Coming of Age in Canada: A Study of Population-Based Genetic Testing for Breast and Ovarian Cancer

Abstract

The BRCA1 and BRCA2 genes are the two most commonly mutated in hereditary breast and ovarian cancer, and they are the canonical pair when it comes to cancer testing 1 . There are many other candidate genes, and large-panel testing is increasingly the norm even though not all practitioners are in agreement 2 that testing for 20 genes is better than testing for 2. Mutations are associated with lifetime risks of 80% for breast cancer and 15%-40% for cancer of the ovary or fallopian tube for BRCA2 and BRCA1 respectively 3 . BRCA2 is the most frequently mutated gene in both prostate cancer 4,5 and pancreatic cancer [6][7][8] , and patients with BRCA2 mutations can benefit from novel therapies such as cis-platinum 9 . Annually, about 8500 cases of prostate cancer and 2150 cases of pancreatic cancer are diagnosed in Ontario, but very few of those patients are being tested for BRCA2.Genetic screening is now mainstream as a consequence of diminished sequencing costs, increased public awareness, celebrity endorsement, and the now wide availability to women of preventive surgery through public and private health insurance. Intensified screening for mutation carriers with annual magnetic resonance imaging is advocated and is increasingly available 10 . Additionally, women with hereditary breast cancer can benefit from personalized treatment (both surgical and medical), which might include bilateral mastectomy, salpingo-oophorectomy, and tailored chemotherapy (cis-platinum or olaparib) 11 .The current model of delivering genetic testing for the BRCA genes in North America dates to the mid-1990s, at a time when genetic testing was expensive and the clinical benefits were largely unproven. Because of the high cost, public and private insurers were not willing to pay for testing for all comers. In the resulting model, a women is referred by her physician to a specialized cancer genetics clinic, where a formal assessment is conducted. If the risk estimate for carrying a mutation exceeds a threshold value (usually 10%), then genetic testing for the BRCA genes ensues. If not, then the woman is reassured and sent off with a number of recommendations based on her personal and family history of cancer. In many clinics, the volume of patient requests now exceeds the number of available appointments, and triage is conducted by mail or telephone. The genetics counsellor serves two purposes: informing women about cancer risk, management options, and the testing process; and ensuring that testing is rationed first to the women who are the most suitable candidates.We believe that the current model is outdated, and here we propose an alternative model based on direct-toconsumer population-based testing. The reasons are these:■ First, a significant proportion of BRCA mutation carriers do not reach the 10% threshold; they therefore represent missed opportunities for identification 12 . ■ Very few patients with prostate cancer or pancreatic cancer are being tested. In addition, many individuals who do qualify for genetic testing fail to be ide...

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry

“…In recent years, several groups have called for broader access to BRCA genetic testing among Ashkenazi Jews and among women in the general population, which could enable women and men with a BRCA variant to learn their status, take steps to reduce their cancer risk, and encourage cascade testing of close family members [5][6][7]10,11 . Among Ashkenazi Jews, where testing for the three founder variants can identify most BRCA carriers, population-wide screening is cost-effective or even cost-saving 14 ; in other ethnicities, more comprehensive genetic testing would be required to identify most individuals carrying a BRCA variant, but depending on the source of testing, this may also be cost-effective 15 .…”

Hereditary Breast and Ovarian Cancer in Families from Southern Italy (Sicily)—Prevalence and Geographic Distribution of Pathogenic Variants in BRCA1/2 Genes

“…Recently, several studies have demonstrated that the prevalence of germline PVs and gene-specific risk estimates could change, not only based on family history and type/molecular subtype of the tumors but also on the basis of race, ethnicity and different geographic location [28][29][30].…”

Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry

“…These individuals would likely not qualify for clinical genetic testing unless they developed cancer themselves, representing a missed opportunity for cancer prevention. Because BRCA variants predispose to very high breast and ovarian cancer risks even among carriers without a family history [5,9], these findings have spurred calls for broader access to BRCA genetic testing, among Ashkenazi Jews and in the general population [5-7,10,11].…”