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POLE-Mutant and Microsatellite-Unstable Endometrial Tumors May Be Candidates for Anti–PD-1 Treatment

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Key Points

  • POLE-mutant and microsatellite-unstable tumors had a higher neoantigen load and higher levels of tumor-inflitrating lymphocytes vs microsatellite-stable tumors.
  • Overexpression of PD-1 was significantly more common in POLE-mutant and microsatellite-unstable tumors vs microsatellite-stable tumors.

In a study reported in JAMA Oncology, Howitt et al found that polymerase e (POLE)-mutant and microsatellite-unstable endometrial tumors may be candidates for anti–PD-1 (programmed cell death protein 1) immunotherapy.

Study Details

In the study, neoantigen load was predicted on the basis of sequencing data from The Cancer Genome Atlas. Tumor-infiltrating lymphocytes and expression of PD-1 and its ligand PD-L1 were measured in 63 patients with endometrial cancer referred to Brigham and Women’s Hospital. Of them, 31 had POLE-mutant or microsatellite-unstable tumors, and 32 had microsatellite-stable tumors.

Neoantigen Load and Tumor-Infiltrating Lymphocytes

The predicted median neoantigen load (predicted neoepitopes per sample) was proportional to the mutational load: 8,342 (range = 628–20,440) in ultramutated POLE tumors; 541 (range = 146–8,063) in hypermutated microsatellite-unstable tumors (P < .001 vs POLE); and 70.5 (range = 7–1,877) in microsatellite-stable tumors (P < .001 vs microsatellite-unstable tumors). The mean numbers of CD3+ (44.5 vs 21.8, P = .001) and CD8+ (32.8 vs 13.5, P < .001) tumor-infiltrating lymphocytes were significantly greater in POLE-mutant and microsatellite-unstable tumors vs microsatellite-stable tumors.

PD-1 and PD-L1 Expression

POLE-mutant and microsatellite-unstable tumors also exhibited overexpression of PD-1 in tumor-infiltrating lymphocytes (81% vs 28%, P < .001) and peritumoral lymphocytes (90% vs 28%, P < .001) vs microsatellite-stable tumors. PD-L1 expression was infrequent in tumor cells and did not differ among POLE-mutant, microsatellite-unstable, and microsatellite-stable tumors. However, PD-L1 expression was common in intraepithelial immune cells and more common in POLE-mutant and microsatellite-unstable tumors vs microsatellite-stable tumors (39% vs 13%, P = .02). PD-L1 expression in ≥ 10% of peritumoral immune cells was also more common among POLE-mutant and microsatellite-unstable tumors vs microsatellite-stable tumors (84% vs 56%, P = .03).  

The investigators concluded: “Polymerase e–mutated and [microsatellite-unstable endometrial cancers] are associated with high neoantigen loads and number of [tumor-infiltrating lymphocytes], which is counterbalanced by overexpression of PD-1 and PD-L1. Polymerase e–mutated and [microsatellite-unstable endometrial cancer] tumors may be excellent candidates for PD-1–targeted immunotherapies.”

Panagiotis A. Konstantinopoulos, MD, PhD, of the Dana-Farber Cancer Institute, is the corresponding author of the JAMA Oncology article.

The study was supported by the Blavatnik Family Foundation, National Cancer Institute, Susan Smith Center for Women’s Cancers, Department of Defense, and Center for Immuno-Oncology at the Dana-Farber Cancer Institute. For full disclosures of the study authors, visit oncology.jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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