Uncommon types of ovarian cancer
The Nicola Murray Centre for Ovarian Cancer Research brings together the laboratories of Professor Charlie Gourley (left), Professor Simon Herrington (centre) and Dr Robb Hollis (right)
By Robb Hollis
There are at least six different ‘types’ of ovarian cancer, each with their own unique behaviour, including differences in responsiveness to treatments. One of these types (called high grade serous ovarian cancer) accounts for the majority of ovarian cancer diagnoses, but 30% of patients are diagnosed with ovarian cancers that are of other, less common types. Because of their relative rarity, we know far less about these uncommon forms of ovarian cancer, and new treatment strategies have lagged behind due to a lack of research. This problem is exacerbated by the fact that these uncommon types are often non-responsive to conventional chemotherapy.
Over the last 10 years, researchers within the Cancer Research UK Scotland Centre at the University of Edinburgh have led significant advancements in our understanding of these uncommon types of ovarian cancer. The findings from these studies are paving the way for developing new treatment approaches for these under-served patient groups. The programme of ovarian cancer research is unified under The Nicola Murray Centre for Ovarian Cancer Research, bringing together the laboratories of Professor Charlie Gourley, Professor Simon Herrington and Dr Robb Hollis.
Endometrioid ovarian cancer
Endometrioid ovarian cancer accounts for around 10% of ovarian cancers. The clinical behaviour of these tumours is extremely variable: many are diagnosed at early stage and do not come back after initial treatment, but a subset are much more aggressive and are resistant to current treatments.
Over the last five years, work at The Nicola Murray Centre has unravelled some of the genetic mutations that underpin endometrioid ovarian cancer. Researchers discovered that the presence or absence of two specific gene mutations can be used to identify patients who are at higher and lower risk of their cancer coming back after initial therapy. Being able to accurately distinguish these risk groups is extremely important; high risk groups represent those who urgently need new treatment strategies. These are the cancers we need to design new therapies against by using our knowledge of the biology that is driving their growth. In contrast, future studies of low-risk cancers may highlight opportunities to spare individuals the toxic side effects of chemotherapy if an individual’s cancer is unlikely to come back after surgical removal, even without chemotherapy treatment. Building on these initial findings, further work has refined the approach for identifying high- and low-risk endometrioid ovarian cancers so that they are more readily identifiable within the current diagnostic pathway. Work is currently ongoing to validate the approaches for identifying these risk groups, which is a critical step toward implementing the findings in routine clinical practice.
Figure. Uncommon ovarian cancers under the microscope. Left panel shows endometrioid ovarian cancer. Middle panel shows low grade serous ovarian cancer. Right panel shows ovarian carcinosarcoma.
Low grade serous ovarian cancer
Low grade serous ovarian cancer represents about 5% of ovarian cancers. This form of the disease is extremely resistant (non-responsive) to chemotherapy, and often affects younger women.
The Nicola Murray Centre has led several studies that have expanded our understanding of low grade serous ovarian cancer. Gene sequencing of tumour samples has shown that many of these ovarian cancers have gene mutations affecting a single biological pathway called “MAPK”. Individuals whose tumours have these mutations tend to survive their cancer for longer compared to those who do not. The appearance of these “MAPK mutated” tumours is also different, showing a unique architectural pattern when viewed under the microscope.
A separate study used cancer cells grown in the lab to identify potential new drug treatments for low grade serous ovarian cancer. Cells were grown on plastic and treated with 1610 different drugs to determine if any of these agents are able to kill the cancer cells. This study led to the identification of a drug called dasatinib, which is currently used to treat other types of cancer, as a potential treatment for low grade serous ovarian cancer.
Charlie Gourley was also the UK lead investigator for the first successful late-phase clinical trial in low grade serous ovarian cancer. This clinical study involved 260 patients across over 80 hospitals in the UK and the US, and showed that a drug called trametinib is effective for treating low grade serous ovarian cancer that has come back after initial treatment. The team at The Nicola Murray Centre were heavily involved in the analysis of tumour samples from patients in this trial, and showed that responses to trametinib were more pronounced in patients whose tumours had the MAPK mutations mentioned above.
Ovarian carcinosarcoma
Ovarian carcinosarcoma is a highly unusual type of ovarian cancer that accounts for less than 5% of diagnoses. Ovarian carcinosarcoma is the most aggressive and deadly type of ovarian cancer, but very little research has been performed to identify new ways to treat it.
The Nicola Murray Centre houses the largest collection of tumour samples from this type of ovarian cancer anywhere in the world. Researchers at the centre have used this unique resource to show that ovarian carcinosarcoma is a distinct and unique cancer type, which is more aggressive and less treatment responsive than other forms of ovarian cancer. They have also performed the first comprehensive molecular analysis of this type of ovarian cancer, including detection of gene mutations. This work is shedding light on the underlying processes that drive these tumours, and has revealed potential vulnerabilities to upcoming classes of new drugs.
Funding
We are extremely grateful to the following organisations for funding that has empowered our research into uncommon ovarian cancers: Tenovus Scotland, Target Ovarian Cancer, Wellbeing of Women, British Gynaecological Cancer Society, The University of Edinburgh, Cancer Research UK. The Nicola Murray Centre for Ovarian Cancer Research was established following an incredibly generous donation from The Nicola Murray Foundation, which kick-started our research into uncommon ovarian cancers.
Our key studies in endometrioid ovarian cancer, low grade serous ovarian cancer and ovarian carcinosarcoma:
Hollis RL, et al. Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification. NPJ Precision Oncology. 2021;5(1):47.
Hollis RL, et al. Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome. Nature Communications. 2020;11(1):4995.
Hollis RL, et al. High throughput screening identifies dasatinib as synergistic with trametinib in low grade serous ovarian carcinoma. Gynecol Oncol 2024; 186:42-52.
Hollis RL, et al. Distinct histopathological features are associated with molecular subtypes and outcome in low grade serous ovarian carcinoma. Scientific Reports 2023; 13:7681
Thomson JP, et al. Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome. Gynecologic Oncology 2023; 174:157-166
Gershenson DM, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. The Lancet 2022;399(10324):541-553
Herrington CS, et al. Compartment-specific multiomic profiling identifies SRC and GNAS as candidate drivers of epithelial-to-mesenchymal transition in ovarian carcinosarcoma. Brit J Cancer 2024; 130(2):327-335
Hollis RL, et al. Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma. British Journal of Cancer 2022;127(6):1034-1042
Share
