Molecular Classification to Prognosticate Response in Medically Managed Endometrial Cancers and Endometrial Intraepithelial Neoplasia

Abstract

Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.

Molecular Classification in Patients With Endometrial Cancer After Fertility-Preserving Treatment: Application of ProMisE Classifier and Combination of Prognostic Evidence

“…After literature searching, we found three studies that tested the PromisE classifier on EC patients who received FPT so far ( 11 – 13 ). The characteristics and outcome measures of each study are summarized in Table 1 .…”

“…Puechl et al. ( 13 ) reported that 1/4 of EC patients with MMR-D and 4/17 with p53wt developed progression or underwent definitive surgery after levonorgestrel intrauterine system (LNG-IUS) treatment. They also included 37 endometrial intraepithelial neoplasia (EIN) patients.…”

“…This classifier has been validated and applied to EC patients who underwent standard surgical treatment. However, its application to EC patients who received FPT is relatively novel, and there are only a few studies tested on a cohort of EC patients who were conservatively treated, with differences in outcomes among these studies ( 11 – 13 ). This study further validated whether the ProMisE classifier could predict treatment response in women with endometrial cancer who underwent fertility-sparing treatment.…”

The Advance and Correlation of KRAS Mutation With the Fertility-Preservation Treatment of Endometrial Cancer in the Background of Molecular Classification Application

“…In a recent study performing molecular analysis on 15 fully evaluable EC patients, three of the eight patients in the CN-L subgroup respectively relapsed at the 8th, 11th, and 41st months of conservative treatment ( 22 ). Another study showed similar results ( 24 ), suggesting the lack of the effective molecular signature of the CN-L subgroup might impair the value of the molecular strategy to stratify the patients under fertility-preservation treatment. All these problems suggest that further molecular stratification to subdivide the patients is urgently needed.…”

“…The patients under fertility-preservation treatment might also profit from the molecular classification. Since the conventional progesterone receptor and estrogen receptor isoforms showed insufficient predictive accuracy ( 21 ), the ProMisE strategy has also been practiced in the population of fertility preservation to identify the MSI status and the potential TP53 abnormality ( 22 – 24 ). POLE mutation could be detected only by sequencing (the next-generation sequencing or Sanger sequencing), considering its superior prognostic value, and it might be of use for young patients with strict fertility-spared conditions.…”