gastric adenocarcinoma, colorectal adenocarcinoma, uterine endometrial adenocarcinoma, esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma (OR: 5.2, 1.9, 3.2, 3.7 and 6.5, respectively; p<0.05)). Conversely, CD274 CN changes were not significantly correlated with tumor mutational burden in almost all the tumor types.ConclusionCD274 CN changes and PD-L1 expression were highly correlated in multiple tumor types. These prevalence data on CD274 CN changes across a large cohort of different solid tumors can be used to design future clinical studies to assess whether CD274 CN changes could be a potential biomarker for ICPI.

scholarly journals Value of PD-L1 Protein Expression in the Combined Prognostic Model of Diffuse Large B-Cell Lymphoma

2021 ◽  
Vol 14 (3) ◽  
pp. 308-314
Author(s):  
Svetlana Valerevna Samarina ◽  
N.Yu. Semenova ◽  
N.V. Minaeva ◽  
D.A. Dyakonov ◽  
V.A. Rosin ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
L1 Protein ◽  
Large B Cell

scholarly journals Biomarkers for Predicting Response to Immunotherapy with Immune Checkpoint Inhibitors in Cancer Patients

2019 ◽  
Vol 65 (10) ◽  
pp. 1228-1238 ◽  
Author(s):  
Michael J Duffy ◽  
John Crown
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Future Research ◽  
Specific Gene ◽  
Tumor Type ◽  
Clinical Use ◽  
Durable Response ◽  
Cancer Types

Abstract BACKGROUND Immunotherapy, especially the use of immune checkpoint inhibitors, has revolutionized the management of several different cancer types in recent years. However, for most types of cancer, only a minority of patients experience a durable response. Furthermore, administration of immunotherapy can result in serious adverse reactions. Thus, for the most efficient and effective use of immunotherapy, accurate predictive biomarkers that have undergone analytical and clinical validation are necessary. CONTENT Among the most widely investigated predictive biomarkers for immunotherapy are programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden (TMB). MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types (e.g., for predicting response to first-line pembrolizumab monotherapy in non-small cell lung cancer). Although not yet approved for clinical use, TMB has been shown to predict response to several different forms of immunotherapy and across multiple cancer types. Less widely investigated predictive biomarkers for immunotherapy include tumor-infiltrating CD8+ lymphocytes and specific gene signatures. Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving. An urgent focus of future research should be the optimization and standardization of method for determining these biomarkers. SUMMARY Biomarkers for predicting response to immunotherapy are paving the way for personalized treatment for patients with diverse cancer types. However, standardization of the available biomarker assays is an urgent requirement.

scholarly journals A Comprehensive Pan-Cancer Analysis of RBM8A Based on Data Mining

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Nan Mei ◽  
Heyan Chen ◽  
Ni Zhao ◽  
Ye Yi ◽  
Chunli Li
Keyword(s):  
Rna Binding ◽  
Checkpoint Inhibitors ◽  
Study Data ◽  
Binding Motif ◽  
Exon Junction Complex ◽  
Tumor Type ◽  
Missense Mutations ◽  
Normal Tissues ◽  
Kaplan Meier ◽  
Cancer Types

Background. As a member of the exon junction complex (EJC), RNA-binding motif protein 8A (RBM8A) plays a crucial role in the maintenance of mRNA and multiple activities of an organism. Immunotherapy has been proven to be a staple type of cancer treatment. However, the role of RBM8A and immunity across cancer types is unclear. Objective. This study aims to visualize the expression, prognosis, mutations, and coexpressed gene results of RBM8A across cancer types and to explore the link between RBM8A expression and immunity. Methods. In this study, data were collected from multiple online databases. We analyzed the data using the HPA, UALCAN Database, COSMIC, cBioPortal, Cancer Regulome tools, Kaplan–Meier Plotter, and TIMER website. Results. For the expression of RBM8A in normal tissues, higher expression of RBM8A was observed in immune-related cells than in nonimmune organs. The expression level of RBM8A was related to tumor type. Missense mutations in RBM8A were found in most tumors and affected the prognosis of carcinomas with coexpressed genes. RBM8A was strongly associated with immune-infiltrating cells and immune checkpoint inhibitors, especially in LIHC. Conclusions. RBM8A is a gene worth exploring and may be a unique immune target in the future.

