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	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References