Reference Detail

Ref Type

PMID

(34875656)

Authors

Schenck K, Masetti M, Pfarr N, Lorenzen S

Title

PD-1 Blockade Elicits Ongoing Remission in Two Cases of Refractory Microsatellite-Stable Cancer Harboring a POLE Mutation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncology research and treatment	45	4	2022	222-226	Oncol Res Treat

URL

Abstract Text

In the last decade, immune-checkpoint therapy has led to a break-through in the treatment of cancer across all entities, while molecular markers have grown in importance for the choice of the appropriate chemotherapeutic agents. Accordingly, in 2017, the US Food and Drug Administration approved the programmed cell death protein 1 inhibitor pembrolizumab, a tissue agnostic cancer drug, for the treatment of cancer that displays microsatellite instability, regardless of histological entity and site of origin. However, a growing number of studies report that cases of microsatellite-stable (MSS) tumors harboring a DNA polymerase ε (POLE) mutation, a gene associated with proofreading deficiency, leading to an increased tumor mutational burden, likewise benefit from immune-checkpoint therapy.Here, we present 2 cases - one advanced adenocarcinoma of the ileum and one mixed neuroendocrine non-neuroendocrine neoplasm, both MSS and carrying a POLE mutation - that were refractory to initial chemotherapy but responded on immunotherapy with pembrolizumab.Colorectal cancer is a clinically and molecularly heterogenic disease which requires comprehensive genetic testing to screen for rare genetic alterations like POLE mutations to detect tumors harboring an ultramutator phenotype, especially in patients that are refractory to standard chemotherapy.

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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
POLE	R34L	missense	unknown	POLE R34L does not lie within any known functional domains of the Pole protein (UniProt.org). R34L has been identified in the scientific literature (PMID: 34875656), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 over exp POLE R34L	small intestine adenocarcinoma	predicted - sensitive	Pembrolizumab	Case Reports/Case Series	Actionable	In a clinical case study, Keytruda (pembrolizumab) treatment resulted in a reduction of primary tumor and metastatic lesions and an ongoing progression-free survival at 31 months in a patient with microsatellite stable (MSS) ileum adenocarcinoma that had high CD274 (PD-L1) expression (TPS = 75%) and harbored POLE R34L, but had low tumor mutational burden (PMID: 34875656).	34875656