Evan Weber

Pathogenic variants in breast cancer predisposition genes are associated with poor clinical outcomes but also offer an opportunity for more individualized therapeutic pathways. Given increasing knowledge, improvements in germline genetic testing efficiency, and the availability of novel systemic targeted treatment options, the importance of appropriately identifying patients for testing has never been greater. A pan-Canadian expert working group (EWG) consisting of 10 healthcare professionals (HCPs) was convened to review recent international guidelines for germline genetic testing in breast cancer and develop Canadian recommendations. The group identified four clinical questions to address which patients should undergo testing, what approaches should be used, how patients should be counselled, and what steps are needed for implementation. In response to these questions, the EWG agreed upon 12 recommendations that emphasized broader incorporation of germline genetic testing and more standardized, streamlined testing and counselling approaches. The group also offered multiple suggestions to support effective and equitable implementation across Canada. These recommendations provide guidance for HCPs and represent a call to action for the Canadian government and other organizations to support genetic testing pathways, drug access, and ultimately improved outcomes for patients with breast cancer and their families.

Pathogenic variants in breast cancer predisposition genes are associated with poor clinical outcomes but also offer an opportunity for more individualized therapeutic pathways. Given increasing knowledge, improvements in germline genetic testing efficiency, and the availability of novel systemic targeted treatment options, the importance of appropriately identifying patients for genetic testing has never been greater. A pan-Canadian expert working group (EWG) consisting of 10 healthcare professionals was convened to review recent international guidelines for germline genetic testing in breast cancer and develop Canadian recommendations. The group identified four clinical questions to address which patients should undergo testing, what approaches should be used, how patients should be counselled, and what steps are needed for implementation. In response to these questions, the EWG agreed upon 12 recommendations that emphasized broader incorporation of germline genetic testing and more standardized, streamlined testing and counselling approaches. The group also offered multiple suggestions to support effective and equitable implementation across Canada. These recommendations provide guidance for healthcare professionals and represent a call to action for the Canadian government and other organizations to support genetic testing pathways, drug access, and ultimately improved outcomes for patients with breast cancer and their families.

Background: Up to 20% of women diagnosed with tubo-ovarian carcinoma carry a germline pathogenic variant in a cancer-predisposing gene (e.g., BRCA1/BRCA2). Identifying these variants can help to inform eligibility for therapies, guide surveillance and prevention of new primary cancers, and assess risk to family members. The Gynecologic Oncology-Initiated Genetic Testing Model (GOIGT) was initiated at the McGill University Health Centre (MUHC) to streamline universal germline genetic testing for this population, while addressing the limited resources in the public healthcare system. This study aimed to evaluate the patient experience of participating in this model. Methods: Study participants were patients diagnosed with high-grade non-mucinous epithelial tubo-ovarian cancer who underwent genetic testing through the GOIGT model between 1 January 2017 and 31 December 2020. Eligible participants completed the retrospective questionnaires at least one month after result disclosure. Results: A total of 126 patients were tested through the GOIGT model during the study period, of which 56 were invited to participate. Thirty-four participants returned the study questionnaire. Overall, participants did not report decision regret following the genetic testing and were satisfied with the GOIGT model. Participants reported low levels of uncertainty and distress related to the implications of their test results for themselves and their family members. Conclusions: The results of this study support the continued implementation of mainstreamed genetic testing models for women with high-grade non-mucinous tubo-ovarian cancer. Further studies are required to compare experiences for patients with different genetic test results.

Defects in DNA repair genes have been extensively associated to cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathway predispose to cancers arising mainly in breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago, when germline variants were associated to non-BRCA1/2 familial ovarian cancer. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, integrating this list with variants identified by in house patient screening. A comprehensive catalogue of 341 variants that have been classified applying ACMG/AMP criteria has been generated pinpointing to the existence of recurrent variants in both genes. Recurrent variants have been extensively discussed compiling data on population frequencies and functional characterization if available, highlighting variants that have not been fully characterized yet to properly establish their pathogenicity. Finally, we have complemented this data with relevant information regarding conservation of mutated residues among RAD51 paralogs and modeling of hotspot areas, which contributes to generate an exhaustive update on these two cancer predisposition genes.

Background: Approximately 2–6% of endometrial cancers (ECs) are due to Lynch Syndrome (LS), a cancer predisposition syndrome caused by germline pathogenic variants (PVs) affecting the DNA mismatch repair (MMR) pathway. Increasingly, universal tissue-based screening of ECs has been proposed as an efficient and cost-effective way to identify families with LS, though few studies have been published on Canadian cohorts. The purpose of this study was to evaluate the feasibility and overall performance of a universal immunohistochemistry (IHC) screening program for women with EC within a single Canadian university hospital centre. Methods and Results: From 1 October 2015 to 31 December 2017, all newly diagnosed ECs (n = 261) at our centre were screened for MMR protein deficiency by IHC. MMR deficiency was noted in 69 tumours (26.4%), among which 53 had somatic MLH1 promoter hypermethylation and were considered “screen-negative”. The remaining MMR-deficient cases (n = 16) were considered “screen-positive” and were referred for genetic counselling and testing. Germline PVs were identified in 12/16 (75%). One additional PV was identified in a screen-negative individual who was independently referred to the Genetics service. This corresponds to an overall LS frequency of 5.0% among unselected women with EC, and 6.4% among women diagnosed under age 70 years. Our algorithm detected MMR gene pathogenic variants in 4.6% and 6.2% of unselected individuals and individuals under age 70 years, respectively. Four germline PVs (30.8%) were identified in individuals who did not meet any traditional LS screening criteria. Conclusions: Universal IHC screening for women with EC is an effective and feasible method of identifying individuals with LS in a Canadian context.

Background: Hereditary tumor predisposition syndromes (HTPSs) are being recognized more frequently in the etiology of pediatric cancer. Previous research indicates that disclosure of tumor susceptibility is a significant event in adolescents’ lives. Insight into adolescents’ adjustment to knowledge of their syndromes can guide healthcare delivery, particularly genetic counseling. This study explored the experiences of adolescents with hereditary tumor predisposition and their perceptions of living at risk.Methods: Seven adolescents, ages 14 to 17, representing six different childhood‐onset HTPSs, were purposively sampled and interviewed using a study‐specific semistructured interview guide. We explored the disclosure process, support systems, and the perceived benefits and harms of knowledge of hereditary tumor susceptibility. Interview transcripts were analyzed via interpretive description.Results: Three major themes emerged from the data: (1) The benefits of knowledge outweigh the harms; (2) context surrounding genetic testing must be recognized; and (3) self‐concept is influenced but not defined by tumor risk.Conclusions: We conclude that adolescents recognize the challenges associated with awareness of tumor predisposition but may also identify positive aspects in their experiences, reflecting a changed life perspective. Results of this exploratory study suggest strategies that can guide pretest and posttest genetic counseling of adolescents for HTPSs, facilitating the adaptive incorporation of genetic information into an adolescent's self‐concept.