Report from the 24th Annual Western Canadian Gastrointestinal Cancer Consensus Conference on Colorectal Cancer, Richmond, British Columbia, 28-29, October 2022.

The 24th annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Richmond, British Columbia, on 28-29 October 2022. The WCGCCC is an interactive multidisciplinary conference attended by healthcare professionals from across Western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; radiologists; and allied health care professionals such as dieticians, nurses and a genetic counsellor participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer.

Workforce Implications of Increased Referrals to Hereditary Cancer Services in Canada: A Scenario-Based Analysis.

Over the last decade, utilization of clinical genetics services has grown rapidly, putting increasing pressure on the workforce available to deliver genetic healthcare. To highlight the policy challenges facing Canadian health systems, a needs-based workforce requirements model was developed to determine the number of Canadian patients in 2030 for whom an assessment of hereditary cancer risk would be indicated according to current standards and the numbers of genetic counsellors, clinical geneticists and other physicians with expertise in genetics needed to provide care under a diverse set of scenarios. Our model projects that by 2030, a total of 90 specialist physicians and 326 genetic counsellors (1.7-fold and 1.6-fold increases from 2020, respectively) will be required to provide Canadians with indicated hereditary cancer services if current growth trends and care models remain unchanged. However, if the expansion in eligibility for hereditary cancer assessment accelerates, the need for healthcare providers with expertise in genetics would increase dramatically unless alternative care models are widely adopted. Increasing capacity through service delivery innovation, as well as mainstreaming of cancer genetics care, will be critical to Canadian health systems' ability to meet this challenge.

Genetic testing practices among specialist physicians who treat prostate cancer A Canadian, cross-sectional survey.

INTRODUCTION: In patients with prostate cancer (PCa), the identification of an alteration in genes associated with homologous recombination repair (HRR) has implications for prognostication, optimization of therapy, and familial risk mitigation. The aim of this study was to assess the genomic testing landscape of PCa in Canada and to recommend an approach to offering germline and tumor testing for HRR-associated genes. METHODS: The Canadian Genitourinary Research Consortium (GURC) administered a cross-sectional survey to a largely academic, multidisciplinary group of investigators across 22 GURC sites between January and June 2022. RESULTS: Thirty-eight investigators from all 22 sites responded to the survey. Germline genetic testing was initiated by 34%, while 45% required a referral to a genetic specialist. Most investigators (82%) reported that both germline and tumor testing were needed, with 92% currently offering germline and 72% offering tissue testing to patients with advanced PCa. The most cited reasons for not offering testing were an access gap (50%), uncertainties around who to test and which genes to test, (33%) and interpreting results (17%). A majority reported that patients with advanced PCa (74-80%) should be tested, with few investigators testing patients with localized disease except when there is a family history of PCa (45-55%). CONCLUSIONS: Canadian physicians with academic subspecialist backgrounds in genitourinary malignancies recognize the benefits of both germline and somatic testing in PCa; however, there are challenges in accessing testing across practices and specialties. An algorithm to reduce uncertainty for providers when ordering genetic testing for patients with PCa is proposed.

Development and early-stage evaluation of a patient portal to enhance familial communication about hereditary cancer susceptibility testing: A patient-driven approach.

INTRODUCTION: Genetic testing for hereditary cancer syndromes (HCSs) can improve health outcomes through cancer risk mitigation strategies. Effective communication between tested individuals and their family members is key to reducing the hereditary cancer burden. Our objective was to develop a patient portal to improve familial communication for patients undergoing HCS genetic testing, followed by an early-phase evaluation. METHODS: The portal was developed following the completion of 25 semistructured interviews with individuals having undergone HCS susceptibility testing at BC Cancer. Following initial development, we recruited patients and healthcare providers to provide critical feedback informing portal refinement. Quantitative feedback was summarized using descriptive statistics, and qualitative feedback was synthesized by two reviewers who engaged in iterative discussion within the research team to prioritize recommendations for integration. RESULTS: The patient portal includes four key components consisting of (a) targeted educational information about hereditary cancer and HBOC syndrome associated risks and testing process overview, (b) a general frequently asked questions 'FAQ' page informed by the qualitative interviews, patient partner feedback, and consultation with the HCP, (c) guidance to support familial communication including a video developed with a patient partner describing their lived experience navigating the communication process and (d) a series of lay summaries of genetic test findings to support information transfer among family members. Thirteen healthcare providers and seven patients participated in user testing. Domains within which participant recommendations were provided included presentation, educational content and process clarification. CONCLUSIONS: This investigation demonstrates the value of continual integration of patient and provider preferences through the development of tools endeavouring to assist with complex genomics-informed decision-making. Our work aims to broaden the population-wide impact of HCS testing programs by improving communication processes between probands and their potentially affected family members. PATIENT OR PUBLIC CONTRIBUTION: This work involved a patient partner who was actively engaged in all aspects of the research investigation including protocol development, review and editing of all study documentation (including that of the previously published qualitative investigation), interpretation of results, as well as reviewing and editing the manuscript. Patient partners and healthcare professionals were recruited as research participants to provide critical feedback on the patient portal.

