Associations between molecular classification and response to intra-uterine levonorgestrel device therapy in patients with medically managed endometrial cancer and endometrial intra-epithelial neoplasia: a multi-center Endometrial Cancer Molecularly Targeted Therapy (ECMT2) Consortium study.

OBJECTIVE

To determine the association between molecular classification and response in patients with endometrial intra-epithelial neoplasia or endometrial cancer treated with a levonorgestrel intra-uterine device.

METHODS

Eligible patients were treated with a levonorgestrel intra-uterine device for endometrial intra-epithelial neoplasia or endometrial cancer for at least 6 months. Immunohistochemistry for MLH1, MSH2, MSH6, PMS2, and p53 was performed. Specimens were categorized using a modified Proactive Molecular Risk Classifier for Endometrial Cancer algorithm as deficient mismatch repair, p53 abnormal, or p53 wild-type. A subset underwent single-gene POLE sequencing. Best response was recorded as pathologic complete response, partial response, stable disease, or progressive disease. Kruskal-Wallis tests and Fisher exact tests were used for statistical analysis.

RESULTS

There were 143 patients, including 83 with endometrial intra-epithelial neoplasia and 60 with endometrial cancer. Fertility preservation was desired in 35.7%, 53.8% had significant medical co-morbidities precluding hysterectomy, and 10.5% had levonorgestrel intra-uterine device placement for other indications, including patient preference, placement during the coronavirus disease 2019 pandemic, and logistical considerations for other cancer diagnoses. Molecular characterization showed 90.9% p53 wild-type, 7.0% deficient mismatch repair, and 2.1% p53 abnormal. Only 4.4% of specimens with sequencing had a POLE mutation (2 of 45). The overall response rate was 86.7% (endometrial cancer: complete response 38.3%, partial response 36.7%; endometrial intra-epithelial neoplasia: complete response 67.5%, partial response 27.7%). In patients with endometrial cancer, the response rate was 75% (45 of 60), varying by molecular sub-group: 50% in the p53 abnormal group (1 of 2) and 50% in the deficient mismatch repair group (5 of 10). Only 1 patient with endometrial intra-epithelial neoplasia had p53 abnormal expression; the remaining patients had intact MMR expression and p53 wild-type.

CONCLUSIONS

The complete response to levonorgestrel intra-uterine device therapy was lower than expected for endometrial intra-epithelial neoplasia. Response rates varied by molecular classification, with worse outcomes observed in deficient mismatch repair and p53 abnormal sub-types. Although limited by sample size, these findings suggest that levonorgestrel intra-uterine device therapy may not be sufficient for all molecular sub-groups.