Hereditary Cancer Program Research Articles

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System

BackgroundGermline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil.MethodsA cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes.ResultsThe prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time.ConclusionOne in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

Abstract 3947: Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population

Abstract Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T>C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3947.

Variant curation and interpretation in hereditary cancer genes: An institutional experience in Latin America.

Variant curation refers to the application of evidence-based methods for the interpretation of genetic variants. Significant variability in this process among laboratories affects clinical practice. For admixed Hispanic/Latino populations, underrepresented in genomic databases, the interpretation of genetic variants for cancer risk is challenging. We retrospectively evaluated 601 sequence variants detected in patients participating in the largest Institutional Hereditary Cancer Program in Colombia. VarSome and PathoMAN were used for automated curation, and ACMG/AMP and Sherloc criteria were applied for manual curation. Regarding the automated curation, 11% of the variants (64/601) were reclassified, 59% (354/601) had no changes in its interpretation, and the other 30% (183/601) presented conflicting interpretations. With respect to manual curation, of the 183 variants with conflicting interpretations, 17% (N= 31) were reclassified, 66% (N= 120) had no changes in their initial interpretation, and 17% (N= 32) remained with conflicting interpretation status. Overall, 91% of the VUS were downgraded and 9% were upgraded. Most VUS were reclassified as benign/likely benign. Since false-positive and -negative results can be obtained with automated tools, manual curation should also be used as a complement. Our results contribute to improving cancer risk assessment and management for a broad range of hereditary cancer syndromes in Hispanic/Latino populations.

A152 ASSESSING THE USE OF A VALIDATED LYNCH SCREENING QUESTIONNAIRE IN THE OUTPATIENT SETTING AND SUBSEQUENT CHANGES IN PATIENT MANAGEMENT

Abstract Background Colorectal cancer (CRC) is the second most common cause of cancer related deaths in Canada. Approximately 1 in 13 males and 1 in 18 females will develop colorectal cancer in their lifetimes. As many as 10% of CRC may be associated with an inherited syndrome. Lynch Syndrome (LS) is the most common cause of inherited CRC, estimated to account for 3-4% of all CRC cases. . A study by Kastrinos et al. found that a simple, 3 item survey, identified 77% of individuals with known LS. Implementation of this questionnaire at a gastroenterology office may help identify patients at risk for LS. Purpose To assess whether implementation of a validated questionnaire to screen for LS is feasible in an outpatient gastroenterology clinic, and if these results would change patient management by gastroenterologists. Method Included in this study were all patients 18 years or older, who had been referred to one of the gastroenterologists at Pacific Gastroenterology Associates in Vancouver, British Columbia. Exclusion criteria included those patients less than 18 years of age, and patients previously seen by the HCP. Each subject was asked the following three questions: (1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50? (2) Have you had CRC or polyps diagnosed before age 50? (3) Do you have ≥3 relatives with CRC?. Answering yes to any question was considered a positive screen. Gastroenterologists were initially blinded to the content of the questionnaire and results. After completion of the questionnaire and formal gastroenterology consultation, the patients who screened positive for an increased risk of LS had their results unblinded to their primary gastroenterologist. Gastroenterologists were then asked if the survey results changed their management. Result(s) A total of 655 patients were screened, with 33 (5.0%) screening positive for question 1, 71 (10.8%) screening positive for question 2, and 17 (2.6%) screening positive for question 3. In total, 106 (15.9%) of individuals surveyed screened positive indicating higher risk for hereditary colorectal cancer. Subsequent reassessment by gastroenterologists of patients screening positive with the LS questionnaire (n=51) yielded no change to 47 patients (92%), screening with colonoscopy not originally planned for 1 patient (2%), re-consultation for further risk assessment for 2 patients (4%) and 1 referral to the Hereditary Cancer Program (2%). Conclusion(s) Utilization of a simple 3-question survey as part of regular patient intake in a gastroenterology office resulted in an increased number of individuals being identified as being high risk for Lynch syndrome, with a subsequent increase in endoscopic screening not otherwise planned, further assessment for colon cancer risk, and an increased referral to the Hereditary Cancer Program. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

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.

SDHB exon 1 deletion: A recurrent germline mutation in Colombian patients with pheochromocytomas and paragangliomas.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) (known as PPGL in combination) are rare neuroendocrine tumors of the adrenal medulla and extra-adrenal ganglia. About 40% of the patients with PPGL have a hereditary predisposition. Here we present a case-series of 19 unrelated Colombian patients with a clinical diagnosis of PPGL tumors that underwent germline genetic testing as part of the Hereditary Cancer Program developed at the Instituto Nacional de Cancerología, Colombia (INC-C), the largest reference cancer center in the country. Ten of 19 patients (52.63%) were identified as carriers of a pathogenic/likely pathogenic (P/LP) germline variant in a known susceptibility gene. The majority of the P/LP variants were in the SDHB gene (9/10): one corresponded to a nonsense variant c.268C>T (p.Arg90*) and eight cases were found to be carriers of a recurrent CNV consisting of a large deletion of one copy of exon 1, explaining 42% (8/19) of all the affected cases. Only one additional case was found to be a carrier of a missense mutation in the VHL gene: c.355T>C (p.Phe119Leu). Our study highlights the major role of SDHB in Colombian patients with a clinical diagnosis of PGL/PCC tumors and supports the recommendation of including the analysis of large deletions/duplications of the SDHB gene as part of the genetic counselling to improve the detection rate of hereditary cases and their clinical care.

Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5–95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1–41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

Genetic testing outcome disparities in minority racial and ethnic sub-populations within a hereditary breast and ovarian cancer program serving a diverse, urban-based population (191)

Genetic testing outcome disparities in minority racial and ethnic sub-populations within a hereditary breast and ovarian cancer program serving a diverse, urban-based population (191)

Programmatic Efforts Increase Adoption of Genomic Precision Medicine in Cancer Care in a Community Cancer Center.

PURPOSEThe adoption of precision medicine (PMed) depends on the critical curation of data and interpretation of genomic results. Herein, we sought to study the effect of a coordinated multidisciplinary program to assess results in a community cancer center clinic.METHODSIn a retrospective review from July 2018 to July 2021, we analyzed the implementation of a multidisciplinary PMed program in a tertiary referral community cancer center. Germline genetics test results have been reviewed since 2017.RESULTSA total of 3,131 tumor samples were analyzed by large panel somatic genomic testing through commercial laboratories during the study period. The number of reviewed cases rose from 661 in the first year to 1,532 in year 3. Additional recommendations beyond what was reported by the commercial laboratory were made in 42.9% of cases. Referrals to the hereditary cancer program for germline testing increased by 32% from the 2017 baseline. Process improvement efforts reduced the rate of DNA quantity nonsufficient for testing to 3.3% compared with a national average of 4.89%. The average time from receipt of orders to issuing of a report of the somatic panel was 15.5 days, compared with 19.1 days for other institutions using the same laboratory. The PMed team has been critical in support of clinical research by assisting in trial procurement and feasibility assessment to the identification of patients for clinical trials.ConclusionThe use of somatic genomic testing is increasing at our cancer center. Education and in-depth analysis of the data are valued by cancer physicians. The development and implementation of a PMed program has demonstrated improved physicians' understanding of molecular testing, resulting in improved outcomes for patients.

Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification

ObjectivesWe measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. MethodsCenters from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. ResultsA total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14–100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0–55% and 64–100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). ConclusionMolecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Abstract P3-19-06: Radiation toxicity in ATM mutation carriers with breast cancer

Abstract Background Heterozygous carriers with pathogenic germline variants in the ataxia-telangiectasia (ATM) gene are associated with increased cancer risk. While some reports suggest increased toxicity from radiation therapy (RT) among heterozygous ATM mutation carriers, the literature is conflicting. We performed a retrospective study of ATM mutation carriers with breast cancer to identify clinical factors that may impact risk of RT toxicity. Methods A retrospective chart review was conducted using the provincial British Columbia Hereditary Cancer Program electronic database to identify all breast cancer pts with heterozygous germline ATM mutations referred between January 1, 2000 to January 1, 2020. Germline genetic testing was expanded to routinely include ATM in 2019 for pts meeting testing criteria, and a subset of ATM-positive pts prior to 2019 were identified through updated testing. Pt data collected included age at diagnosis, pathologic features including grade, biomarker status, histologic subtype, stage, and treatment details. RT-related toxicity data were collected from the date of last RT treatment to date of last follow-up were classified retrospectively based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Toxicity was defined as acute if ≤6 months and chronic if &amp;gt;6 months after last RT treatment. Any toxicity grade ≥ 2 was considered clinically relevant. Results In total, 48 pts with pathogenic ATM germline mutations with a personal history of breast cancer were identified. Of these, 28 received RT to breast/chest wall and/or locoregional nodes between 1992-2020 and had evaluable records; 7 pts received RT of other anatomic sites, 13 pts did not receive any RT. Of the 28 ATM-positive pts who received locoregional RT, 19 (67.9%) had pathogenic and 9 (32.1%) had likely pathogenic ATM variants. The median time from last RT to last follow-up date was 91 months (range 4-257 months). The median time to first-reported acute and delayed toxicities grade ≥ 2 were 8 days and 18 months, respectively. Acute grade ≥ 2 toxicity was observed in 6/14 (43%) pts receiving conventional breast RT (≤2Gy/fraction) as compared to 5/14 (36%) pts who received hypofractionated breast RT (&amp;gt;2Gy/fraction). Four out of 28 pts (14%) who received locoregional breast RT developed recurrent disease (2 locoregional, 2 distant relapses). Among 20 ATM carriers who did not receive locoregional RT (n=7) or no RT (n=13), only 1 pt (5%) developed distant relapse. Of note, 5/13 (38%) pts who did not have adjuvant RT opted for completion mastectomies to avoid RT based on ATM status. Conclusions The overall frequency of RT grade ≥ 2 acute and/or chronic toxicity in ATM mutation carriers was 39% (11/28) and 18% (5/28), respectively. We did not identify a high frequency of severe (grade 3 or higher) acute or chronic RT toxicities among heterozygous carriers undergoing RT for breast cancer . The majority of acute and chronic toxicities were grade 2, and there were no reports of severe (grade 4 or 5) acute or chronic toxicities among pts receiving locoregional and/or non-locoregional RT. ATM-positive pts who received hypo-fractionated breast RT experienced fewer acute and chronic RT toxicities compared to those who received conventional breast RT, although the numbers were limited. In this retrospective study, there was no clear evidence of excessive severe toxicity among heterozygous ATM mutation carriers with breast cancer undergoing radiotherapy. Ongoing discussions are warranted between clinicians and ATM-positive pts to guide local treatment decision-making. Citation Format: Brandon Lee, Elisa Chan, Phoebe T.M. Cheng, Scott Tyldesley, Kasmintan A. Schrader, Sophie Sun. Radiation toxicity in ATM mutation carriers with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-06.

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 4weeks 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 (4weeks 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 80min as compared to 42min 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.

Current Testing Guidelines: A Retrospective Analysis of a Community-Based Hereditary Cancer Program.

It is estimated that 5% to 10% of all cancers are related to a hereditary cancer syndrome. However, specific cancers, such as pancreatic and ovarian cancers, are related to hereditary cancer syndromes 15% to 20% of the time. Genetic testing guidelines for hereditary cancer syndromes are frequently reviewed and updated by the National Comprehensive Cancer Network (NCCN). The purpose of this retrospective analysis is to identify carriers of pathogenic variants or hereditary cancer syndrome who do not meet NCCN criteria for testing and compare the results with previous studies. The data obtained can be used to provide recommendations to assess current guidelines for testing and evaluate the benefit of comprehensive panel testing vs. standard testing for specific hereditary cancer syndromes. This project is a retrospective review of clinical histories of patients who had multigene panel testing between September 2015 and February 2019 through a cancer outreach and risk assessment (CORA) program. Frequencies analyses were performed to analyze results. A total of 233 individuals were included in the analysis: 171 met BRCA1/2 testing criteria, 66 met Lynch syndrome criteria, and 4 met polyposis criteria. Of the individuals meeting established criteria for testing, 39 were identified with pathogenic variants. However, only 10 of these individuals were identified with a pathogenic variant associated with the criteria for which they met. Genetic testing that is limited to only those patients with genes associated with hereditary cancer syndromes may lead to exclusion of other potentially actionable genes, which may impair a patient's ability to receive additional screening or preventative measures.

