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

Abstract

<div>AbstractPurpose:<p>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.</p>Materials and Methods:<p>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 <i>in silico</i> cell type deconvolution and pathway analyses were employed on longitudinal biopsy samples from five patients across pre-treatment, on-treatment, and relapse.</p>Results:<p>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 (<i>P</i> < 0.05), but only 6-month response status remained a significant predictor in a multivariate model (<i>P</i> = 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 <i>PRF1</i> (log<sub>2</sub>FC = 1.62, FDR = 0.025) and <i>GZMA</i> (log<sub>2</sub>FC = 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). <i>IDO1</i> expression, reflecting immune exhaustion, was upregulated at relapse (FDR < 0.05).</p>Conclusions:<p>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.</p><p><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-24-2034" target="_blank"><i>See related commentary by Johannet and Friedman, p. 5001</i></a></p></div>