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Oncogenetic analysis of female patients with a breast cancer risk and/or ovarian cancer risk (family tree at bottom). The DNA sequencing is seen on computer, each peak matched to a nucleotide basic unit of gene and DNA Centre Oscar Lambret/Phanie/Rex Features
Dr Sharon O’Toole, Senior Scientist in TCD and the DISCOVARY consortium, outlines the progress made on the diagnosis, treatment and management of ovarian cancer, ahead of the first World Ovarian Cancer Day on May 8.
The first World Ovarian Cancer Day will take place on May 8 to help create and raise awareness of the disease. Ovarian cancer has the lowest survival rate of all gynaecological cancers. The disease is diagnosed annually in nearly a quarter of a million women globally, and is responsible for 140,000 deaths each year.
Some 70 per cent of women diagnosed with ovarian cancer die within five years. According to the latest report from the National Cancer Registry, between 1994 and 2010, an average of 376 new cases presented in Ireland each year. In terms of incidence rates, Ireland ranked fourth-highest of 30 countries surveyed and had the highest mortality rate in Europe (source: European Cancer Observatory).
Symptoms are often misdiagnosed, as they can be confused with symptoms of other less severe illnesses, particularly gastrointestinal complaints. The majority of patients are identified in the advanced stages, when the disease becomes more difficult to treat.
Awareness of the risk factors, signs and symptoms, as well as family history, are all important in identifying the disease sooner. Experts now believe it is the frequency and combination of symptoms that can help doctors distinguish between ovarian cancer and other conditions.
If a woman experiences one or more of the following symptoms on most days within a three-week period, they should discuss their concerns with their doctor:
• Increased abdominal size/ persistent bloating (not bloating that comes and goes);
• Difficulty eating/feeling full quickly;
• Abdominal or pelvic pain;
• Needing to pass urine more urgently or more frequently.
Women with ovarian cancer are most likely to have one or more of the above symptoms on a frequent basis. There can be other symptoms which also occur, including change in bowel habits, abnormal
vaginal bleeding, fatigue, and unexpected weight loss or weight gain (in this instance around the abdomen). However, these are less helpful when a doctor is trying to determine whether or not ovarian cancer is the cause.
Ovarian cancer has remained the most challenging of gynaecological malignancies, for two reasons. First, early-stage disease, which has a good prognosis, cannot be detected easily. Second, standard chemotherapy often fails and patients develop chemoresistant disease.
Given the poor mortality rate associated with ovarian cancer, the DISCOVARY consortium was established to improve the diagnosis, treatment and management of ovarian cancer. It is a multidisciplinary and trans-institutional consortium lead by Prof John O’Leary in Trinity College Dublin.
Much of the consortium’s efforts have focused on the area of early diagnosis and overcoming chemoresistance. The consortium has been fortunate to receive funding from the Emer Casey Foundation — http://www.emercaseyfoundation.com — an Irish charity focusing on improving diagnosis of ovarian cancer.
Family and friends of Emer established the foundation following her untimely death from ovarian cancer in June 2006. The Emer Casey Foundation has supported three Emer Casey PhD fellows in the DISCOVARY consortium whose work focused on early detection of ovarian cancer, chemoresistance and cancer stem cells.
At present, there are no established national ovarian cancer screening programmes in place. Current detection strategies include ultrasound and cancer antigen-125 (CA-125), however, both have their drawbacks, resulting in the lack of a reliable, sensitive screening test for ovarian cancer.
Results are awaited from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, see http://www.ukctocs.org.uk/) trial, which will report in 2014 on the effectiveness of ultrasound and CA-125 for screening. The trial uses a calculation called the ‘Risk of Ovarian Cancer Algorithm’ (ROCA). Rather than just looking at the results of a single CA-125 test, they looked for changes in CA-125 over time to try to predict the woman’s risk of having the disease.
Clearly, novel biomarkers would help improve the diagnosis of ovarian cancer and DISCOVARY has presented some of its exciting work in this area at recent scientific meetings.
The work examining auto-antibody profiles in ovarian cancer generated significant interest from the diagnostic industry, as this technology is now a major focus of interest in ovarian cancer diagnostics.
This work has produced a hugely important set of biomarkers that can be taken forward to develop a diagnostic and therapeutic platform in collaboration with industry partners.
DISCOVARY is also focusing efforts in the area of circulating tumour cells in terms of diagnosis and management of ovarian cancer. This work is funded by Science Foundation Ireland as part of the Biomedical Devices Institute-2 (BDI-2) SFI CSET (Centres for Science Engineering and Technology) and is aimed at developing novel ‘lab-on-a-chip’ devices for isolating and characterising CTCs.
In a major publication, the consortium recently outlined the importance of platelets in cancer metastasis using ovarian cancer as a model3. The idea of platelets cloaking tumour cells and preventing them from being recognised by the immune system has now gained significant interest in the scientific community and is becoming the subject of high-impact publications. They are currently investigating anti-platelet strategies as treatments for metastasis.
