Molecular Profiling of Endometrial Cancer From TCGA to Clinical Practice

Authors:
Amy JamiesonDivision of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, Canada

Search for other papers by Amy Jamieson in
Current site
Google Scholar
PubMed
Close
 MBChB
and
Jessica N. McAlpineDivision of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, Vancouver, Canada

Search for other papers by Jessica N. McAlpine in
Current site
Google Scholar
PubMed
Close
 MD
View More View Less
Restricted access

Molecular classification provides an objective, reproducible framework for categorization of endometrial cancers (ECs), informing prognosis and selection of therapy. Currently, the uptake of molecular classification, integration in to EC management algorithms, and enrollment in molecular subtype-specific clinical trials lags behind what it could be. Access to molecular testing is not uniform, and subsequent management (surgical, adjuvant therapy) is unacceptably variable. We are in the midst of a critical landscape change in this disease site, with increasing emphasis on the integration of molecular features in EC care that can potentially improve standard of care globally. This article summarizes the rationale for molecular classification of ECs, strategies for implementation in low and high resource settings, and actionable opportunities based on this information.

Submitted August 15, 2022; final revision received October 6, 2022; accepted for publication November 7, 2022.

Disclosures: Dr. McAlpine has disclosed receiving an education grant from GlaxoSmithKline. Dr. Jamieson has disclosed no relevant financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Jessica N. McAlpine, MD, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, University of British Columbia, 2775 Laurel Street, Vancouver, BC V6L-1Z5, Canada. Email: jessica.mcalpine@vch.ca
  • Collapse
  • Expand
  • 1.

    Gu B, Shang X, Yan M, et al. Variations in incidence and mortality rates of endometrial cancer at the global, regional, and national levels, 1990-2019. Gynecol Oncol 2021;161:573580.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Gilks CB, Oliva E, Soslow RA. Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol 2013;37:874881.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Thomas S, Hussein Y, Bandyopadhyay S, et al. Interobserver variability in the diagnosis of uterine high-grade endometrioid carcinoma. Arch Pathol Lab Med 2016;140:836843.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    de Boer SM, Wortman BG, Bosse T, et al. Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer. Ann Oncol 2018;29:424430.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Jamieson A, Huvila J, Thompson EF, et al. Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification. Gynecol Oncol 2022;165:201214.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Bernardini MQ, Gien LT, Lau S, et al. Treatment related outcomes in high-risk endometrial carcinoma: Canadian high risk endometrial cancer consortium (CHREC). Gynecol Oncol 2016;141:148154.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:6773.

  • 8.

    Talhouk A, McConechy MK, Leung S, et al. A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 2015;113:299310.

  • 9.

    Talhouk A, McConechy MK, Leung S, et al. Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer 2017;123:802813.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Kommoss S, McConechy MK, Kommoss F, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol 2018;29:11801188.

    • Search Google Scholar
    • Export Citation
  • 11.

    van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res 2015;21:33473355.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Stelloo E, Nout RA, Osse EM, et al. Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 2016;22:42154224.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Stelloo E, Bosse T, Nout RA, et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol 2015;28:836844.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    McAlpine JN, Chiu DS, Nout RA, et al. Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: an individual patient data meta-analysis. Cancer 2021;127:24092422.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Leon-Castillo A, Horeweg N, Peters EEM, et al. Prognostic relevance of the molecular classification in high-grade endometrial cancer for patients staged by lymphadenectomy and without adjuvant treatment. Gynecol Oncol 2022;164:577586.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Plotkin A, Kuzeljevic B, De Villa V, et al. Interlaboratory concordance of ProMisE molecular classification of endometrial carcinoma based on endometrial biopsy specimens. Int J Gynecol Pathol 2020;39:537545.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Stelloo E, Nout RA, Naves LC, et al. High concordance of molecular tumor alterations between pre-operative curettage and hysterectomy specimens in patients with endometrial carcinoma. Gynecol Oncol 2014;133:197204.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Talhouk A, Hoang LN, McConechy MK, et al. Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: earlier prognostic information to guide treatment. Gynecol Oncol 2016;143:4653.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Abdulfatah E, Wakeling E, Sakr S, et al. Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens: towards early personalized patient management. Gynecol Oncol 2019;154:467474.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    León-Castillo A, de Boer SM, Powell ME, et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J Clin Oncol 2020;38:33883397.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Britton H, Huang L, Lum A, et al. Molecular classification defines outcomes and opportunities in young women with endometrial carcinoma. Gynecol Oncol 2019;153:487495.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Kim SR, Cloutier BT, Leung S, et al. Molecular subtypes of clear cell carcinoma of the endometrium: opportunities for prognostic and predictive stratification. Gynecol Oncol 2020;158:311.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    DeLair DF, Burke KA, Selenica P, et al. The genetic landscape of endometrial clear cell carcinomas. J Pathol 2017;243:230241.

