Reference Detail

Ref Type

Journal Article

PMID

(35398880)

Authors

Rousseau B, Bieche I, Pasmant E, Hamzaoui N, Leulliot N, Michon L, de Reynies A, Attignon V, Foote MB, Masliah-Planchon J, Svrcek M, Cohen R, Simmet V, Augereau P, Malka D, Hollebecque A, Pouessel D, Gomez-Roca C, Guimbaud R, Bruyas A, Guillet M, Grob JJ, Duluc M, Cousin S, de la Fouchardiere C, Flechon A, Rolland F, Hiret S, Saada-Bouzid E, Bouche O, Andre T, Pannier D, El Hajbi F, Oudard S, Tournigand C, Soria JC, Champiat S, Gerber DG, Stephens D, Lamendola-Essel MF, Maron SB, Diplas BH, Argiles G, Krishnan AR, Tabone-Eglinger S, Ferrari A, Segal NH, Cercek A, Hoog-Labouret N, Legrand F, Simon C, Lamrani-Ghaouti A, Diaz LA, Saintigny P, Chevret S, Marabelle A

Title

PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	12	6	2022 06 02	1435-1448	Cancer Discov

URL

Abstract Text

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with a specific single-base substitution signature, high T-cell infiltrates, and a high response rate to anti-PD-1 monotherapy. This study illustrates how specific DNA repair defects sensitize to immunotherapy. POLE proofreading deficiency represents a novel agnostic biomarker for response to PD-1 checkpoint blockade therapy.POLE proofreading deficiency leads to high tumor mutational burden with high tumor-infiltrating lymphocytes and predicts anti-PD-1 efficacy in mismatch repair-proficient tumors. Conversely, tumors harboring POLE mutations not affecting proofreading derived no benefit from PD-1 blockade. POLE proofreading deficiency is a new tissue-agnostic biomarker for cancer immunotherapy. This article is highlighted in the In This Issue feature, p. 1397.

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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
POLE	A463V	missense	unknown	POLE A463V lies within the exonuclease domain of the Pole protein (PMID: 29352080). A463V has been identified in the scientific literature (PMID: 35398880, PMID: 29056344), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	D435G	missense	unknown	POLE D435G lies within the exonuclease domain of the Pole protein (PMID: 29352080). D435G has been identified in the scientific literature (PMID: 35398880), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	G330R	missense	unknown	POLE G330R lies within the exonuclease domain of the Pole protein (PMID: 29352080). G330R has been identified in the scientific literature (PMID: 35398880), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	G6R	missense	unknown	POLE G6R does not lie within any known functional domains of the Pole protein (UniProt.org). G6R has been identified in the scientific literature (PMID: 35398880, PMID: 27244218, PMID: 39513959), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Dec 2024).
POLE	R446Q	missense	unknown	POLE R446Q lies within the exonuclease domain of the Pole protein (PMID: 29352080). R446Q has been identified in the scientific literature (PMID: 35398880), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	R47W	missense	unknown	POLE R47W does not lie within any known functional domains of the Pole protein (UniProt.org). R47W has been identified in the scientific literature (PMID: 35398880, PMID: 31240875, PMID: 32546565), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	S297F	missense	unknown	POLE S297F lies within the exonuclease domain of the Pole protein (PMID: 29352080). S297F has been identified in the scientific literature (PMID: 29559562, PMID: 27491810, PMID: 35398880), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	S297Y	missense	unknown	POLE S297Y lies within the exonuclease domain of the Pole protein (PMID: 29352080). S297Y has been identified in the scientific literature (PMID: 35398880), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	V464A	missense	unknown	POLE V464A lies within the exonuclease domain of the Pole protein (PMID: 29352080). V464A has been identified in the scientific literature (PMID: 35398880), but has not been biochemically characterized and therefore, its effect on Pole protein function is unknown (PubMed, Mar 2024).
POLE	W775G	missense	unknown	POLE W775G lies within the polymerase domain of the Pole protein (PMID: 29352080). W775G has been identified in the scientific literature (PMID: 35398880), 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
POLE P286R	colorectal cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in a complete response in a colorectal cancer patient harboring POLE P286R, along with high tumor mutational burden and CD8-positive high tumor infiltrating lymphocytes, and a partial response in a different colorectal cancer patient also harboring POLE P286R, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE V464A	colorectal cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in a durable complete response in a colorectal cancer patient harboring POLE V464A, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE P286R	endometrial cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in stable disease in an endometrial cancer patient harboring POLE P286R, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE A463V	endometrial cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in stable disease in a patient with endometrial cancer harboring POLE A463V, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE N363K	endometrial cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in stable disease in an endometrial cancer patient harboring POLE N363K, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE G330R	biliary tract cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in stable disease in a biliary tract cancer patient harboring POLE G330R (PMID: 35398880; NCT03012581).	35398880
POLE S459F	colorectal cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in a durable partial response in a colorectal cancer patient harboring POLE S459F, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE D435G	colorectal cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in a partial response in a colorectal cancer patient harboring POLE D435G (PMID: 35398880; NCT03012581).	35398880
POLE V411L	endometrial cancer	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in a partial response in two patients with endometrial cancer harboring POLE V411L, along with high tumor mutational burden (PMID: 35398880; NCT03012581).	35398880
POLE inact mut	Advanced Solid Tumor	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a Phase II trial, Opdivo (nivolumab) resulted in an objective response rate (ORR) of 38% (7/19; all partial responses) and a disease control rate (DCR) of 58% (11/19) at 12 weeks in patients with advanced solid tumors harboring a POLE mutation, and among assessable patients with an inactivating POLE mutation, along with high tumor mutational burden, treatment resulted in an ORR of 46% (5/11) and a DCR of 73% (8/11) (PMID: 35398880; NCT03012581).	35398880