Evaluation of out-of-pocket pay genetic testing in a publicly funded healthcare system.

When genetic tests are not funded publicly, out-of-pocket (OOP) pay options may be discussed with patients. We evaluated trends in genetic testing and OOP pay for two publicly funded British Columbia clinical programs serving >12 000 patients/year (The Hereditary Cancer Program [HCP] and Provincial Medical Genetics Program [PMGP]) between 2015-2019. Linear and regression models were used to explore the association of OOP pay with patient demographic variables at HCP. An interrupted time series and linear and logistic regression models were used on PMGP data to examine the effect of a change in the funding body. The total number of tests completed through PMGP, and HCP increased by 260% and 320%, respectively. OOP pay increased at HCP by 730%. The mean annual income of patients who paid OOP at HCP was ≥$3500 higher than in the group with funded testing (p < 0.0001). The likelihood of OOP pay increased at PMGP before the funding body change (OR per month: 1.07; 95% CI: 1.04, 1.10); while this likelihood had an immediate 87% drop when the change occurred (OR: 0.13; 95% CI: 0.06, 0.32). Patients with higher incomes are more likely to pay OOP. Financial barriers can create disparities in clinical outcomes. Funding decisions have a significant impact on rate of OOP pay.

Large-scale group genetic counseling: Evaluation of a novel service delivery model in a Canadian hereditary cancer clinic.

Increasing demand for genetic services has led to the development of streamlined genetic counseling (GC) models. We piloted large-scale group pre-test GC with up to 50 patients per group and compared this to a traditional one-on-one approach. Patients referred to the British Columbia (BC) Cancer Hereditary Cancer Program were eligible if they had: (a) family history meeting our program's referral criteria; (b) no relevant personal history of cancer; (c) no prior genetic testing in the family; and (d) no living testable relative in BC. Patient-reported outcome measures included: (a) Genetic Counselling Outcome Scale (GCOS) prior to pre-test GC (T1) and at 4 weeks post-test GC (T2); (b) Satisfaction Survey after pre-test GC; and (c) the Multidimensional Impact of Cancer Risk Assessment (MICRA) for patients undergoing testing (4 weeks after post-test GC). In total, 391 patients underwent GC, 184 by group and 207 by one-on-one appointments. Between May 2018 and May 2019, 6 pre-test group sessions were conducted (median number of patients per group = 28; range 15-48). 8% of patients (n = 32) declined large group GC due to personal preference for one-on-one GC. There were no statistically significant differences in MICRA and GCOS survey results when comparing the pre-test large group versus traditional pre-test one-on-one models (based on 3 MICRA subscales: p = 0.063, p = 0.612, p = 0.842; and GCOS p = 0.169). Overall, the large group pre-test counseling approach was more time-efficient with 15-48 patient group sessions conducted over a mean duration of 80 min as compared to 42 min per patient with the traditional one-on-one GC model. Large-scale group GC was feasible and acceptable to patients and represents a novel streamlined model for GC to enable timely access to cancer genetic services.

Patient ethnicity and cascade genetic testing: a descriptive study of a publicly funded hereditary cancer program.