scholarly journals Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy

2021 ◽  
Vol 9 (1) ◽  
pp. e001642
Author(s):  
April A N Rose ◽  
Susan M Armstrong ◽  
David Hogg ◽  
Marcus O Butler ◽  
Samuel D Saibil ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Primary Tumor ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Advanced Melanoma ◽  
Unknown Primary ◽  
Tumor Type ◽  
Multivariable Analyses ◽  
Primary Tumor Type

PurposeAnti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.MethodsWe performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019. Primary tumor type, BRAF and NRAS mutation status, and other covariates were abstracted from chart review. Log-rank tests and multivariable Cox regression models were used to assess differences in clinical progression-free (cPFS) and overall survival (OS).ResultsWe identified 230 patients who received 249 lines of anti-PD1±anti-CTLA4 ICI for unresectable or metastatic disease. Of these patients, 74% were cutaneous, 11% mucosal, 8% unknown primary and 7% acral. BRAF and NRAS mutations were identified in 35% and 28% of patients, respectively. In multivariable analyses of the entire cohort, acral or mucosal primary tumor type, >3 metastatic sites, elevated LDH were predictive of shorter cPFS and OS. Combination ICI therapy was associated with longer cPFS (HR 0.57, 95% CI 0.38 to 0.86, p=0.007) and OS (HR 0.42, 95% CI 0.28 to 0.65, p<0.001). Combination ICI was significantly associated with longer OS in unknown primary and mucosal melanoma. There was a non-significant trend toward longer OS with anti-PD1+anti-CTLA4 in cutaneous melanoma, but not in acral melanoma. In multivariable analyses, combination ICI was associated with longer OS in NRAS (HR 0.24, 95% CI 0.10 to 0.62, p=0.003, n=69) and BRAF V600E/K (HR 0.47, 95% CI 0.24 to 0.90, p=0.024, n=86) mutant melanoma but not BRAF/NRAS wild-type (n=94) melanoma.ConclusionsIn our cohort, primary melanoma tumor type and genomic subtype were independent predictive markers of cPFS and OS for patients with metastatic melanoma receiving anti-PD1 ICI. Primary tumor type and genomic subtype—including NRAS—should be further evaluated in prospective clinical trials to determine their value as predictive markers. Biologic subtypes may facilitate clinical decision-making when recommending combination ICI treatment (anti-PD1±anti-CTLA4) versus anti-PD1 alone for patients with metastatic melanoma.

scholarly journals The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 586 ◽  
Author(s):  
Cyrillo G. Brahm ◽  
Myra E. van Linde ◽  
Roelien H. Enting ◽  
Maaike Schuur ◽  
René H.J. Otten ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Retrospective Studies ◽  
Checkpoint Inhibitors ◽  
Current Status ◽  
Future Research ◽  
Tumor Type ◽  
Immunological Responses ◽  
Novel Treatment ◽  
Limited Efficacy

The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified (n = 8 in glioblastoma and n = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients.

scholarly journals PD-L1 Expression Is Low in Large B-Cell Lymphoma with MYC or Double-Hit Translocation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4113-4113 ◽  
Author(s):  
Mette Vestergaard Elbæk ◽  
Mette Ø Pedersen ◽  
Marie Fredslund Breinholt ◽  
Anupama Reddy ◽  
Cassandra Love ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Mrna Expression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tissue Samples ◽  
Large B Cell Lymphoma ◽  
L1 Protein ◽  
Mrna Expression Levels ◽  
Large B Cell

Abstract Introduction: In large B-cell lymphoma (LBCL) MYC translocation and MYC/BCL2 or BCL6 double hit (DH) is associated with poor prognosis and there is an unmet need for novel treatment targets in this patient group. Treatment targeting the PD-L1/PD-1 pathway has been successfully introduced in Hodgkin lymphoma and solid cancers but are still poorly elucidated in LBCL. PD-L1 expression might predict response to treatment targeting the PD-L1/PD-1 pathway. We therefore investigated the relationship between PD-L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. Material and Methods: MYC, BCL2 and BCL6 translocations were detected by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 patients had DH and 81 without MYC translocation. PD-L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD-L1 mRNA expression by next-generation RNA sequencing (NGS) in another 77 patients. 24 patients overlapped, i.e. were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. Results: PD-L1 protein expression level was lower in patients with MYC translocation (n=42, median=3,3%, IQR 0,0-10,8) or DH (n=31, median=3,3%, IQR 0,0-10,0) compared to patients with no MYC translocation (n=35, median=16,7%, IQR 3,3-30,0) or DH (n=46, 13,3%, IQR 2,5-30,0), P=0.004 and P<0,001 respectively (Fig.1). PD-L1 mRNA expression was also significantly lower in patients with MYC translocation or DH, P=0,001 and P=0,006 respectively. Higher PD-L1 protein and mRNA expression levels were associated with non-GC-type compared to GC-type DLBCL, P= 0,004 and P=0,002 respectively. Conclusions: We report a highly significant association between low PD-L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD-L1/PD-1-inhibitors compared to patients without these translocations. This should be evaluated in larger, prospective, consecutive trials. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD274 (PD-L1) Copy Number Changes (Gain) & Response to Immune Checkpoint Blockade Therapy in Carcinomas of the Urinary Tract

