Type of Proposal
24-3-2015 11:00 AM
24-3-2015 11:50 AM
Schulich School of Medicine Windsor
Dr. Marcus Bernardini, Princess Margaret Cancer Center
Importance of the Project
Ovarian cancer is the fifth leading cause of cancer-related death in Canadian women and is the most lethal cancer of the female reproductive tract. Unfortunately, there are no reliable tests for early detection of ovarian cancer, and many women seek medical treatment when they experience symptoms of advanced disease. This contributes to the poor long-term survival in women with ovarian cancer. However we can prevent the development of ovarian cancer if we identify women who are at increased risk of ovarian cancer beforehand. The most significant risk factor for ovarian cancer is genetic mutations in genes called the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2), the mismatch repair pathway (MMR) genes, the Fanconi Anemia pathway (FA) genes, as well as ATM, CDH1, EPCAM, MUTYH, NF1, PTEN, STK11, TP53. Individuals with these gene mutations have an increased risk of developing ovarian and other cancers, such as breast, colon and endometrial cancer (known as Lynch Syndrome). Currently the most effective way to reduce the number of deaths from ovarian cancer is by preventing the onset of ovarian cancer in women who are known to be at increased risk of developing this deadly disease. The most effective way to prevent ovarian cancer is by surgical removal of the ovaries and fallopian tubes. The purpose of the study is to identify women who carry mutations in BRCA1/2 and other risk genes through genetic testing and provide the opportunity to prevent ovarian cancer by risk-reducing surgery. The psychosocial impact and barriers to genetic testing and surgical removal of the ovaries and fallopian tubes will also be studied. Furthermore, the study is a pilot initiative for a long term comprehensive Target Ovarian Cancer Program.
Existing State of Knowledge
‘Ovarian cancer’ represents a heterogeneous collection of five distinct diseases – high grade and low grade serous, endometrioid, clear cell and mucinous carcinoma – all with unique sites of origin, molecular aberrations and clinical behaviour. The most common and lethal form, high-grade serous carcinoma (HGSC), accounts for 70% of cases, presents at an advanced stage and predominately originates in the fallopian tube. Up to 15% of unselected epithelial ovarian cancer (EOC) and 20-25% of HGSC are associated with inherited BRCA1/2 mutations. Despite advances in surgery and chemotherapy drug choices and delivery, survival rates at 1, 3 and 5 years have only changed 1%, 5% and 4% respectively in the past decade.
Attempts at screening in BRCA1/2 carriers have also been ineffective at shifting diagnosis to an early stage, despite a greatly increased incidence of disease in this population. In light of the failure of screening and the limited ability to change outcome through treatment of advanced disease, targeted prevention must be a priority if we want to make a true impact.
An estimated 1 in 300 women have an inherited mutation in BRCA1/2. While the lifetime risk of developing ovarian cancer is low in the general population (~1.5%), this risk increases to 20-60% and 10-30% for BRCA1 or BRCA2 mutation carriers respectively. The breast cancer risk in BRCA mutation carriers has been reported to be 57-65% for BRCA1 and 45-55% for BRCA2 carriers. There is a 50% chance that the first-degree relatives (FDRs) of a BRCA1/2 mutation carrier will have the same mutation. In women with known BRCA1/2 mutation status HGSC can be prevented prior to onset by surgical removal of the fallopian tubes and ovaries (risk-reducing salpingo-oophorectomy, RRSO).
Due to the strong link between BRCA1/2 and HGSC, the Ontario Ministry of Health and Long-Term Care (OMHLTC) released recommendations in 2001 that made all women with serous EOC eligible for BRCA1/2 testing. However, only a minority of eligible patients were referred in the decade that followed. An analysis of women diagnosed with HGSC in Ontario from 2002-04 revealed that only 19% (80/416) had undergone genetic testing. The low long-term survival probability of women with HGSC, combined with current referral practices for unaffected family members, has resulted in a large cohort of female FDRs who may be at risk and not know it. If we extrapolate over the past 10 years in Ontario, we identify a clinical gap of up to 2000 women with inherited BRCA1/2 mutations who have not been identified and are unaware of their high risk for ovarian cancer.
