Background

Ovarian cancer is the most serious gynecological cancer and the 5th most common cause of cancer death in women due to the poor survival of the majority of women who present with advanced disease. In the absence of an effective ovarian cancer screening test, which is the current situation, the only remaining way to manage ovarian cancer risk is prevention. This requires identifying a cohort of women at most risk of developing the disease, due to either environmental and/or genetic risk, and targeting efforts on them. The most well-defined risk factors are the presence of an inherited alteration in either of the BRCA1 or BRCA2 genes.

Recent findings in Europe and North America demonstrate a surprisingly high frequency of BRCA1/2 alterations in women with ovarian cancer, including among women who would not normally be considered substantially at risk of having such mutations. If these findings are corroborated, then it will mandate a change in global clinical practice in defining women who should be targeted for BRCA1/2 genetic testing.

Research Methods

We will perform genetic testing for alterations in the BRCA1/2 genes in women who participated in a population-based cohort of ovarian cancer, the Australian Ovarian Cancer Study (AOCS). The results of the genetic testing will be returned to consenting women for their own use, as well as be used for additional studies: We will investigate the effectiveness of current family history assessment tools used to identify families who are eligible for BRCA1/2 genetic testing as well as provide a profile of those tumor, personal, and family history factors that are most associated with the presence of a significant BRCA1/2 alteration in women with ovarian cancer.

We will also investigate the reasons why women are willing to participate in this type of genetic research and why some of these women elect not to find out their genetic test results. The BRCA1/2 genetic test results will permit a more in-depth analysis of the underlying genetic changes that occur in ovarian cancer by using the information to help explain our results from previous experiments in the AOCS group, looking at the genetic changes in the tumors from these women.

Expected Outcomes

Near-term applications: Most importantly, we will improve the ability to identify families at genetic risk of ovarian cancer and hence impact on the mortality of ovarian and breast cancer in this group. If we validate previous studies of key factors predictive of BRCA1/2 alterations, this will mandate a global change in clinical practice of defining women who should be targeted for BRCA1/2 genetic testing. We will define the strengths and limitations of current BRCA1/2 mutation prediction models and therefore identify ways of improving these widely-used genetic risk assessment tools.

Contributions to future research: We will gain important insights into the relationship between inherited alterations in BRCA1/2 genes and the genetic changes that occur in the development of ovarian cancer. These insights will help to develop more effective treatments for ovarian cancer either by highlighting those women most likely to respond to certain treatments and/or to suggest new targets for drug development in this disease.

Identifying families with BRCA1/2 mutations offers the best chance of reducing mortality for ovarian and breast cancer within these families; however, it appears that many women who carry these mutations remain unaware of their mutation status. The only effective way of reducing overall mortality from ovarian cancer is prevention by risk-reducing bilateral salpingo-oophorectomy in women at highest risk of the disease. Ovarian cancer screening is currently not effective and overall 5-year survival for advanced ovarian cancer has remained <40% for decades, so prevention of ovarian cancer in these families is the most effective method of reducing overall mortality for ovarian cancer.

Most publicly funded BRCA1/2 mutation detection programs require a strong family history of breast and/or ovarian cancer, and to change selection criteria to include the majority of women who present with ovarian cancer, regardless of family history, requires strong evidence in support of this paradigm shift in clinical practice. A recent large-scale population-based study of BRCA mutation frequency in Canadian women with ovarian cancer suggests that a radical re-evaluation of the current criteria for deciding which women with ovarian cancer are offered genetic testing for BRCA1/2 germline mutation is needed. Because of the workforce, medical, and cost implications of this change, it is vital that the conclusions of the Canadian study are evaluated in a second study of similar scale. The results from this work will be very important in determining whether BRCA-testing guidelines need to be substantially broadened, and will provide a framework for the combined use of genetic risk assessment and targeted prevention of ovarian cancer.

A second major goal of this study is to perform detailed genomic analysis of tumors from BRCA1 and BRCA2 carriers, and to compare their patterns of gene expression and DNA gain/loss with tumors from non-carriers. The goals of this work are to determine the extent to which tumors from non-carriers molecularly resemble tumors arising in carriers, and to understand the patterns of genomic change that are associated with tumors arising in the presence of heterozygous germline BRCA mutations. This work will increase our understanding of the molecular etiology of ovarian cancer and provide insights into the use of novel anticancer agents that target BRCA-defective tumors in non-carriers.