Long-Term Follow-up of Levonorgestrel Intrauterine Device for Atypical Hyperplasia and Early Endometrial Cancer Reveals Relapse Characterized by Immune Exhaustion

Authors

Mikayla B Bowen
Brenda Melendez
Qian Zhang
Richard K Yang
Bryan M Fellman
Barrett C Lawson
Naomi N Adjei
Joseph Celestino
Khalida M Wani
Bhavana Singh
Diana L Urbauer
Alexander J Lazar
Karen H Lu
Jennifer A Wargo
Shannon N Westin
Melinda S Yates

Publication Date

11-15-2024

Journal

Clinical Cancer Research

Abstract

Purpose: Nonsurgical treatment options are increasingly needed for endometrial atypical hyperplasia (AH) and endometrioid endometrial cancer (EEC). Despite promising initial response rates, prospective long-term data and determinants for relapse are limited.

Materials and methods: Follow-up data from patients in our prospective phase II trial of levonorgestrel intrauterine device (LIUD) for AH/G1EEC were collected from medical records. Spatial transcriptomics (Nanostring GeoMX digital spatial profiling) with in silico cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse.

Results: Of 43 participants exhibiting initial response to LIUD, 41 had follow-up data. Sixteen (39%) experienced relapse. Clinical factors associated with shorter response duration included younger age, initial diagnosis of G1EEC, lack of response at 6 months, premenopausal status, and Hispanic ethnicity (P < 0.05), but only 6-month response status remained a significant predictor in a multivariate model (P = 0.023). LIUD increased abundance of NK cells (ΔMCP-counter score = 46.13, FDR = 0.004) and cytotoxic lymphocytes (ΔMCP-counter score = 277.67, FDR = 0.004), as well as lymphocyte cytotoxicity markers PRF1 (log2FC = 1.62, FDR = 0.025) and GZMA (log2FC = 2.47, FDR = 0.008). NK cells were reduced at relapse (ΔMCP-counter score = -55.96, FDR = 0.02). Immune-related pathways (IFNα response and TGFβ signaling) were enriched at relapse (FDR < 0.05). IDO1 expression, reflecting immune exhaustion, was upregulated at relapse (FDR < 0.05).

Conclusions: Upfront resistance and relapse after initial response to LIUD for AH/G1EEC impacts nearly half of patients, remaining a major hurdle for nonsurgical treatment of AH/G1EEC. Molecular studies evaluating longitudinal biopsies from a small cohort implicate immune mechanisms at relapse, including reversal of progestin-related immunomodulation and increased immune exhaustion. See related commentary by Johannet and Friedman, p. 5001.

Keywords

Humans, Female, Levonorgestrel, Endometrial Neoplasms, Intrauterine Devices, Medicated, Middle Aged, Endometrial Hyperplasia, Follow-Up Studies, Neoplasm Recurrence, Local, Adult, Prospective Studies, Aged, Killer Cells, Natural, Immune System Exhaustion

DOI

10.1158/1078-0432.CCR-24-0362

PMID

38922360

PMCID

PMC11567806

PubMedCentral® Posted Date

5-15-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes