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

SIMPLE SUMMARY: Uterine cancer is the most common gynecologic cancer. The treatment for women with a newly diagnosed uterine cancer is surgery to remove the uterus, fallopian tubes, ovaries, and lymph nodes. For women who desire future pregnancy or are not healthy enough to undergo surgery with hysterectomy, treatment with hormonal therapy, using the levonorgestrel intrauterine device (IUD), is an option. Response rates to this type of therapy are promising and range between 50% and 88%. This project explores a molecular classification scheme and applies it to women with uterine cancer and pre-cancer who opt for treatment with an IUD. Evaluating the genetic alterations underlying tumor development can identify patients who would be more or less likely to respond to treatment with IUDs. Additionally, this knowledge can help physicians counsel women with uterine cancer who may be interested in non-surgical options about her odds of having her cancer respond to a hormonal treatment. 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.