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 49years 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.

Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition

Next-generation sequencing assays are capable of identifying cancer patients eligible for targeted therapies and can also detect germline variants associated with increased cancer susceptibility. However, these capabilities have yet to be routinely harmonized in a single assay because of challenges with accurately identifying germline variants from tumor-only data. We have developed the Oncology and Hereditary Cancer Program targeted capture panel, which uses tumor tissue to simultaneously screen for both clinically actionable solid tumor variants and germline variants across 45 genes. Validation using 14 tumor specimens, composed of patient samples and cell lines analyzed in triplicate, demonstrated high coverage with sensitive and specific identification of single-nucleotide variants and small insertions and deletions. Average coverage across all targets remained >2000× in 198 additional patient tumor samples. Analysis of 55 formalin-fixed, paraffin-embedded tumor samples for the detection of known germline variants within a subset of cancer-predisposition genes, including one multiexon deletion, yielded a 100% detection rate, demonstrating that germline variants can be reliably detected in tumor samples using a single panel. Combining targetable somatic and actionable germline variants into a single tumor tissue assayrepresents a streamlined approach that can inform treatment for patients with advanced cancers as well as identify those with potential germline variants who are eligible for confirmatory testing, but would not otherwise have been identified.

Prophylactic Surgery in the BRCA+ Patient: Do Women Develop Breast Cancer While Waiting?

Breast cancer susceptibility gene (BRCA) mutation carriers have an increased risk of breast cancer. Mitigation of this risk can be achieved via surveillance or prophylactic mastectomy with or without breast reconstruction. Those that choose surgery expect to reduce their chance of developing cancer. The purpose of this study was to determine the incidence of patients developing breast cancer prior to surgery and to identify modifiable contributing factors within the patient journey. This is a historical cohort study of all BRCA mutation carriers identified through the British Columbia Cancer Hereditary Cancer Program between 2000 and 2012. Patients were divided into two groups: surveillance (S) and prophylactic mastectomy with immediate breast reconstruction (PM/IBR). The incidence of cancer, time to PM/IBR and patient journeys were analyzed. A total of 333 women were identified. The time to surgery from mutation disclosure was a median of 31 (5.3, 75.7) months. During this period, 6% of patients developed breast cancer compared with a 14% incidence of breast cancer in patients choosing surveillance. The majority of time to surgery was attributed to the period between mutation disclosure and the decision to proceed with surgery. Strategies to facilitate decision-making as well as wait list prioritization and dedicated operative time should be targeted to this population to decrease the number of women developing an interval cancer prior to surgery.

Increased ease of access to genetic counseling for low-income women with breast cancer using a point of care screening tool.

Increased access to genetic counseling services is of prime importance in minority and underserved populations where genetic testing is currently underutilized. Our study tested a point of care screening tool to identify high-risk low-income patients for genetic counseling in a busy county hospital oncology clinic. Eligible breast patients treated at a "safety-net" hospital, were scored into 'high-risk' (> or = 6) or 'low-risk' (< 6) groups using a screening tool on personal and family history of cancer. Genetic counseling and testing were provided at the Vanderbilt Hereditary Cancer Program (VHCP) to all 'high-risk' and some 'low-risk' participants considered to need genetic counseling by their oncologist. Ninety-nine women with a history of breast cancer were enrolled onto the study over a period of 26months. 53.5% (53/99) had a 'high-risk' score and ethnic predominance of African-American (60.4%). Of these, 67.9% (36/53) were counseled, and 91.6% (33/36) tested with a 9% (3/33) mutation positive rate. In the 'low-risk' group, 28.2% (13/46) still met current NCCN guidelines and were referred by their oncologist. 69.2% (9/13) were counseled and tested. The 'low-risk' group of predominantly Caucasian (41.3%) participants carried a 20% (2/10) mutation positive rate; which was later adjusted to 10% to exclude a mutation not conferring a strong breast cancer risk. The screening tool was well accepted by patients; and increased access to genetic counseling. There was a subset of breast cancer affected women under 45 with no reported family history that failed to be identified. Minor alterations to the tool would enhance concordance with current NCCN guidelines.