The study is a first step towards establishing a comprehensive, multidisciplinary Target Ovarian Cancer Program (TOCP) for prevention of ovarian cancer in high risk women. The overall goal is systematic detection of inherited mutations in BRCA1/2 and emerging risk genes through panel-based testing to determine mutation prevalence and fill an existing clinical gap of a large cohort of high-risk women with uknown BRCA1/2 mutation status in Ontario.
The following specific research questions are addressed in this study:
1) How many additional pathogenic mutations are detected through panel-based testing? We hypothesize a mutation detection rate of 10% BRCA1/2 (N=100), and 2.5-5% other genes (N=25-50) rate.
2) What are the barriers to genetic testing? We hypothesize that genetic testing is acceptable to patients with awareness as the main barrier.
This study is a pilot initiative for the Target Ovarian Cancer Program. A media campaign will be launched to recruit study participants that will provide basic education about ovarian cancer, genetic testing, prevention, etc. and direct potentially eligible participants to a dedicated website (www.preventovariancancer.ca). The media campaign will be primarily directed at female FDRs of previously untested HGSC patients who are now deceased. Self-identified potential participants will be instructed on our website to create an account to which an anonymous user ID will be assigned. In order to confirm HGSC in the participant’s relative, detailed instructions will be given on how to obtain a pathology report for a deceased individual and fax it to us. In addition, there will be a family history questionnaire to fill out on the website. Following pathologic confirmation and family history review eligible participants who are female FDRs of HGSC patients will be identified and enrolled in the study. The number of participants to be enrolled in this pilot study will depend on the number of self-identified female FDRs of previously untested HGSC patients wishing to participate in the study. It is estimated that there are up to 2000 female FDRs with inherited BRCA1/2 mutations who have not been identified.
Participants in this study will undergo genetic testing and data on ovarian cancer risk genes will be collected through panel-based germline sequencing. The panel includes the following genes: BRCA1 and BRCA2; MMR genes MLH1, MSH2, MSH6 and PMS2; FA genes BARD1, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD51C and RAD51; as well as ATM, CDH1, EPCAM, MUTYH, NF1, PTEN, STK11, TP53. Genetic testing will be performed using blood samples. Psychosocial research will be conducted in parallel with genetic testing and data will be gathered in the form of questionnaires. There will be several online questionnaires for participants to fill out regarding the psychosocial impact of and attitude towards all elements of the genetic testing process (e.g. disclosure of mutation results, patient and family decision-making) and risk-reducing surgery.
The study is a pilot initiative for a long-term systematic Target Ovarian Cancer Program. The study is multi-factorial with clinical, research and public awareness components scheduled to run until 2016. During the summer months I was involved with the early planning stages of the pilot initiative including business planning and presenting the initiative in order to secure a large amount of funding; liaising with hospitals across Ontario for pathology reports; developing the website content and design; as well as obtaining research ethics approval for the study.
The media campaign is currently scheduled to launch on World Ovarian Cancer Day on May 8, 2015. The dedicated website www.preventovariancancer.ca has been finalized and includes basic education about ovarian cancer, genetic testing, prevention, etc. The details of the media campaign are currently being confirmed with attempts to involve celebrity endorsement from Angelina Jolie. The logistics of genetic testing, research questionnaires and clinical intervention are being worked out.
At the conclusion of the study scheduled in 2016, we will achieve identification of a high-risk cohort of women in which we can prevent ovarian cancer, address important research questions and provide necessary evidence for a shift in genetic referral and testing practices for relatives of women with high-grade serous carcinoma of the ovaries.
The Princess Margaret Cancer Center Target Ovarian Cancer Program