Reference Detail

Ref Type

Journal Article

PMID

(33926917)

Authors

Chida K, Kawazoe A, Kawazu M, Suzuki T, Nakamura Y, Nakatsura T, Kuwata T, Ueno T, Kuboki Y, Kotani D, Kojima T, Taniguchi H, Mano H, Ikeda M, Shitara K, Endo I, Yoshino T

Title

A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	13	2021 Jul 01	3714-3724	Clin Cancer Res

URL

Abstract Text

This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade.Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC.Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; P = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type PTEN (21.4 vs. 54.8%; odds, 4.45; P = 0.045). Compared with wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; P = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; P < 0.001), lower intratumoral CD8+ T-cell levels, higher intratumoral CD204+ macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas PTEN mutations in the C2 domain were not.Low TMBs and PTEN mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

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
PTEN mutant	gastrointestinal system cancer	decreased response	Nivolumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with MSI high, dMMR gastrointestinal tumors including gastric (n=18), colorectal (n=17), cholangiocarcinoma (n=5), small intestine (n=2), pancreatic (n=2), and duodenal cancer (n=1) harboring PTEN mutations demonstrated a decreased objective response rate (21.4 vs 54.8%), overall survival (15.2 vs 25.7 mo), and progression-free survival (4.3 vs 15.6 mo) compared to PTEN-wild-type patients when treated with Keytruda (pembrolizumab) or Opdivo (nivolumab) (PMID: 33926917).	33926917
PTEN mutant	gastrointestinal system cancer	decreased response	Pembrolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with MSI high, dMMR gastrointestinal tumors including gastric (n=18), colorectal (n=17), cholangiocarcinoma (n=5), small intestine (n=2), pancreatic (n=2), and duodenal cancer (n=1) harboring PTEN mutations demonstrated a decreased objective response rate (21.4 vs 54.8%), overall survival (15.2 vs 25.7 mo), and progression-free survival (4.3 vs 15.6 mo) compared to PTEN-wild-type patients when treated with Keytruda (pembrolizumab) or Opdivo (nivolumab) (PMID: 33926917).	33926917