Oral Presentation 36th Lorne Cancer Conference 2024

Molecular profiling and testing matched therapeutic strategies in preclinical models aid treatment decision making for rare gynaecological cancers (#21)

Holly E Barker 1 2 , Cassandra Vandenberg 1 2 , Gayanie Ratnayake 3 , Justin Bedo 1 2 , Jocelyn Penington 1 , Matthew Wakefield 1 2 , Joseph Vissers 2 , Oliver Hofmann 2 , Sean Grimmond 2 , Tony Papenfuss 1 2 , Clare Scott AM 1 2 3 4 , for the WEHI Stafford Fox Rare Cancer Program 1
  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. The Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Collectively, rare cancers account for ~24% of all cancer diagnoses and ~33% of all cancer deaths each year, representing a substantial burden of disease [1, 2]. Until recently, basic science research, clinical trials, and approval of new therapies for rare cancers have been lacking, due mostly to insufficient funding and accrual difficulties for traditional clinical trials. This translates into a worse prognosis for rare cancer patients than for those with common cancers, with a 5-year survival of 48.5% compared to 63.4%, respectively [1, 2].

The WEHI-Stafford Fox Rare Cancer Program (SFRCP) was designed with streamlined ethics, governance and consenting processes, including remote consent from home anywhere in Australia, and data collection protocols to allow analysis of data and tissue from patients with a rare cancer. In this way, we enable matched therapies to be identified for individual patients, as well as develop preclinical research projects to further understand specific rare cancers, underpinning new treatment options for future patients. To date, 812 rare cancer patients have consented to the WEHI-SFRCP, with 972 independent tumours that account for 188 different types of rare cancer.

To date, we have carried out whole genome sequencing (WGS) on 201 tumours, with targetable aberrations identified in ~60% of cases. Tumours with a high level of actionability included those with high TMB, a dominant mutational signature 3 and mutations in the RAS/RAF pathway, indicative of response to immunotherapy, PARP inhibitors (PARPi), and a dual RAS/RAF inhibitor, respectively. Simultaneously, we have developed 96 patient-derived xenograft (PDX) models of different rare cancers and generated many cell line and organoid models for further study. We have tested double and triple combination therapies, selected based on the molecular profiling, on some of our PDX models. Promising results in these aggressive and hard to treat PDX models indicate these rationally chosen combination therapies are worth pursuing in the clinic.