Reference Detail

Ref Type

Abstract

PMID

Authors

G. Maddalena F.A. Zeineddine S. Chowdhury M. Zeineddine A. Yousef M.J. Overman E.S. Kopetz J.P.Y-C. Shen

Title

631P Using the unique somatic mutation profile of POLE loss of proof-reading mutation helps in selection of patients who may benefit from immunotherapy

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	34	Supplement 2	October 2023

URL

https://www.annalsofoncology.org/article/S0923-7534(23)02658-3/fulltext

Abstract Text

Background It has been reported that POLE mutant tumors are likely to respond to immune therapy, however, most POLE mutations are passenger mutations and do not induce a hypermutated phenotype. Current methods to classify POLE mutations are limited in both accuracy and completeness complicating the selection of patients (pts) most likely to benefit from immunotherapy. Methods A curated list of 13 known loss of proof-reading (LOP) POLE mutations was used to identify 66 tumors with POLE LOP mutation from which we extracted somatic mutation signatures, these averaged together defined a positive control POLE LOP signature. POLE mutant tumors with mutational signatures highly correlated with the positive control (> 0.7) were determined to be LOP. Results A total of 1467 POLE mutations (mut) were identified from 50962 tumors accessed from cBioPortal. Correlation with the positive control POLE LOP signature was sensitive (all tumors with known POLE LOP mutation from literature were recovered) and specific (92/97 = 94.8% had high TMB, a hallmark feature of POLE LOP). In addition to recovering known LOP mut found in the exonuclease region, several new LOP were discovered including R705W mut, which is in the DNA polymerase domain and positioned to interface with the binding to DNA. To evaluate POLE LOP as a predictive biomarker a cohort of pts with POLE mutant mCRC treated with immunotherapy (IO) (n=29) was identified from institutional databases. All 7 pts with POLE LOP achieved clinical benefit (3 CR, 3 PR, 1 SD) and remain on immunotherapy at the time of submission (median follow up time = 36 months). In contrast, none of the 7 MSS pts with Non-LOP POLE mut achieved an objective response to IO therapy (2 SD, 5 PD), and had disease progression with median PFS of 3.6 months (log-rank p<0.0003). For the other 15 pts with Non-LOP POLE mut response was supported by MSI-H status. Conclusions Identifying of the subset of POLE mut that cause LOP is critical in order to correctly identify pts most likely to benefit from immune therapy. CRC tumors with LOP POLE mutation were found to have deep, sustained response to IO therapy, in contrast to those with non-LOP POLE mutations.

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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
POLE inact mut	colorectal cancer	predicted - sensitive	unspecified immune checkpoint inhibitor	Clinical Study - Cohort	Actionable	In a clinical study, immunotherapy resulted in improved clinical benefit in patients with metastatic colorectal cancer harboring POLE inactivating mutations (n=7, 3 complete responses, 3 partial responses, 1 stable disease (SD)) and durable response (remained on therapy with median follow up of 36 months) compared to microsatellite stable (MSS) patients harboring non-loss-of-function POLE mutations (n=7, 2 SD; median progression-free survival 3.6 months, p<0.0003) (Ann Oncol (2023) 34 (suppl_2): S448-S449).	detail...