  • 24.

    Bosse T, Nout RA, McAlpine JN, et al. Molecular classification of grade 3 endometrioid endometrial cancers identifies distinct prognostic subgroups. Am J Surg Pathol 2018;42:561568.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Jamieson A, Leung S, Thompson E, et al. Molecular subtype stratified response to adjuvant therapy in endometrial cancer. Gynecol Oncol 2022;166(Suppl 1):Abstract 086.

    • Search Google Scholar
    • Export Citation
  • 26.

    Jumaah AS, Al-Haddad HS, McAllister KA, et al. The clinicopathology and survival characteristics of patients with POLE proofreading mutations in endometrial carcinoma: a systematic review and meta-analysis. PLoS One 2022;17:e0263585.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    WHO Classification of Tumours Editorial Board. WHO Classification of Tumours: Female Genital Tumours, 5th ed. IARC; 2020.

  • 28.

    Abu-Rustum NR, Yashar CM, Bradley K, et al. NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms. Version 1.2022. Accessed February 5, 2022. To view the most recent version, visit https://www.nccn.org

    • Search Google Scholar
    • Export Citation
  • 29.

    Concin N, Matias-Guiu X, Vergote I, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer 2021;31:1239.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Benichou J, Schwall C, Sastre-Garau X, et al. Impact of the new molecular classification of endometrial cancer: a French cohort study. Gynecol Oncol. Published online July 5, 2022. doi:10.1016/j.ygyno.2022.07.012

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Thiel KW, Devor EJ, Filiaci VL, et al. TP53 sequencing and p53 immunohistochemistry predict outcomes when bevacizumab is added to frontline chemotherapy in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2022;40:32893300.

    • Search Google Scholar
    • Export Citation
  • 32.

    Talhouk A, Jamieson A, Crosbie E, et al. Targeted molecular testing in endometrial carcinoma: validation of a restricted testing protocol. Int J Gynecol Cancer 2021;31(Suppl 4):A1617. Abstract OP014/#480.

    • Search Google Scholar
    • Export Citation
  • 33.

    Singh N, Jamieson A, Morrison J, et al. BAGP POLE NGS testing guidance. Accessed July 1, 2022. Available at: https://www.bgcs.org.uk/wp-content/uploads/2022/04/BAGP-POLE-testing-in-Endometrial-cancer-v1.1-2022-04-08.pdf

    • Search Google Scholar
    • Export Citation
  • 34.

    Van den Heerik AS, Ter Haar N, Horeweg N, et al. Multiplex qPCR hotspot testing of pathogenic POLE mutations: a rapid, simple and reliable approach for POLE assessment in endometrial cancer. Int J Gynecol Cancer 2021;31(Suppl 3):A367368. Abstract 212.

    • Search Google Scholar
    • Export Citation
  • 35.

    León-Castillo A, Britton H, McConechy MK, et al. Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 2020;250:323335.

  • 36.

    Post CCB, Stelloo E, Smit VT, et al. Prevalence and prognosis of Lynch syndrome and sporadic mismatch repair deficiency in endometrial cancer. J Natl Cancer Inst 2021;113:12121220.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Borden L, Dvorak J, Barrett Z et al. MLH1 hypermethylation predicts poor outcomes with pembrolizumab in recurrent endometrial cancer. Gynecol Oncol 2022;166(Suppl 1):Abstract 087.

