My major research focus is high grade serous carcinoma (HGSC), the most common and most aggressive type of ovarian cancer, and the cancer associated with germline mutations of genes BRCA1 and BRCA2. This cancer most commonly presents at an advanced and incurable stage, and in the absence of effective screening and preventative strategies, it is important to understand the early molecular and genetic changes of this cancer. For the last decade, my research has been focused on understanding the pre-malignant alterations in the fallopian tube epithelium, the cell of origin of most cases of HGSC. To achieve this we have addressed the classification of cancer precursor lesions in the fallopian tube, studied gene expression profiles in normal tubal epithelium in carriers and non-carriers of germline BRCA mutations, and analyzed gene expression in high vs low anatomic risk regions of the tube. We have also developed in vitro models of tumour development using human tubal epithelium. Ongoing studies include determining the clinical relevance of cancer precursors in the fallopian tube.

HGSC is frequently associated with germline mutations of BRCA1 and BRCA2.  Although genetic testing and counselling is available to women with a diagnosis of high grade ovarian cancer, in Ontario, and across Canada, fewer than 20% of women eligible are tested. This has implications not only for the patient but also for family members, who may not be aware they are at genetic risk, and are not otherwise eligible for testing using existing criteria. At Princess Margaret, we have initiated the prevent Ovarian Cancer Program (POCP) to perform comprehensive germline testing and genetic counselling in 500 women with a first-degree relative who died from high-grade serous ovarian cancer, but who may not have received BRCA1/2 genetic testing as per Ontario Ministry of Health criteria. In another 500 cases, tumor testing will be performed in tissues of women who died of HGSC with the consent of first degree relatives.  Women identified as carrying a germline mutation may undergo risk-reducing salpingo-oophorectomy, which markedly reduces the lifetime risk of ovarian cancer.

Very few non-surgical strategies exist for the prevention of HGSC. Epidemiological evidence suggests ASA may be preventative, and we are currently embarking on an international trial in known BRCA1/2 mutation carriers considering risk reducing surgery. The novel primary end-point is to compare the frequency of precursor lesions and occult carcinomas in the resected specimens between patients taking ASA vs placebo. The primary review and adjunct studies will elucidate much about early cancers and precursor lesions.

Most cases of HGSC respond initially to chemotherapy, but most develop secondary resistance. HGSC is a genomically unstable disease with copy number alterations throughout the genome, with few recurrent mutations.  A new generation of therapies targets the deficiency of heterologous DNA repair, a feature seen in about 50% of these tumours. I am working with a team of oncologists, geneticists and scientists in an attempt to further understand the genomics in the course of disease of HGSC patients undergoing multiple lines of treatment.