Low-grade serous cancer research in Australia
Author: ANNA deFAZIO BSc, PhD
Professor, Sydney-West Chair in Translational Cancer Research, University of Sydney; Co-Director, Centre for Cancer Research, Westmead Institute for Medical Research, Sydney Australia
Low-grade serous carcinoma background
Ovarian cancer is a complex disease from many perspectives. As we continue to further our understanding of ovarian cancer biology, it is becoming increasingly clear that it is not a single disease, but is instead comprised of a number of very distinct subtypes.
While some subtypes can be classified by specialist pathologists by looking down the microscope, others can only be seen by looking more deeply at the patterns of mutated genes and altered proteins.
Importantly, it is only through understanding the changes in these genes and proteins, and how they drive ovarian cancer to grow, that we will be able to find the best treatment for each individual patient.
Emerging evidence from research over the last few years has made it clear that one of these subtypes, low-grade serous carcinoma (LGSC), is a molecularly and clinically distinct ovarian cancer subtype, quite different from it’s more common counterpart, high-grade serous carcinoma.
LGSC is not common, making up less than 10% of all epithelial ovarian cancers. It is also diagnosed at a younger age than other types of ovarian cancer, sometimes in women only in their early 20s.
LGSC does not respond to standard ovarian cancer chemotherapy as well as other subtypes, and while some LGSC patients respond to hormone or anti-angiogenesis treatments, these responses are not predictable, and new treatment approaches are needed.
Our team from the Westmead Institute for Medical Research in Sydney, and the Peter McCallum Cancer Centre in Melbourne, has a major focus on understanding LGSC and finding new and effective treatment options.
Mutations found in LGSC differ from those in other ovarian cancer subtypes. About half of the LGSC we have tested have mutations in the closely related genes, KRAS, BRAF or NRAS (1) (2) (3). We are using intensive gene sequencing strategies to find the genes driving LGSC, particularly in the ~50% of LGSC that don’t have one of the known mutations, with the aim of identifying new treatment targets.
In a parallel approach, we plan to test ‘libraries’ of thousands of compounds and potential new therapies in robotic, high-throughput screens in a panel of LGSC cell lines, that have similar mutation patterns to those found in LGSC in patients.
In what could be considered proof of concept, our team has shown that BRAF inhibitors are very effective in LGSC patients with a BRAF mutation, at least in the few patients on trials so far (4).
In partnership with ANZGOG, we are in the advanced stages of planning a much larger clinical trial to test a new combination we predict will be effective, not only in patients with BRAF mutations, but also in a proportion of other LGSC patients.
With more treatments becoming available, including immunotherapy that harnesses the immune system to help fight cancer, and new combination therapies, there are a range of clinical trials that LGSC patients may be eligible for. Through studies such as INOVATe and the Australian Ovarian Cancer Study we are collecting data on how patients respond to different treatments and matching this with patient and tumour characteristics. This information will help to predict which patients may respond in the future, and will help in the design of new clinical trials.
Through our partnership with ANZGOG, we have a clear path from fundamental laboratory research, through to clinical trials, and hope to establish this as a platform to develop and test new effective treatment strategies for women with LGSC.
1. Emmanuel C, Chiew YE, George J, Etemadmoghadam D, Sharma R, Russell P, Kennedy C, Fereday S, Hung J, Galletta L, Australian Ovarian Cancer Study, Hogg R, Wain GV, Brand A, Balleine R, Anglesio MS, MacConaill LE, Palescandolo E, Hunter SM, Campbell I, Dobrovic A, Wong SQ, Do H, Clarke CL, Harnett PR, Bowtell DD, deFazio A. Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS-pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver. Clin Cancer Res 2014; 20: 6618-30.
2. Hunter SM, Anglesio MS, Ryland GL, Sharma R, Chiew YE, Rowley SM, Doyle MA, Li J, Gilks CB, Moss P, Allan PE, Stephens AN, Huntsman DG, deFazio A, Bowtell DD, Australian Ovarian Cancer Study Group, Gorringe KL, Campbell IG. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes. Oncotarget 2015; 6: 37663-77.
3. Etemadmoghadam D, Azar WJ, Lei Y, Moujaber T, Garsed DW, Kennedy CJ, Fereday S, Mitchell C, Chiew YE, Hendley J, Sharma R, Harnett PR, Li J, Christie EL, Patch AM, George J, Au-Yeung G, Mir Arnau G, Holloway TP, Semple T, Pearson JV, Waddell N, Grimmond SM, Kobel M, Rizos H, Lomakin IB, Bowtell DDL, deFazio A, Australian Ovarian Cancer Study Group. EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas. Cancer Res 2017; 77: 4268-78.
4. Moujaber T, Etemadmoghadam D, Kennedy CJ, Chiew Y-E, Balleine RL, Saunders C, Wain GV, Gao B, Hogg R, Srirangan S, Kan C, Fereday S, Traficante N, Australian Ovarian Cancer Study, Patch A-M, Pearson JV, Waddell N, Grimmond SM, Dobrovic A, Bowtell DDL, Harnett PR, deFazio A. BRAF mutations in low-grade serous ovarian cancer and response to BRAF inhibition. JCO Precision Oncology 2018; published online May 14, 2018
Published 28th May 2019