Preoperative endocrine treatment response in primary postmenopausal endometrial cancer.

5619 Background: While preoperative endocrine therapy with letrozole has become an established approach for treatment decisions in estrogen receptor (ER) positive breast cancer, this concept has not been transferred to endometrial cancer so far. We hypothesized that preoperative endocrine treatment response to letrozole, assessed by changes in Ki67 expression between baseline and surgery as a marker for cellular proliferation, can be evaluated in primary endometrial cancer as a predictive, patient-specific biomarker. Methods: Postmenopausal patients with first diagnosis of endometrial cancer planned to undergo definitive surgical management with hysterectomy were prospectively included in this single-arm biomarker analysis. Letrozole was administered orally at a daily dose of 2.5mg for a period of 2 to 4 weeks until surgery. Eligibility criteria included all molecular subtypes and histologies and no prior treatment for endometrial cancer was allowed. Ki67 expression was assessed immunohistochemically by two independent pathologists as the percentage of positive tumour nuclei. Relative change in Ki67 (%) from pre-treatment biopsy to post-treatment specimen was assessed using the Wilcoxon signed-rank test, substantial response was defined as relative reduction of Ki67 expression ≥50%. Results: A total of 23 patients were prospectively enrolled with median age of 70 years (range 52-88) and median BMI of 32 kg/m² (range 20-48). 22 patients had endometrioid histology (22/23, 95.7%), of those 86.4% (19/22) low-grade and three high-grade (13.6%). One patient had a high-grade serous tumor. 17 of the 23 patients (73.9%) were classified as NSMP (no specific molecular profile), 14 of them ER positive (82.3%). 5 of 23 patients were classified as dMMR (mismatch repair deficient, 21.7%) and one as p53mut (p53 mutant). Median pre-treatment Ki67 expression was 50% (range 10-85) compared to 15% (range 1-80) post-treatment (p<0.0002). Following preoperative letrozole treatment, 16 of 23 patients (69.6%) had a relative reduction of more than 50% in Ki67 expression, 13 of these (81.3%) were of NSMP, three (18.8%) of dMMR molecular subtype. Regarding ER expression in these responders, all dMMR and 11/13 NSMP tumors (84.6%) were ER positive. Two NSMP tumors (14.5%) showed a response to endocrine treatment despite being ER negative. Conclusions: Short-term preoperative letrozole treatment enables identification of patients with substantial endocrine treatment response in primary endometrial cancer. Using this preoperative window-of opportunity, dynamic Ki67 evaluation might serve as an easily accessible predictive biomarker to tailor patient-specific treatment decisions.