2021 ◽  
pp. 1-6
Author(s):  
Sounak Gupta ◽  
Chad M. Vanderbilt ◽  
Yanming Zhang ◽  
Satish K. Tickoo ◽  
Samson W. Fine ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Next Generation Sequencing ◽  
Protein Expression ◽  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
L1 Protein ◽  
Generation Sequencing

BACKGROUND: Immune checkpoint inhibitors are an important therapeutic option for urothelial carcinoma, but durable responses are achieved in a minority of patients. Identifying pre-treatment biomarkers that may predict response to these therapies or who exhibit intrinsic resistance, is of paramount importance. OBJECTIVE: To explore the prevalence of PD-L1 copy number alteration in urothelial carcinoma and correlate with response to immune checkpoint inhibitors. METHODS: We analyzed a cohort of 1050 carcinomas of the bladder and upper urinary tract that underwent targeted next generation sequencing, prospectively. We assessed PD-L1 protein expression, copy number status (next generation sequencing/FISH), and detailed treatment response. RESULTS: We identified 9 tumors with PD-L1 amplification and 9 tumors with PD-L1 deletion. PD-L1 protein expression was the highest in PD-L1 amplified tumors. Of the 9 patients whose tumors harbored PD-L1 amplification, 6 received immunotherapy with 4 deriving clinical benefit, and two achieving durable response. Of the 9 patients whose tumors had PD-L1 copy number losses, 4 received immunotherapy with 3 experiencing disease progression. CONCLUSIONS: PD-L1 copy number alterations may serve as potential biomarkers of response to immunotherapy in urothelial carcinoma patients, if validated in larger cohorts.

Use of cancer immunotherapies in the real-world in the setting of microsatellite instability.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 30-30
Author(s):  
Vineeta Agarwala ◽  
Anala Gossai ◽  
Gaurav Singal ◽  
Claire O'Connell ◽  
Gerald Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Real World ◽  
Checkpoint Inhibitors ◽  
Clinical Care ◽  
Unknown Primary ◽  
Tumor Type ◽  
Real World Data ◽  
The Real ◽  
Genomic Marker

30 Background: In May 2017, the FDA approved for the first time a cancer therapy (pembrolizumab) for use in patients based on the presence of a genomic marker (microsatellite instability, or MSI) rather than anatomical tumor type. Real-world data on the rates and clinical impact of MSI on treatment selection and response are scant, especially outside of colorectal cancer. Methods: We performed a retrospective study of all patients treated in the Flatiron Health network (>265 oncology practices across the U.S.) between January 2011 and June 2017, and who underwent FoundationOne tumor sequencing as part of routine clinical care. Tumor type was determined by pathologist review of specimens submitted to Foundation Medicine. Data on therapy use was sourced from electronic health records (EHRs). Assessment of MSI was performed from DNA sequencing across the coding regions of >300 genes. Results: Our overall cohort included n=16,020 patients. Among patients in whom MSI status could be assessed (n=12,411), 207 patients had MSI-high tumors. The observed rate of MSI-high was 1.7% across all tumor types combined; tumor-specific rates varied significantly, from 4.9% in colorectal adenocarcinoma to 0.3% in breast and non-small cell lung cancer. The rate of MSI-high was 2.4% in patients with an unknown primary based on specimen review. A total of 1,329 patients received common checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab). Among the checkpoint-inhibitor treated patients with known MSI status (n=1,175), 14 (1.2%) had MSI-high tumors, and the majority of these patients (n=8) had colorectal cancer. Conclusions: Evidence of MSI-high is rare in real world cancer care settings. Early identification of patients with this biomarker is important in order to efficiently match them to treatment. Further evaluation of the real-world effectiveness of immune checkpoint inhibitors in the MSI-high population is still needed. Because most patients receiving these therapies today do not have high MSI, exploration of additional biomarkers for immunotherapy response is also critical.

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