The success of this work has now resulted in the head of the DISCOVARY consortium, Prof O’Leary, being awarded a clinician scientist award from the Health Research Board. The HRB Clinician Scientist Awards are part of a strategic aim to develop a culture of research and innovation in the health services, both for the benefit of patients and the Irish economy.
This prestigious award will allow further investigation into what the circulating tumour cell is and how it evades the immune system and how to develop novel therapies against these.
The accepted standard of care treatment for ovarian cancer is debulking surgery and carboplatin/paclitaxel chemotherapy. While many women respond well to chemotherapy, the disease usually recurs and patients develop chemoresistant disease. New targeted biologic agents, particularly those involved in anti-angiogenesis (e.g. Bevacizumab) and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold some promise for improving outcomes in ovarian cancer.
The consortium has identified two prognostic markers in ovarian cancer which can predict how a tumour will respond to chemotherapy. MyD884 and MAD25 status may allow the triage of ovarian cancer patients into chemosensitive and chemoresistant groups and the consortium is currently seeking funding to carry out a trial of these markers through the All-Ireland Co-operative Oncology Research Group (ICORG).
Other research being carried out internationally includes improving drug delivery, improving surgical management of the disease, examining the epigenetics of the disease and determining the origin of ovarian cancer, as recent studies have shown that some ovarian cancers originate in the fallopian tube6.
Second-generation sequencing is changing how we look at this disease and holds great promise for patient-tailored therapy in the future.
• Further details of World Ovarian Cancer Day can be found on http://www.ovacare.com.
• Dr Sharon O’Toole, Senior Scientist in TCD with the DISCOVARY consortium, also chairs the medical panel of OvaCare, a national ovarian cancer charity established in 2011 to provide a nationwide network and support system for people affected by ovarian cancer in Ireland.
The DISCOVARY research consortium was formed to specifically address issues in relation to ovarian and endometrial cancer diagnostics and prognostics and supports the development of translational research in Ireland.
The consortium is built on ongoing collaborations between gynaecologists, oncologists, pathologists, scientists and bioinformaticians throughout Ireland, representing the following institutions: Obstetrics and Gynaecology, Histopathology, IMM, TCD; the Conway Institute, UCD; Biomedical Diagnostics Institute, DCU; Centre for Cancer Research and Cell Biology, Queen’s University Belfast; and the following hospitals: St James’s; the Coombe Women and Infants’ University Hospital; the Mater; St Vincent’s University Hospital; Belfast City; University College Hospital, Galway; and University College Hospital, Cork.
The consortium has the backing of ICORG and the Irish Cancer Society and has been fortunate to receive funding from the Emer Casey Foundation. Family and friends of Emer established the foundation following her untimely death from ovarian/uterine cancer in June 2006.
1. Menon U, Kalsi J, Jacobs I, ‘The UKCTOCS Experience — Reasons for Hope?’ Int J Gynecol Cancer. 2012 May;22 Suppl 1:S18-20.
2. Murphy MA, O’Connell DJ, O’Kane SL, O’Brien JK, O’Toole S, Martin C, Sheils O, O’Leary JJ, Cahill DJ, ‘Epitope Presentation is an Important Determinant of the Utility of Antigens Identified from Protein Arrays in the Development of Autoantibody Diagnostic Assays’, Journal of Proteomics, 2012 Mar 4 [Epub ahead of print].
3. Egan K, Crowley D, Smyth P, O’Toole S, Spillane C, Martin C, Gallagher M, Canney A, Norris L, Conlon N, McEvoy L, Ffrench B, Stordal B, Keegan H, Finn S, McEneaney V, Laios A, Ducrée J, Dunne E, Smith L, Berndt M, Sheils O, Kenny D, O’Leary J, ‘Platelet Adhesion and Degranulation Induce Pro-survival and Pro-angiogenic Signalling in Ovarian Cancer Cells’. PLoS One. 2011;6(10):e26125.
4. D’Adhemar C, O’Toole SA, Stordal B, Martin CM, McEvoy L, Crowley DJ, Sheils OM, O’Leary JJ, ‘Alterations in MyD88 and microRNA Expression are Associated with Chemoresistance in Epithelial Ovarian Cancer’. Modern Pathology/Laboratory Investigations 2011.
5. Furlong F, Fitzpatrick P, O’Toole S, Phelan S, McGrogan B, Maguire A, O’Grady A, Gallagher M, Prencipe M, McGoldrick A, McGettigan P, Brennan D, Sheils O, Martin C, W Kay E, O’Leary J, McCann A, ‘Low MAD2 Expression Levels Associate with Reduced Progression-free Survival in Patients with High-grade Serous Epithelial Ovarian Cancer. J Pathol. 2011 Nov 8. doi: 10.1002/path.3035.
6. Crum CP, Drapkin R, Miron A, Ince TA, Muto M, Kindelberger DW, Lee Y, ‘The Distal Fallopian Tube: A New Model for Pelvic Serous Carcinogenesis’. Curr Opin Obstet Gynecol. 2007 Feb;19(1):3-9.
May 2, 2013