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Improving response to progestin treatment of low-grade endometrial cancer
  1. Eva Baxter1,
  2. Donal J Brennan2,3,
  3. Jessica N McAlpine4,5,
  4. Jennifer J Mueller6,7,
  5. Frédéric Amant8,9,
  6. Mignon D J M van Gent9,
  7. David G Huntsman5,10,
  8. Robert L Coleman11,
  9. Shannon N Westin11,
  10. Melinda S Yates11,
  11. Camilla Krakstad12,13,
  12. Michael A Quinn14,
  13. Monika Janda15 and
  14. Andreas Obermair1
  1. 1Queensland Centre for Gynaecological Cancer Research, The University of Queensland, Brisbane, Queensland, Australia
  2. 2Department of Gynaecological Oncology, UCD School of Medicine, Mater Misericordiae University Hospital, Dublin, Ireland
  3. 3Systems Biology Ireland, University College Dublin, Dublin, Ireland
  4. 4Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, The University of British Columbia, Vancouver, British Columbia, Canada
  5. 5BC Cancer Agency, Vancouver, British Columbia, Canada
  6. 6Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  7. 7Department of Obstetrics & Gynecology, Weill Cornell Medical College, New York, New York, USA
  8. 8Department of Oncology, KU Leuven, Leuven, Flanders, Belgium
  9. 9Centre for Gynaecologic Oncology Amsterdam, Antoni van Leeuwenhoek Netherlands Cancer Institute and Amsterdam University Medical Centres, Amsterdam, Noord-Holland, The Netherlands
  10. 10Departments of Pathology and Laboratory Medicine and Gynecology and Obstetrics, The University of British Columbia, Vancouver, British Columbia, Canada
  11. 11Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  12. 12Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Vestland, Norway
  13. 13Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Vestland, Norway
  14. 14Royal Women's Hospital, Melbourne, Victoria, Australia
  15. 15Centre for Health Services Research, The University of Queensland, Brisbane, Queensland, Australia
  1. Correspondence to Dr Eva Baxter, Queensland Centre for Gynaecological Cancer Research, Centre for Clinical Research, The University of Queensland, Brisbane, QLD 4029, Australia; e.baxter{at}


Objectives This review examines how response rates to progestin treatment of low-grade endometrial cancer can be improved. In addition to providing a brief overview of the pathogenesis of low-grade endometrial cancer, we discuss limitations in the current classification of endometrial cancer and how stratification may be refined using molecular markers to reproducibly identify ‘low-risk’ cancers which may represent the best candidates for progestin therapy. We also discuss constraints in current approaches to progestin treatment of low-grade endometrial cancer and perform a systematic review of predictive biomarkers.

Methods PubMed,, and Cochrane Library were searched for studies reporting pre-treatment biomarkers associated with outcome in women with low-grade endometrial cancer or endometrial hyperplasia with an intact uterus who received progestin treatment. Studies of fewer than 50 women were excluded. The study protocol was registered in PROSPERO (ID 152374). A descriptive synthesis of pre-treatment predictive biomarkers reported in the included studies was conducted.

Results Of 1908 records reviewed, 19 studies were included. Clinical features such as age or body mass index cannot predict progestin response. Lesions defined as ‘low-risk’ by FIGO criteria (stage 1A, grade 1) can respond well; however, the reproducibility and prognostic ability of the current histopathological classification system is suboptimal. Molecular markers can be reproducibly assessed, have been validated as prognostic biomarkers, and may inform patient selection for progestin treatment. DNA polymerase epsilon (POLE)-ultramutated tumors and a subset of p53 wild-type or DNA mismatch repair (MMR)-deficient tumors with ‘low-risk’ features (eg, progesterone and estrogen receptor-positive) may have improved response rates, though this needs to be validated.

Discussion Molecular markers can identify cases which may be candidates for progestin treatment. More work is needed to validate these biomarkers and potentially identify new ones. Predictive biomarkers are anticipated to inform future research into progestin treatment of low-grade endometrial cancer and ultimately improve patient outcomes.

  • endometrial neoplasms
  • endometrial hyperplasia

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  • Correction notice This article has been corrected since it was first published. The funding statement has been amended to acknowledge the NIH/NCI Cancer Center Support Grant P30 CA008748.

  • Contributors EB, DJB, and AO conceived and designed the work and drafted the manuscript. EB, DJB, JNM, JJM, FA, MDJMvG, DGH, RLC, SNW, MSY, CK, MAQ, MJ, and AO all revised the manuscript critically for important intellectual content and approved the final version.

  • Funding This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

  • Competing interests DGH is a founder and Chief Medical Officer of Contextual Genomics, a for-profit company that provides genomic diagnostics and reporting to assist in cancer patient treatment.

  • Provenance and peer review Commissioned; externally peer reviewed.