Reference Detail

Ref Type

Journal Article

PMID

(29998005)

Authors

Wang C, Gong J, Tu TY, Lee PP, Fakih M

Title

Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of gastrointestinal oncology	9	3	2018 Jun	404-415	J Gastrointest Oncol

URL

Abstract Text

Microsatellite instability-high (MSI-H) and polymerase ε (POLE)-mutated metastatic colorectal cancer (mCRC) represent hypermutated and ultramutated tumor phenotypes, respectively, that may predict benefit to checkpoint blockade [anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1)].Immune profiling through multispectral fluorescent immunohistochemistry (IHC) using a multi-marker staining panel was performed on pretreatment tumor specimens from a cohort of MSI-H or POLE-mutated mCRC patients treated with PD-1 blockade at our institution to identify candidate predictors of response to checkpoint inhibitors.From 4/2013 to 1/2017, a total of 237 mCRC patients with molecularly profiled tumors were screened. Five MSI-H and three POLE-mutated mCRC patients were treated with checkpoint inhibitors. Immune profiling identified higher CD8+ tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment (TME) of responders (CR or PR as best response) than nonresponders (SD or PD as best response). Responders had significantly higher densities of CD8+ PD-1+ TILs than nonresponders (P=0.0007). PD-L1 expression (P=0.73), CD4+ T-cell density (P=0.39), and CD4+ FOXP3+ T-cell density (P=0.68) did not significantly differ, but the percentage of CD4+ Tbet+ T-cells (Th1 phenotype) was also significantly higher in responders than nonresponders (P=0.0007).Higher densities of CD8+ TILs, PD-1-expressing CD8+ TILs, and tumor-infiltrating immune cells with a Th1 phenotype in the TME may predict response to checkpoint inhibitors in MSI-H and POLE-mutated mCRC.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
POLE	NCBI	CRCS12\|FILS\|IMAGEI\|POLE1		POLE, DNA polymerase epsilon catalytic subunit, mediates proofreading activity during DNA repair and replication (PMID: 26822575, PMID: 29604063) and plays a role in genomic stability (PMID: 31747945). Somatic mutations in POLE have been identified in colorectal cancer (PMID: 29998005, PMID: 29072370), frequently in endometrial cancer (PMID: 26822575, PMID: 28795426, PMID: 30733993), and are often associated with high tumor mutational burden (PMID: 30733993, PMID: 29880869), but are less likely to be associated with DNA mismatch repair (MMR) deficiency (PMID: 30585826).	Tumor suppressor

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 pos POLE mut	colorectal cancer	no benefit	Pembrolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, treatment with Keytruda (pembrolizumab) (n=7) or an anti-PD-1/anti-CTLA4 combination therapy (n=1) resulted in responses in 50% (4/8; 1 complete response, 3 partial responses) of metastatic colorectal cancer patients with high microinstability or POLE mutations, and PD-L1 (CD274) expression was not associated with response (PMID: 29998005).	29998005