Abstract
High-grade serous endometrial carcinoma (HGSEC) accounts for just 10% of endometrial cancer (EC) cases but is responsible for at least 40% of all EC-related deaths. It typically arises in ...post-menopausal women, with 70% of patients presenting with stage III or IV disease, does not respond to hormone therapy unlike the less aggressive forms of EC, and has a lower overall survival rate of just 18-27%, which has not improved over the past two decades. The primary treatment for HGSEC is surgery, followed by a combination of standard chemotherapies (platinum and taxane) with or without localised radiotherapy. However, recurrent HGSEC is less responsive to chemotherapy than are other subtypes of EC and even initial responses to chemotherapy are poor. Therefore, there is a great unmet clinical 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%). Focal amplifications of the genes MYC, ERBB2, CCNE1, FGFR3 and SOX17 are also common. The presence of ERBB2 amplification and/or HER2 over-expression in around 30% of HGSEC suggests these patients may respond to HER2-targeting drugs, such as trastuzumab. However, only modest benefit has so far been seen for single-agent HER2-targeted therapies (ie trastuzumab or lapatinib) against HGSEC, suggesting resistance mechanisms are present. Another feature of HGSEC that could be exploited therapeutically is homologous recombination deficiency (HRD), which may be targeted with PARP inhibitors (PARPi). It is not clear what proportion of HGSEC are HRD and neither HER2-targeting drugs or PARPi have been 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 33 HGSEC patients consented to the WEHI-Stafford Fox Rare Cancer Program and have developed pre-clinical models from fresh patient tumour samples received (4 patient-derived xenograft (PDX) models validated, with 3 pending). Preliminary molecular analysis of whole-genome sequencing (5 samples, one of which gave rise to a PDX model), whole-exome sequencing (4 samples), and cancer panel sequencing (3 samples, 2 of which gave rise to PDX models; one harbouring ERBB2 amplification and one harbouring an AKT mutation) data from our HGSEC cohort has been performed. This has identified potential treatment targets, including ERBB2 amplifications and mutations in HR genes. I am using the PDX models for initial in vivo therapeutic characterization studies and 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. By combining specific targeted drugs I hope to overcome de novo resistance mechanisms and prevent acquired resistance. Results from this study will guide future decisions about therapeutic strategies to improve survival of women with HGSEC.
Citation Format: Holly E. Barker, Ratana Lim, Amandine Carmagnac, Cassandra Vandenberg, Gayanie Ratnayake, Genevieve Dall, Briony Milesi, Angela Komiti, Emily O'Grady, Joshua Tram, Kym Pham Stewart, Justin Bedo, Jocelyn Penington, Joep Vissers, Sean Grimmond, Matthew Wakefield, Tony Papenfuss, Clare Scott. Identifying effective combinations of targeted therapies, using novel pre-clinical models, to improve treatment options for high-grade serous endometrial cancer abstract. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO037.
Abstract
Uterine sarcomas make up 1-4% of uterine malignancies. Of these 60% are classified as leiomyosarcoma (uLMS). The 5-year survival rate of uLMS is 35-65.2% for tumours that have not spread ...beyond the uterus. However, women are often diagnosed at a late stage due to a lack of screening options by which time the tumour has often spread to adjacent and distant tissues. Current standard of care for uLMS patients is surgical de-bulking followed by adjuvant chemotherapy, but significant improvement in progression free survival and overall survival is not consistently observed. The lack of advances for the treatment and screening of uLMS is due in part to the scarcity of appropriate research resources for this rare disease. Genetic analyses have been performed but on relatively small samples and there are just 14 reported patient-derived xenograft (PDX) models of uLMS in the literature to date. Through the WEHI Stafford Fox Rare Cancer Program, as well as collaborations (facilitated by ANZGOG) throughout the country and internationally, we have access to a large biobank of uLMS tissue. We have received 8 fresh uLMS samples in the laboratory, 2 of which have established PDX lines that were validated as uLMS by our anatomical pathologist. All fresh samples received into the laboratory are snap frozen for whole-genome sequencing as well as viably frozen to enable regeneration of the tissue for future applications. One application is organoid culturing, which allows the tissue to retain its 3D growth properties and is significantly cheaper than growing tissue as a PDX. Organoid culturing also allows for higher throughput of samples in drug screening assays, enabling us to fast-track the selection of drugs for validation in our PDX models. In addition to these fresh samples we also have 23 archival uLMS samples (formalin fixed, paraffin embedded) that can be used for lower coverage genetic analysis, and protein expression by immunohistochemistry. This unique biobank of uLMS tissue is the first of its kind in Australia and with it we will endeavour to gain a comprehensive understanding of this disease. Through our PDX modelling we also have the opportunity to predict resistance to therapy and test emerging therapies in a clinically relevant context. We believe this biobank will provide a critical resource which will ultimately lead to better outcomes for uLMS patients.
Citation Format: Genevieve Dall, Cassandra Vandenberg, Amandine Carmagnac, Ratana Lim, Briony Milesi, Angela Komiti, Emily O'Grady, Joshua Tram, Gayanie Ratnayake, Kym Pham Stewart, Justin Bedo, Jocelyn Penington, Joep Vissers, Inger Olesen, Sean Grimmond, Holly Barker, Tony Papenfuss, Clare Scott. Developing pre-clinical models of uterine leiomyosarcoma abstract. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO021.
