BACKGROUND: Approximately 20% of women with endometrial cancer have advanced-stage disease or suffer from a recurrence. For these women, prognosis is poor, and palliative treatment options include hormonal therapy and chemotherapy. Lack of predictive biomarkers and suboptimal use of existing markers for response to hormonal therapy have resulted in overall limited efficacy. OBJECTIVE: This study aimed to improve the efficacy of hormonal therapy by relating immunohistochemical expression of estrogen and progesterone receptors and estrogen receptor pathway activity scores to response to hormonal therapy. STUDY DESIGN: Patients with advanced or recurrent endometrial cancer and available biopsies taken before the start of hormonal therapy were identified in 16 centers within the European Network for Individualized Treatment in Endometrial Cancer and the Dutch Gynecologic Oncology Group. Tumor tissue was analyzed for estrogen and progesterone receptor expressions and estrogen receptor pathway activity using a quantitative polymerase chain reaction-based messenger RNA model to measure the activity of estrogen receptor-related target genes in tumor RNA. The primary endpoint was response rate defined as complete and partial response using the Response Evaluation Criteria in Solid Tumors. The secondary endpoints were clinical benefit rate and progression-free survival. RESULTS: Pretreatment biopsies with sufficient endometrial cancer tissue and complete response evaluation were available in 81 of 105 eligible cases. Here, 22 of 81 patients (27.2%) with a response had estrogen and progesterone receptor expressions of >50%, resulting in a response rate of 32.3% (95% confidence interval, 20.9-43.7) for an estrogen receptor expression of >50% and 50.0% (95% confidence interval, 35.2-64.8) for a progesterone receptor expression of >50%. Clinical benefit rate was 56.9% for an estrogen receptor expression of >50% (95% confidence interval, 44.9-68.9) and 75.0% (95% confidence interval, 62.2-87.8) for a progesterone receptor expression of >50%. The application of the estrogen receptor pathway test to cases with a progesterone receptor expression of >50% resulted in a response rate of 57.6% (95% confidence interval, 42.1-73.1). After 2 years of follow-up, 34.3% of cases (95% confidence interval, 20-48) with a progesterone receptor expression of >50% and 35.8% of cases (95% confidence interval, 20-52) with an estrogen receptor pathway activity score of >15 had not progressed. CONCLUSION: The prediction of response to hormonal treatment in endometrial cancer improves substantially with a 50% cutoff level for progesterone receptor immunohistochemical expression and by applying a sequential test algorithm using progesterone receptor immunohistochemical expression and estrogen receptor pathway activity scores. However, results need to be validated in the prospective Prediction of Response to Hormonal Therapy in Advanced and Recurrent Endometrial Cancer (PROMOTE) study.

Center for Gynecologic Oncology Amsterdam Netherlands Cancer Institute Amsterdam the Netherlands

Department of Gynaecology and Obstetrics Amsterdam University Medical Centers University of Amsterdam Amsterdam the Netherlands

Department of Gynaecology Catharina Hospital Eindhoven the Netherlands

Department of Gynecologic Oncology Erasmus MC Cancer Institute Erasmus Medical Center Rotterdam Rotterdam the Netherlands

Department of Gynecology and Obstetrics Haukeland University Hospital Bergen Norway

Department of Gynecology and Obstetrics Haukeland University Hospital Bergen Norway; Centre for Cancer Biomarkers Department of Clinical Science University of Bergen Bergen Norway

Department of Medical Oncology Leiden University Medical Center Leiden the Netherlands

Department of Medical Oncology University Medical Center Utrecht Utrecht the Netherlands

Department of Obstetrics and Gynaecology Radboud Institute of Health Sciences Radboud university medical center Nijmegen the Netherlands

Department of Obstetrics and Gynecology Canisius Wilhelmina Hospital Nijmegen the Netherlands

Department of Obstetrics and Gynecology Masaryk University and University Hospital Brno Czech Republic

Department of Obstetrics and Gynecology Rijnstate Hospital Arnhem the Netherlands

Department of Obstetrics and Gynecology University Medical Center Groningen Groningen the Netherlands

Department of Pathology Radboud University Medical Center Nijmegen the Netherlands

Division of Medical Oncology Department of Internal Medicine Maastricht University Medical Center Maastricht the Netherlands; GROW School of Oncology and Developmental Biology Maastricht University Medical Center Maastricht the Netherlands

Division of Medicine Department of Gynecological Oncology Oslo University Hospital Oslo Norway

Division of Medicine Department of Gynecological Oncology Oslo University Hospital Oslo Norway; Faculty of Medicine Institute of Clinical Medicine University of Oslo Oslo Norway

Division of Obstetrics and Gynecology A Nocivelli Institute for Molecular Medicine ASST Spedali Civili di Brescia Brescia Italy

GROW School of Oncology and Developmental Biology Maastricht University Medical Center Maastricht the Netherlands; Department of Obstetrics and Gynecology Maastricht University Medical Center Maastricht the Netherlands

Molecular Pathway Diagnostics Philips Eindhoven the Netherlands

Royal Cornwall Hospital NHS Trust Truro Cornwall United Kingdom

Unit of Gynecologic Oncology Department of Obstetrics and Gynecology Hospital Universitari Vall d'Hebron Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

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