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

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. 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. 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. 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.

Abstract 1211: Recurrent germline mutations in RAD51D and PALB2 are present in Colombian hereditary breast and ovarian cancer families

Abstract Hereditary breast cancer (BC) syndromes corresponds to 10% - 15% of all cases diagnosed worldwide. Most of these cases are due to deleterious germline genetic variants in BRCA1/2 genes; nevertheless, multipanel testing have contribute to the identification of other risk genes, including other homologous recombination (HR) repair genes, such as PALB2, ATM, CHEK2 and RAD51D. Here we explore the mutation spectrum of Hereditary Breast and Ovarian Cancer (HBOC) Colombian cases as part of the Hereditary Cancer Program from the National Cancer Institute from Colombia, the largest reference cancer center in the country, that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 358 patients fulfilling criteria for HBOC have been so far analyzed with Next Generation Sequencing using a multigene panel. Overall, 47% have negative results and in the 33% we identified VUSs. In general, 20% have a pathogenic or potentially pathogenic genetic variant; from those, BRCA1 (n = 17) and BRCA2 (n = 17) were the most frequently mutated genes (47.2% among all positive results). Deleterious mutations in RAD51D and PALB2 (also important HR repair genes) were found in 7% and 5.6% of the cases tested. Interestingly, genotype:phenotype correlations were found for these genes, as breast cancer molecular subtypes were distributed differently depending on the gene affected. In concordance with other reports, triple negative breast cancers (TNBC) were more frequent in BRCA1 (9/17, 53%) and PALB2 (4/4, 100%) carriers, and luminal subtypes were more frequent in BRCA2 carriers (10/17, 59%). Mutations in RAD51D: c.94_95del (p.Val32Phefs*67) and PALB2: c.2288_2291del (p.Leu763Ter), were both recurrent mutations in our Colombian cases. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry. Citation Format: Maria Carolina Sanabria-Salas, Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Luis G. Carvajal-Carmona, Martha Lucía Serrano-López. Recurrent germline mutations in RAD51D and PALB2 are present in Colombian hereditary breast and ovarian cancer families [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1211.

Abstract 2356: Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes

Abstract Hereditary colorectal cancer (CRC) syndromes accounts for approximately 5-10% of total CRC cases. Among those, Lynch syndrome (LS) is the most frequent, but the penetrance depends on the mismatch repair gene (MMR) affected. On the other hand, the Familial Adenomatous Polyposis (FAP) syndrome is less frequent, but with penetrance near to 100%. In Colombia we don't know the prevalence of these syndromes. In the National Cancer Institute from Colombia, the largest reference cancer center in the country, we aim to performed germline genetic analyses in Colombian CRC patients with a suspected hereditary cancer syndrome, as part of the Hereditary Cancer Program that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 66 patients with CRC fulfilling criteria have been so far analyzed with Next Generation Sequencing using a multigene panel. From those, the 32% have negative results, 41% have VUSs and 27% have positive results (meaning a pathogenic or potentially pathogenic genetic variant). The most prevalent CRC syndrome is Lynch (11/18, 61% with MMR mutated genes), followed by polyposis syndromes such as FAP (11% APC) and MAP (1.5% biallelic MUTYH). Most of our Lynch syndrome families fulfilled Bethesda or Amsterdam criteria. Two recurrent mutations in MLH1 were found in Lynch syndrome families (6/11, 54.5%), which are MLH1: c.1918C&amp;gt;T (p.Pro640Ser) and MLH1: c.790+1G&amp;gt;A. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry. Citation Format: Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Martha Lucía Serrano-López, Luis G. Carvajal-Carmona, María Carolina Sanabria-Salas. Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2356.