    • Search Google Scholar
    • Export Citation
  • 38.

    Tinker AV, Sabatier R, Gravina A, et al. Post-hoc analysis of objective response rate by mismatch repair protein dimer loss/mutation status in patients with mismatch repair deficient endometrial cancer treated with dostarlimab. Int J Gynecol Cancer 2022;32(Suppl 2):A414. Abstract 2022-RA-1198-ESGO.

    • Search Google Scholar
    • Export Citation
  • 39.

    Talhouk A, Derocher H, Schmidt P, et al. Molecular subtype not immune response drives outcomes in endometrial carcinoma. Clin Cancer Res 2019;25:25372548.

    • Search Google Scholar
    • Export Citation
  • 40.

    Horeweg N, de Bruyn M, Nout RA, et al. Prognostic integrated image-based immune and molecular profiling in early-stage endometrial cancer. Cancer Immunol Res 2020;8:15081519.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Jamieson A, Leung S, Thompson E, et al. Are all stage IA p53abn endometrial cancers the same? Seeking clarity in the management of stage IA p53abn and/or non-endometrioid endometrial cancers without myometrial invasion. Int J Gynecol Cancer 2022;32(Suppl 3):A94. Abstract EP115/#640.

    • Search Google Scholar
    • Export Citation
  • 42.

    Yano M, Ito K, Yabuno A, et al. Impact of TP53 immunohistochemistry on the histological grading system for endometrial endometrioid carcinoma. Mod Pathol 2019;32:10231031.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Jamieson A, Thompson EF, Huvila J, et al. p53abn endometrial cancer: understanding the most aggressive endometrial cancers in the era of molecular classification. Int J Gynecol Cancer 2021;31:907913.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Jamieson A, Vermij L, Carlson J, et al. Low-grade p53abn endometrial carcinomas exist and are associated with a high risk of recurrence, even in low-stage disease. Int J Gynecol Cancer 2022;32(Suppl 3):A9495. Abstract EP116/#725.

    • Search Google Scholar
    • Export Citation
  • 45.

    Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 2022;386:437448.

  • 46.

    Vermij L, Singh N, Leon‐Castillo A, et al. Performance of a HER2 testing algorithm specific for p53‐abnormal endometrial cancer. Histopathology 2021;79:533543.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Tymon-Rosario JR, Manara P, Manavella DD, et al. Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to olaparib, a poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. Gynecol Oncol 2022;166:117125.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Jamieson A, de Barros JS, Cochrane D, et al. Application of shallow whole genome sequencing to identify therapeutic opportunities in p53abn endometrial cancers. Int J Gynecol Cancer 2022;32(Suppl 3): A95. Abstract EP117/#763.

    • Search Google Scholar
    • Export Citation
  • 49.

    de Jonge MM, Auguste A, van Wijk LM, et al. Frequent homologous recombination deficiency in high-grade endometrial carcinomas. Clin Cancer Res 2019;25:10871097.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Jamieson A, Huvila J, Chiu D, et al. Grade and estrogen receptor expression identify a subset of No Specific Molecular Profile (NSMP) endometrial carcinomas at very low risk of disease-specific death. Mod Pathol 2023; in press.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Jamieson A, Thompson EF, Huvila J, et al. Endometrial carcinoma molecular subtype correlates with the presence of lymph node metastases. Gynecol Oncol 2022;165:376384.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Momeni-Boroujeni A, Dahoud W, Vanderbilt CM, et al. Clinicopathologic and genomic analysis of TP53-mutated endometrial carcinomas. Clin Cancer Res 2021;27:26132623.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Kitchener H, Swart AM, Qian Q, et al. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009;373:125136.

    • Search Google Scholar
    • Export Citation
  • 54.

    Benedetti Panici P, Basile S, Maneschi F, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008;100:17071716.

    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 4141 4139 286
PDF Downloads 4273 4273 311
EPUB Downloads 0 0 0