E-Poster Presentation 33rd Lorne Cancer Conference 2021

Identifying effective combinations of targeted therapies, using novel pre-clinical models, to improve treatment options for high-grade serous endometrial cancer (#149)

Holly E Barker 1 2 , Cassandra Vandenberg 1 2 , Genevieve Dall 1 2 , Ratana Lim 1 , Amandine Carmagnac 1 , Gayanie Ratnayake 3 , Briony Milesi 1 , Angela Komiti 1 , Emily O'Grady 1 , Joshua Tram 1 , Justin Bedo 1 2 , Jocelyn Penington 1 , Kym Pham Stewart 2 , Joseph Vissers 2 , Sean Grimmond 2 , Elizabeth Swisher 4 , Matthew Wakefield 1 2 , Tony Papenfuss 1 2 5 , Clare Scott 1 2 3 5
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The University of Melbourne, Melbourne, VIC, Australia
  3. Royal Women's Hospital, Parkville, VIC, Australia
  4. UW Medical Centre, Seattle, United States
  5. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

High-grade serous endometrial carcinoma (HGSEC) accounts for 10% of endometrial cancer (EC) cases but is responsible for at least 40% of EC-related deaths1. It has an overall survival rate of 18-27%, which has not improved over the past two decades2,3. The primary treatment for HGSEC is surgery, followed standard chemotherapy combinations (platinum and taxane) with or without localised radiotherapy, however, HGSEC is less responsive to chemotherapy than are other subtypes of EC1. Therefore, there is a great unmet need to find better treatment options for women with this aggressive cancer.

Apart from TP53 (mutated in up to 90% of cases), the other most frequently mutated genes in HGSEC are PPP2R1A (31%), PIK3CA (22%), FBXW7 (28%), CHD4 (17%) and BRCA2 (12%)5. Focal amplifications of MYC, ERBB2, CCNE1, FGFR3 and SOX17 are also common5. The presence of ERBB2 amplification and/or HER2 over-expression in around 30% of HGSEC suggests these patients may respond to HER2-targeting drugs, however, only modest benefit has so far been seen suggesting resistance mechanisms are present6,7. Another feature of HGSEC that could be exploited therapeutically is homologous recombination deficiency, which may confer sensitivity to PARP inhibitors (PARPi)8. HER2-targeting drugs and PARPi are yet to be approved for the treatment of HGSEC.

Due to its rarity and a lack of pre-clinical models, HGSEC has so far been understudied, resulting in a lack of effective treatment options. We currently have 34 HGSEC patients consented to the WEHI-Stafford Fox Rare Cancer Program and have developed pre-clinical models from fresh patient tumour samples (5 patient-derived xenograft (PDX) models and 2 cell lines validated). Preliminary molecular analysis of next-generation sequencing data has identified potential treatment targets. We are using the PDX models to develop organoid models for use in high-throughput drug assays in vitro. This will guide subsequent novel drug combination testing in our PDX models. Results from this study will direct future decisions about therapeutic strategies to improve survival of women with HGSEC.

  1. Moore, K.N. & Fader, A.N. Uterine papillary serous carcinoma. Clin Obstet Gynecol 54, 278-291 (2011).
  2. Hamilton, C.A., et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer 94, 642-646 (2006).
  3. Morice, P., Leary, A., Creutzberg, C., Abu-Rustum, N. & Darai, E. Endometrial cancer. Lancet 387, 1094-1108 (2016).
  4. Zhao, S., et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A 110, 2916-2921 (2013).
  5. Fleming, G.F., et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 116, 15-20 (2010).
  6. Fader, A.N., et al. Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clin Cancer Res (2020).
  7. Morales, J., et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr 24, 15-28 (2014).