Cascade genetic testing for hereditary cancer is highly accurate and cost-effective for identifying individuals at high risk for cancer; however, not all eligible people utilize this service. While sociodemographic factors related to the uptake of cascade genetic testing, such as age and sex, have been fairly well described in the literature, there is limited data available regarding patient ethnicity. We analyzed four years of testing data for this factor, as well as sex, age and genes tested. The patients were seen by the Hereditary Cancer Program of BC Cancer, which serves the entire population of British Columbia and Yukon, Canada. Patient ethnicity was compared to the 2016 Census data from the same region. Fisher's exact test was conducted to explore the cascade genetic testing uptakes. Chi-square test was used to compare the major ethnicity groups to Census data. There was significant variability in the uptake of cascade genetic testing in the three largest population groups (p < 0.05), with individuals of European ethnic origin overrepresented, individuals of Asian ethnic origin modestly underrepresented, and individuals of North American Indigenous origin considerably underrepresented for cascade genetic testing. The proportions represented compared to those expected from census data were significantly different for these three largest groups (p < 0.01). The majority of cascade genetic tests were for BRCA1/BRCA2 (58.8%), followed by 16.9% for Lynch syndrome genes. Most patients were female (70%), and the mean age of patients was 49 years old. This study provides further insight into uptake of cascade genetic testing by patient ethnicity. Examining patient ethnicity and cascade genetic testing rates helps to identify underserved populations. Our analysis highlights significant underrepresentation of North American Indigenous individuals for hereditary cancer cascade genetic testing, and helps recognize the need for development of culturally-safe alternatives to outreach and service promotion.

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

Genetic testing in families with hereditary colorectal cancer in British Columbia and Yukon: a retrospective cross-sectional analysis.

BACKGROUND: Genetic testing in families with hereditary cancer enables identification of people most likely to benefit from intensive screening and preventive measures; however, the uptake of testing in relatives (known as cascade carrier testing) for hereditary colorectal cancer syndromes has been shown to be low. Our objective was to report rates of familial testing for hereditary colorectal cancer syndromes in a publicly funded hereditary cancer clinic in Canada. METHODS: A cross-sectional retrospective database review was used to determine testing uptake between 1997 and 2016 for families served by the provincial Hereditary Cancer Program for British Columbia and Yukon. Analyses were conducted for genes associated with syndromes with an increased risk for colorectal cancer, including Lynch syndrome (MLH1, MSH2, MSH6, PMS2 and EPCAM) and familial adenomatous polyposis (APC), and for additional moderate- to high-penetrance genes (STK11, TP53, SMAD4, MUTYH, PTEN and CHEK2). Descriptive statistics were used and all analyses were 2-tailed. RESULTS: The study cohort included 245 index patients, with carrier testing performed in 382 relatives. The mean age at family member testing was 41.2 years, and most (61.0%) of the family members who underwent testing were women. The median time between disclosure of index cases and their family member's results was 8.3 months. Among eligible first-degree relatives, 32.6% (268/821) underwent testing in BC. Of 67 cancer diagnoses in family members, most (62.7%) occurred before genetic testing. INTERPRETATION: A substantial proportion of people at risk for hereditary colorectal cancer do not undergo genetic testing. This gap highlights the need to explore barriers to testing and to consider interventions to promote uptake; more aggressive efforts by hereditary cancer programs are needed to reach this highest risk population.

Genetic testing for hereditary cancer syndromes: patient recommendations for improved risk communication.

BACKGROUND: Multi-gene panel testing is replacing single-gene testing for patients with suspected hereditary cancer syndromes. The detection of a hereditary cancer syndrome allows tested individuals to initiate enhanced primary and secondary prevention efforts-where available-with a view to reduce disease burden. Current policy prevents testing programmes from communicating genetic test results with potentially affected family members, yet it is well documented that tested individuals face multiple challenges in initiating such discussions with relatives. OBJECTIVE: In response to this challenge, we sought patient recommendations about how to improve genetic risk communication to enhance interfamilial discussions about primary and secondary disease prevention. DESIGN: We conducted 25 semi-structured interviews with individuals who received genetic testing through British Columbia's Hereditary Cancer Program between 2017 and 2018. Interviews were professionally transcribed and analysed using a constant comparative approach. RESULTS: Participants described difficulty engaging in conversations with relatives who were resistant to receiving genetic risk information, when communicating with younger relatives and where participants reported strained familial relationships. Participants recommended that testing facilities provide a summary of results and implications and that resources be made available to prepare patients for challenging discussions with family members. DISCUSSION: Our study demonstrates that individuals undergoing genetic testing for suspected hereditary cancer syndromes would benefit from additional supportive resources alongside genetic counselling. Providing this on-going support will enhance the accurate and transparent communication of risk to facilitate the uptake of cascade testing and enhanced prevention strategies.

