By Rachel Lebovic

Graphic design by Lauren Jones

One in every 300-400 Canadians, which translates to approximately 100 000-    133 000 people, are prone to carrying a mutation in the breast cancer type 1 (BRCA1) or type 2 (BRCA2) gene.¹ BRCA1 and BRCA2 are essential genes that function in preventing cancer. Individuals who have a mutation in one of these genes have an increased risk of developing breast, ovarian, and/or prostate cancers, among others.¹ With a lifetime risk of up to 80% for breast cancer and up to 20-40% for ovarian cancer,¹ there has been significant scientific efforts on evaluating the best way to prevent, treat, and manage these elevated cancer risks.

Dr. Joanne Kotsopoulos, Tier 2 Canada Research Chair in Hereditary Breast and Ovarian Cancer Prevention, is part of a large Women’s College Hospital (WCH) team studying hereditary breast and ovarian cancer. With faculty appointments at the Temerty Faculty of Medicine and Dalla Lana School of Public Health, Dr. Kotsopoulos integrates her vast skill set to conduct epidemiological studies to further our understanding of cancer risk and prognostic factors to improve upon the management of individuals with mutations in a BRCA gene. 

While discussing BRCA-related cancers, the theme of precision and personalized medicine emerged. With regard to prevention, the goal is to understand individual risk factors and their underlying biology to further personalize the screening and prevention regimens to ensure their maximum efficacy. In terms of treatment, the unique features and interplay of cancer cells, biomarkers, and genetics can inform targeted treatment to best fight each disease. Finally,, individualized approaches are being studied post-surgery and in the management of adverse symptoms resulting from cancer treatments to understand which interventions are safe. Dr. Kotsopoulos elaborated on her work in each of these areas. 

Personalizing Prevention Tools

In Ontario, the recommendation for female BRCA mutation carriers is to get yearly mammograms with an ultrasound or MRI starting at 30 years of age.² Unfortunately, there are currently no effective screening tools for the early detection of ovarian cancer. As a result, it is recommended that carriers undergo preventative removal of their fallopian tubes and ovaries (known as an “oophorectomy”) by the ages of 35-45.³ While these guidelines have been practical, they remain imperfect. Undergoing an oophorectomy at a young age forces premature menopause, accompanied by numerous symptoms that impact quality of life, sometimes with few management options. 

A core interest of Dr. Kotsopoulos is prevention through a personalized approach using epidemiological data to assess individual risk among carriers. “We have the largest cohort of women, over 19 000 women from across the globe,” Dr. Kotsopoulos mentions. Those being followed in this cohort complete a series of questionnaires every two years, answering detailed questions related to oral contraception, breastfeeding, and hormone replacement therapy (HRT) to understand which exogenous factors may further influence cancer risk. Dr. Kotsopoulos and her team hope that by understanding risk factors and biomarkers (for example, certain proteins in the blood), they may be able to create some sort of algorithm with the help of machine learning to predict an individual’s risk and safely delay preventive ovary removal surgery as long as possible. 

When it comes to prevention and early detection, one can only act if they are aware of their mutation status. In Canada, individuals must qualify for genetic testing based on various criteria such as a strong family history of cancer or personal cancer diagnosis at a young age (among others). While this remains important for developing a personalized treatment plan, once diagnosed with a BRCA-associated cancer, the window for prevention has passed. The team at WCH, including Dr. Kotsopoulos, are leading The Screen Project,¹ an initiative to make BRCA testing available and accessible to all Canadian adults. She highlights, “We believe that the more people that are aware of their genetic makeup, the more opportunities there are to prevent.” By reducing barriers to access genetic testing, The Screen Project has identified many individuals who carry the mutation without a family history of cancer. The Screen Project also streamlines and simplifies this process, whereby a saliva collection kit is sent for the individual to complete at home and mail back. Informational pre- and post-test videos are shared, and individualized genetic counselling is offered based on the results. Longitudinal results from The Screen Project will inform recommendations for a nationwide, population-based BRCA screening approach. 

Personalizing Treatment and Management 

Precision medicine has gained significant attention in the cancer community, recognizing that each cancer is unique and should be treated with a targeted approach.⁴ When it comes to BRCA-related cancers, treatment can be personalized based on gene carrier status. For example, many BRCA-cancers are treated with poly ADP ribose polymerase (PARP) inhibitors. These inhibitors can specifically target cancer cells caused by the mutated BRCA gene and subsequently treat the cancer. 

An important aspect of personalized care relates to the age discrepancy in cancer diagnosis for BRCA carriers. Dr. Kotsopoulos explained that in BRCA carriers, “it is much more complex. Many female carriers are diagnosed with breast cancer at a young age compared to women without a mutation who are more likely to develop cancer following menopause.” HRT shows promise as a method to help manage menopause symptoms and enhance quality of life post-oophorectomy in BRCA carriers, however, research demonstrates that it may increase the risk of breast cancer. The question then becomes, “Can we safely manage these women with HRT after a diagnosis?” 

To explore this question, Dr. Kotsopoulos is examining her global database of carriers and discovered that, despite existing guidelines, approximately 300 women have chosen to use HRT. With the ability to analyze specific tumour pathologies, treatment records, and risk factors, the hope is to understand who can safely use HRT. This will offer an opportunity to improve quality of life for young women.

Incredible progress has been made in the management of this unique population over the past 30 years since the BRCA mutations were discovered. When asked about her advice to young women, Dr. Kotsopoulos shared that “knowledge is power.” Know your risk and how to manage it. 

References

1. The Screen Project [Internet]. 2024 [cited 2024 Oct 29]. Available from: https://www.womensacademics.ca/active-studies/the-screen-project-study/ 
2. Breast Cancer Screening for People at High Risk [Internet]. [cited 2024 Oct 29]. Available from: https://www.cancercareontario.ca/en/guidelines-advice/cancer-continuum/screening/breast-cancer-high-risk 
3. Prevention & Genetic mutations [Internet]. 2024 [cited 2024 Oct 29]. Available from: https://ovariancanada.org/prevention-genetic-mutations 
4. Precision medicine [Internet]. 2021 [cited 2024 Oct 30]. Available from: https://cancer.ca/en/research/understanding-cancer-research/precision-medicine