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

BACKGROUND: Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling. PATIENTS AND METHODS: All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population-based hereditary cancer program were eligible for multi-gene panel testing, irrespective of cancer family history. Any healthcare provider or patients themselves could refer. RESULTS: A total of 305 patients with PDAC were referred between July 2016 and January 2019. Two hundred thirty-five patients attended a consultation and 177 completed index germline genetic testing. 25/177 (14.1%) of unrelated patients had a pathogenic variant (PV); 19/25 PV were in known PDAC susceptibility genes with cancer screening or risk-reduction implications. PDAC was significantly associated with PV in ATM (OR, 7.73; 95% CI, 3.10 to 19.33, P = 6.14E-05) when comparing age and gender and ethnicity-matched controls tested on the same platform. The overall uptake rate for index testing was 59.2% and was significantly higher with 1-on-1 consultations and group consultations compared to telehealth consultations (88.9% vs 82.9% vs 61.8%, P < .001). CONCLUSION: In a prospective clinic-based cohort of patients with PDAC referred for testing irrespective of family history, germline PV were detected in 14.1%. PV in ATM accounted for half of all PVs and were significantly associated with PDAC. These findings support recent guidelines and will guide future service planning in this population.

Oncology Clinic-Based Hereditary Cancer Genetic Testing in a Population-Based Health Care System.

New streamlined models for genetic counseling and genetic testing have recently been developed in response to increasing demand for cancer genetic services. To improve access and decrease wait times, we implemented an oncology clinic-based genetic testing model for breast and ovarian cancer patients in a publicly funded population-based health care setting in British Columbia, Canada. This observational study evaluated the oncology clinic-based model as compared to a traditional one-on-one approach with a genetic counsellor using a multi-gene panel testing approach. The primary objectives were to evaluate wait times and patient reported outcome measures between the oncology clinic-based and traditional genetic counselling models. Secondary objectives were to describe oncologist and genetic counsellor acceptability and experience. Wait times from referral to return of genetic testing results were assessed for 400 patients with breast and/or ovarian cancer undergoing genetic testing for hereditary breast and ovarian cancer from June 2015 to August 2017. Patient wait times from referral to return of results were significantly shorter with the oncology clinic-based model as compared to the traditional model (403 vs. 191 days; p < 0.001). A subset of 148 patients (traditional n = 99; oncology clinic-based n = 49) completed study surveys to assess uncertainty, distress, and patient experience. Responses were similar between both models. Healthcare providers survey responses indicated they believed the oncology clinic-based model was acceptable and a positive experience. Oncology clinic-based genetic testing using a multi-gene panel approach and post-test counselling with a genetic counsellor significantly reduced wait times and is acceptable for patients and health care providers.

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.

Paraganglioma and pheochromocytoma upon maternal transmission of SDHD mutations.

BACKGROUND: The SDHD gene encodes a subunit of the mitochondrial tricarboxylic acid cycle enzyme and tumor suppressor, succinate dehydrogenase. Mutations in this gene show a remarkable pattern of parent-of-origin related tumorigenesis, with almost all SDHD-related cases of head and neck paragangliomas and pheochromocytomas attributable to paternally-transmitted mutations. METHODS: Here we explore the underlying molecular basis of three cases of paraganglioma or pheochromocytoma that came to our attention due to apparent maternal transmission of an SDHD mutation. We used DNA analysis of family members to establish the mode of inheritance of each mutation. Genetic and immunohistochemical studies of available tumors were then carried out to confirm SDHD-related tumorigenesis. RESULTS: We found convincing genetic and immunohistochemical evidence for the maternally-related occurrence of a case of pheochromocytoma, and suggestive evidence in a case of jugular paraganglioma. The third case appears to be a phenocopy, a sporadic paraganglioma in an SDHD mutation carrier with no immunohistochemical or DNA evidence to support a causal link between the mutation and the tumor. Microsatellite analysis in the tumor of patient 1 provided evidence for somatic recombination and loss of the paternal region of chromosome 11 including SDHD and the maternal chromosome including the centromere and the p arm. CONCLUSIONS: Transmission of SDHD mutations via the maternal line can, in rare cases, result in tumorigenesis. Despite this finding, the overwhelming majority of carriers of maternally-transmitted mutations will remain tumor-free throughout life.

Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer.

Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate-high risk for harboring a Lynch-associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy-two tested cases were included. Twenty-five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model-derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63-0.87), 0.86 (0.7-0.96), 0.89 (0.82-0.97), 0.89 (0.81-0.98) and 0.93 (0.86-0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations.