Genetic Cancer Risk Assessment Research Articles

Assessment of medical knowledge toward genetic testing for individuals with hereditary breast and ovarian cancer syndrome in Brazil

Genetic testing has become increasingly used in medical practice to enable genetic cancer risk assessment. In Hereditary Breast and Ovarian Cancer syndrome (HBOC), it can be used to screen pathogenic germline variants. The access to early diagnosis, from the request until the proper interpretation of genetic tests depends on medical knowledge. The aim of this study was to evaluate the knowledge of family physicians, oncologists, geneticists and gynecologists regarding genetic testing for patients with suspected HBOC in Brazil. A cross-sectional survey of physicians was performed using a self-administered questionnaire. One hundred and ninety-two physicians answered the questionnaire (23 were geneticists, 38 gynecologists, 39 family physicians, and 92 oncologists). Only 15.4% of family physicians and 26% of gynecologists feel prepared to order genetic testing for patients with personal and/or family history of breast and/or ovarian cancer. Even though 87% of the oncologists have genetic testing available in their clinical practice, only 51.1% consider they have sufficient knowledge to manage patients after detecting a pathogenic germline variant and 17.4% do not feel comfortable interpreting them. Most oncologists and geneticists are very knowledgeable about recommendations for genetic testing order and management of HBOC patients. On the other hand, gynecologists and family physicians order genetic testing less frequently (28.9% and 7.7%, respectively) and have difficulties interpreting (26.3% and 2.3%, respectively) and managing these patients. These observations raise important issues regarding the implementation of genetic testing in Brazil, including the development of training programs for physicians from different specialties.

Connecting Black families in Houston, Texas, to hereditary cancer genetic counseling, genetic testing, and cascade testing by using a simple cancer genetic risk assessment and telegenetics.

TPS10638 Background: Hereditary breast and colorectal cancers accounts for 5-10% of all cases, but less than half of all eligible patients undergo NCCN guideline-concordant screening. This proportion is even lower among Black patients, who have a higher breast cancer and colorectal incidence and mortality. Recruitment through community organizations has been shown to identify patients who are eligible for genetic testing but have not been offered it by their doctor. Our one-page cancer genetic risk assessment (CGRA) and telegenetics were previously shown to improve adherence to genetic testing guidelines for hereditary breast and ovarian cancer. Our objective is to identify adults eligible for hereditary breast and colorectal cancer syndromes genetic testing using trusted community organizations that serve the Black community as entry points, reach them with our tailored program, and measure impact. Methods: In this prospective single-arm trial, adults of > 18 years old who self-identify as Black or African American are recruited during events put together by community organizations in Houston, Texas. The CGRA was modified to encompass hereditary breast and colorectal cancer syndromes based on NCCN guidelines. To improve convenience, eligible participants can be consented and fill out the CGRA in-person or via QR code link using a smart phone. Study team members attend community events and are also available via phone to help with informed consent, CGRA, etc. Those at high risk for hereditary breast and colorectal cancer syndromes are provided with educational materials and can be sent the saliva-based kit or complete it on-site. When results of genetic testing include a pathogenic mutation (PV) or variant of uncertain significance, individuals receive telegenetic counseling and risk reduction resources, including about cascade genetic testing. Others are notified of negative results. The program includes education for interested community organization members about importance of genetic testing. The program is projected to reach 1,000 participants with 300 completing genetic testing and identification of 11 PV. The study is overseen by a Community Advisory Board. Impact will be evaluated via a multiple methods design using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) Qualitative Evaluation for Systematic Translation (QuEST) framework six months after program start. Quantitative data will be analyzed using descriptive statistics and standard tests of association. Data collected via semi-structured interviews with participants and program implementers will be audio-recorded, transcribed, double-coded, and analyzed via thematic analysis. Enrollment started December of 2022. 15 participants patients enrolled during two community events. Clinical trial information: NCT05694559 .

Spectrum of germline pathogenic variants among patients with cancer in Mexico.

10620 Background: Up to 10% of patients with cancer harbor pathogenic germline variants (PVs) in one or more cancer susceptibility genes. Genetic cancer risk assessment (GCRA) is an important tool for the management of patients with cancer. It allows the identification of candidates for structured screening protocols, risk reduction strategies, targeted therapies and cascade testing. Knowledge about the prevalence and spectrum of PVs is limited among underrepresented populations. We studied the prevalence of germline PVs in a cohort of Mexican patients with cancer. Methods: Between April 2017 and September 2022, patients with diagnosis of cancer who met clinical criteria for GCRA according to international guidelines (NCCN) and were enrolled in the international Clinical Cancer Genomics Community Research Network (CCGCRN) registry at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran were included. Cancer risk counseling and germline multi-gene panel testing were performed. Post-test counseling and cascade testing with known PV analysis was offered. Results: 1322 patients met inclusion criteria (probands n = 1027, relatives n = 295). Among the probands, 72.4% (744/1027) were women, median age at cancer diagnosis was 48.2 years (range 1-88) and 9.8% (n = 101) had more than one primary tumor. 14.5% (149/1027) of probands had a positive result in which 152 PV were identified ( BRCA1 n = 39, BRCA2 n = 33, ATM n = 11, CHEK2 n = 11, MLH1 n = 11, TP53 n = 7, PALB2 n = 7, NF1 n = 6, MSH2 n = 5, MSH6 n = 3, PTEN n = 3, APC n = 2, BRIP1 n = 2, CDH1 n = 2, RB1 n = 2 and 1 PV in the genes: CDKN2A, MAX, MUTYH, NBN, PTCH1, RAD50, SDHA and SDHB). The frequency of PV according to cancer diagnosis was: breast 15.5% (82/527), prostate 2% (4/198), ovarian 15.6% (12/77), colorectal 26.6% (16/60) and pancreatic 11.9% (5/42). The frequency of recurrent, potentially founder PVs in their respective genes was as follows: BRCA1 del(exons9-12) 30.7% (12/39) and CHEK2 c.707T > C 81.8% (9/11). Among the relatives referred for cascade testing the frequency of PV was 40% (118/295), 18.6% (55/295) had personal history of cancer with a median age at diagnosis of 47 years. Conclusions: Our results show a wide spectrum and a variable frequency of PVs among one of the largest examined cohorts of Mexican patients with cancer, with a high frequency of PVs among cases of breast, ovarian, and colorectal cancer. In contrast to reports from other populations, there was very low frequency of PVs among patients with prostate cancer. The outcomes of this study add to our understanding of the genetic epidemiology of cancer in the Mexican population, and support creating GCRA programs to improve access to multi-gene panel testing among underrepresented patients in limited resource settings.

Digital cancer genetic risk assessment in a gynecologic oncology clinic.

10612 Background: Population-based screening for hereditary cancer syndromes and referral of those who screen positive for genetic testing is a cost effective, evidence-based national health priority. However, under-recognition of hereditary cancer syndromes remains a critical concern, with fewer than 20% of individuals with Hereditary Breast and Ovarian Cancer Syndrome and Lynch Syndrome identified. Here, we evaluate the Ambry Genetics Comprehensive, Assessment, Risk, and Education (CARE) Program, a risk-stratification tool to assess eligibility for National Comprehensive Cancer Network (NCCN) genetic testing criteria and lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm. Methods: Between November 2022 and February 2023, new patients in a gynecologic oncology clinic were prompted by text message to complete CARE prior to their appointment. Those using CARE then completed a System Usability Scale (SUS), a validated 10-item questionnaire for the assessment of perceived usability. Results: Sixty patients presented for a new patient gynecologic oncology appointment and were prompted to complete CARE. The median patient age was 55 years (interquartile range, 40-68). The patients self-identified as Non-Hispanic White (44, 73%), Non-Hispanic Black (5, 8%), Asian (5, 8%), Hispanic (3, 5%), other (2, 3%), and unknown (1, 2%). All identified as female. Forty-three patients (72%) completed CARE. Among CARE users, 11 (26%) were identified as meeting criteria for genetic testing; of these, 9 (82%) proceeded with point-of-care same day genetic testing. Nine (21%) patients were eligible for enhanced breast cancer screening based on an estimated lifetime breast cancer risk of 20% or greater; of these, 100% were referred for high-risk breast screening. There were no patient demographics associated with completion of CARE. Forty-one patients (72%) completed the SUS survey; the median SUS score was 80 (interquartile range, 60-92.5), which corresponded to 85-89th percentile and a letter grade of A-. Conclusions: Implementation of a digital tool for cancer genetic risk assessment identified a quarter of patients to be eligible for genetic testing, among whom 82% completed same-day genetic testing. Additionally, the tool was reviewed favorably by patient users. Large randomized controlled trials of health information technology tools are needed to move closer to the goal of population-based hereditary cancer risk assessment.

A randomized controlled trial evaluating pretest cancer genetics educational video or in-person genetic counseling.

10597 Background: Cancer genetic testing indications are rapidly expanding to determine treatment eligibility for patients with cancer, to identify individual cancer risk as well as to select family members at higher cancer risk when a pathogenic variant (PV) has been identified in the family. Currently, international guidelines recommend that all candidates for genetic testing should have genetic counseling to make an informed decision for genetic testing. However, with the increased demand for genetic testing, innovative ways to deliver pretest information are needed, especially in limited resource settings, where genetic cancer professionals’ availability is scarce. Methods: This is a non-inferiority trial comparing a pretest educational video to in-person genetic counseling. Participants referred for genetic cancer risk assessment at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán in Mexico City were enrolled if they met international cancer genetic testing criteria and did not previously have genetic testing and/or counseling. The primary outcome was the uptake of genetic testing. Secondary outcomes included changes in genetic cancer knowledge, anxiety, and satisfaction using validated tools. Results: A total of 250 participants were included: 124 were randomized to the in-person genetic counseling arm and 126 to the educational video arm. Mean age was 47.9 years (SD 12.7), 86.4% were women, 37.2% had high-school or less and 86.4% had personal history of cancer (70% breast cancer). Overall, test acceptance was 100% in both arms. Cancer genetics knowledge improved in both groups: in-person from. 53 to .74 (diff .20; 95%CI .24-.26; p < 0.05) and video from .51 to .68 (diff .16; 95%CI .20-.12; p < 0.05). However, the in-person arm had a higher post counseling knowledge score (p 0.001). 43.5% and 42% of participants in the in-person and video arms had moderate-severe baseline anxiety. After intervention, both groups had a decrease in anxiety score: in-person from 5.2 to 4.7 (diff .58; 95% CI .09-1.08; p 0.01) and video from 4.9 to 4.1 (diff .75; 95%CI 0.42-1.08; p < 0.05). Both groups were satisfied with genetic services (97.5% and 92.5%, respectively; p 0.34). Conclusions: A pretest educational video was non-inferior regarding genetic testing acceptance. It was also associated with improved genetic cancer knowledge and decreased anxiety levels. These results support the use of educational videos before genetic testing where in-person genetic counseling availability is limited. Clinical trial information: pending .

Evaluating cancer genetic services in a safety net system: overcoming barriers for a lasting impact beyond the CHARM research project

Underserved patients face substantial barriers to receiving cancer genetic services. The Cancer Health Assessments Reaching Many (CHARM) study evaluated ways to increase access to genetic testing for individuals in underserved populations at risk for hereditary cancer syndromes (HCS). Here, we report the successful implementation of CHARM in a low-resource environment and the development of sustainable processes to continue genetic risk assessment in this setting. The research team involved key clinical personnel and patient advisors at Denver Health to provide input on study methods and materials. Through iterative and collaborative stakeholder engagement, the team identified barriers and developed solutions that would both facilitate participation in CHARM and be feasible to implement and sustain long term in clinical care. With a focus on infrastructure building, educational modules were developed to increase awareness among referring providers, and standard methods of identifying and managing HCS patients were implemented in the electronic medical record. Three hundred sixty-four DH patients successfully completed the risk assessment tool within the study, and we observed a sustained increase in referrals to genetics for HCS (from 179 in 2017 to 427 in 2021 post-intervention). Implementation of the CHARM study at a low-resourced safety net health system resulted in sustainable improvements in access to cancer genetic risk assessment and services that continue even after the study ended.Trial registration NCT03426878

Abstract P2-05-02: Potential Empowerment and risk of Genetic Counseling with Genetic Breast cancer risk assessment in Personalized Health Care: Prospective Cohort Study using Genetic Counseling Outcome Scale (GCOS-24)

Abstract [Introduction] Personalized health care is recommended for the prevention and early detection of breast cancer. Advances in technology have made it possible to estimate genetic risk, PGV (pathogenic/likely-pathogenic germline variant) or PRS (polygenic risk score), in practice. However, linkage after risk assessment to personalized health care is still developing. One of the issues is how to tell the result especially in case of newly diagnosed PGV after Genetic Panel Testing or PRS. In this study, we evaluated genetic counseling (GC) using an established patient-reported outcome measure for clinical genetics services scale (Genetic Counseling Outcome Scale24 (GCOS24)) at genetic counseling for disclosure the results of the previous study, and examined the association with management after GC. [Method] We performed targeted sequencing for 11 breast cancer-related genes using peripheral blood DNA from 1995 female breast cancer patients. Of 1995 cases, 101 patients were PGV carriers, who were candidates of this study. Participants were referred to the Clinical Genetics unit, Kyoto University Hospital from 10 institutions (January 2018-March 2022). GCOS24 and relating questionaries were asked before and after GC. GCOS24 is a scale consisting of 24 items that assess five factors: decision control, cognitive control, behavioral control, emotional regulation, and hope. (In light of the current status of hereditary breast cancer care in Japan, 23 items were used.) Each item is rated on a scale of 1-7 points, for a total score of 23-161. In addition, we reviewed medical records to evaluate the post-GC management. [Results] Of the 101 cases, 38 cases were enrolled. The reasons of 63 not-enrolled cases were: 30 cases without follow-up (deaths or transfer to another hospital), 11 cases already diagnosed in clinical practice, 18 cases that did not wish to know their results, and 4 cases whose hospital were developing for hereditary breast cancer care. Median age at the time of genetic GC was 55 (min-max 30-83) years. Details of PGV cases were: BRCA2 23 cases, BRCA1 2, PALB2 4, PTEN 3, TP53 3, ATM 1, CHEK2 1 and NF1 1. GCOS24 after GC were improved than before GC. (Average 99 (min-max 17-124) vs 114 (91-138), Mean difference 23.9, 95% Confidence intervals (CI) 29.6 to 18.3). Thirty patients (79%) had higher increase in scores than 10.3, which was the previously reported Minimum Clinically Important Difference (MCID) of this scale. In all items except 4 items (#6,11,13,21), GCOS24 after GC were significantly improved than before GC. In post-GC management, 8 patients received or planned RRSO (risk reducing salpingo-oophorectomy) among 25 BRCA1/2 cases. There was a case with dysplastic cells detected in the resected ovary. After GC, average of GCOS24 in RRSO cases was 120 (95% CI 110 to 129), while average of GCOS24 of other BRCA1/2 cases was 110 (95% CI 104 to 116). On the other hand, two patients stopped visiting to the hospital because of fear after GC. Average of GCOS24 of 15 junior-high/high school graduate cases were 111 (95% CI 105 to 117), while average of GCOS24 of 23 college graduate cases were 117 (95% CI 111 to 122). [Discussion] In patients diagnosed with hereditary breast cancer by genetic panel testing, GC worked well except for 4 items. These 4 items (#6,11,13,21) were related to emotion. This study revealed there was also a risk to reject surveillance due to fear, suggesting that it is necessary to provide psychological support in some cases. Although the limitation of this study is the small number of cases, GCOS24 were high in RRSO cases, suggesting that GC played an important role when proceeding with intervention. We believe that the findings are helpful for the future implementation of genetic panel testing or PRS testing in healthy subjects for personalized health care. Citation Format: Nobuko Kawaguchi-Sakita, Noriko Senda, Yukiko Inagaki-Kawata, Hiromi Murakami, Sayaka Honda, Takahiro Yamada, Yuki Kataoka, Shoko Takahara, Shigeru Tsuyuki, Kazuhiko Yamagami, Yoshio Moriguchi, Masae Torii, Tatsushi Kato, Hirofumi Suwa, Wakako Tsuji, Eiji Suzuki, Akira Yamauchi, Ryuji Okamura, Shinji Kosugi, Masakazu Toi. Potential Empowerment and risk of Genetic Counseling with Genetic Breast cancer risk assessment in Personalized Health Care: Prospective Cohort Study using Genetic Counseling Outcome Scale (GCOS-24) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-05-02.

Abstract P6-02-05: Prevalence of non-BRCA germline pathogenic variants in Mexican women with breast cancer referred for genetic cancer risk assessment

Abstract Background: The prevalence of germline pathogenic variants in Mexican women with breast cancer who met the reference criteria for genetic cancer risk assessment (GCRA) has been previously reported as close to 20%. However, information regarding the spectrum of gPVs in genes other than BRCA in this population is limited. Methods: This prospective study included Mexican women who were diagnosed with BC and met international criteria for GCRA. Participants were enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry and at two referral breast cancer centers in Mexico, the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City and at the Hospital Zambrano Hellion TecSalud, Monterrey. Participants underwent multigene panel testing (MGPT) for 37 cancer susceptibility genes. For this analysis, only the results of pathogenic and likely pathogenic variants in the index cases were reported. The demographic and molecular characteristics of the variants are described here. Results: From August 2017 to September 2021, 1020 Mexican women with BC underwent MGPT, with a median age at diagnosis of 41 y (range 20-86), of whom 206 (20.2%) were carriers. 208 gPVs were identified with BRCA1/2 representing 70% (145/208) of the gPVs (BRCA1 n=89, BRCA2 n=56). 63 (30%) of gPVs were identified in genes other than BRCA (CHEK2 n=21, PALB2 n=13, TP53 n=7, RAD51C n=5, ATM n=4, NF1 n=3, PTEN n=2, MUTYH homozygous n=2, RAD50 n=1, BRIP1 n=1, CDH1 n=1, NBN n=1, MSH2 n=1 and MSH6 n=1). The recurrent variants previously proposed as founders in the Hispanic population were frequent among those identified in their respective genes: CHEK2 c.707T>C 81% (17/21), PALB2 c.2167_2168delAT 46% (6/13) and BRCA1 del(exons 9-12) 18% (16/89). As a group, the 4 most frequent genes where gPVs were identified (BRCA1, BRCA2, CHEK2 and PALB2) represented 86% (179/208) of the positive results. Conclusion: Among the variants identified in this population of Mexican women with BC, the proportion of gPVs in genes other than BRCA was significant (about 1 out of 3 pts), which justifies the use of MGPT in the assessment of our population. However, a tailored panel (sequencing of BRCA1/BRCA2/CHEK2/PALB2 and MLPA for BRCA1) could be proposed in areas of Mexico with limited medical resources, including the analysis of other genes in selected patients according to clinical suspicion and family history of cancer. Citation Format: Yanin Chavarri-Guerra, Cynthia Villareal Garza, Jose Luis Rodriguez-Olivares, Dione Aguilar-y Mendez, Gregorio Quintero-Beulo, Francisco Gutierrez-Delgado, Josef Herzog, Stephen Gruber. Prevalence of non-BRCA germline pathogenic variants in Mexican women with breast cancer referred for genetic cancer risk assessment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-05.

Improving Uptake of Cancer Genetic Risk Assessment in a Remote Tailored Risk Communication and Navigation Intervention: Large Effect Size but Room to Grow.

Cancer genetic risk assessment (CGRA) is recommended for women with ovarian cancer or high-risk breast cancer, yet fewer than 30% receive recommended genetic services, with the lowest rates among underserved populations. We hypothesized that compared with usual care (UC) and mailed targeted print (TP) education, CGRA uptake would be highest among women receiving a phone-based tailored risk counseling and navigation intervention (TCN). In this three-arm randomized trial, women with ovarian or high-risk breast cancer were recruited from statewide cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TP received a mailed educational brochure. Participants assigned to TCN received the mailed educational brochure, an initial phone-based psychoeducational session with a health coach, a follow-up letter, and a follow-up navigation phone call. Participants' average age was 61 years, 25.4% identified as Hispanic, 5.9% identified as non-Hispanic Black, and 17.5% lived in rural areas. At 6 months, more women in TCN received CGRA (18.7%) than those in TP (3%; odds ratio, 7.4; 95% CI, 3.0 to 18.3; P < .0001) or UC (2.5%; odds ratio, 8.9; 95% CI, 3.4 to 23.5; P < .0001). There were no significant differences in CGRA uptake between TP and UC. Commonly cited barriers to genetic counseling were lack of provider referral (33.7%) and cost (26.5%), whereas anticipated difficulty coping with test results (14.0%) and cost (41.2%) were barriers for genetic testing. TCN increased CGRA uptake in a group of geographically and ethnically diverse high-risk breast and ovarian cancer survivors. Remote personalized interventions that incorporate evidence-based health communication and behavior change strategies may increase CGRA among women recruited from statewide cancer registries.

Implementing digital systems to facilitate genetic testing for hereditary cancer syndromes: An observational study of 4 clinical workflows

PurposeNational efforts have prioritized the identification of effective methods for increasing case ascertainment and delivery of evidence-based health care for individuals at elevated risk for hereditary cancers. MethodsThis study examined the uptake of genetic counseling and testing following the use of a digital cancer genetic risk assessment program implemented at 27 health care sites in 10 states using 1 of 4 clinical workflows: (1) traditional referral, (2) point-of-care scheduling, (3) point-of-care counseling/telegenetics, and (4) point-of-care testing. ResultsIn 2019, 102,542 patients were screened and 33,113 (32%) were identified as at high risk and meeting National Comprehensive Cancer Network genetic testing criteria for hereditary breast and ovarian cancer, Lynch syndrome, or both. Among those identified at high risk, 5147 (16%) proceeded with genetic testing. Genetic counseling uptake was 11% among the sites with workflows that included seeing a genetic counselor before testing, with 88% of patients proceeding with genetic testing after counseling. Uptake of genetic testing across sites varied significantly by clinical workflow (6% referral, 10% point-of-care scheduling, 14% point-of-care counseling/telegenetics, and 35% point-of-care testing, P < .0001). ConclusionStudy findings highlight the potential heterogeneity of effectiveness attributable to different care delivery approaches for implementing digital hereditary cancer risk screening programs.

Understanding cancer genetic risk assessment motivations in a remote tailored risk communication and navigation intervention randomized controlled trial

ABSTRACT Background National guidelines recommend cancer genetic risk assessment (CGRA) (i.e. genetic counseling prior to genetic testing) for women at increased risk for hereditary breast and ovarian cancer (HBOC). Less than one-half of eligible women obtain CGRA, leaving thousands of women and their family members without access to potentially life-saving cancer prevention interventions. Purpose The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE) addressed this translational gap, testing the efficacy of a tailored counseling and navigation (TCN) intervention vs. a targeted print brochure vs. usual care on CGRA intentions. Selected behavioral variables were theorized to mediate CGRA intentions. Methods Breast and ovarian cancer survivors meeting criteria for guideline-based CGRA were recruited from three state cancer registries (N = 654), completed a baseline survey, and were randomized. TCN and targeted print arms received the brochure; TCN also participated in a tailored, telephone-based decision coaching and navigation session grounded in the Extended Parallel Process Model and Ottawa Decision Support Framework. Participants completed a one-month assessment. Logistic regression was used to compare the rate of CGRA intentions. CGRA intentions and theorized mediator scores (continuous level variables) were calculated using mixed model analysis. Results CGRA intentions increased for TCN (53.2%) vs. targeted print (26.7%) (OR = 3.129; 95% CI: 2.028, 4.827, p < .0001) and TCN vs. usual care (23.1%) (OR = 3.778, CI: 2.422, 5.894, p < .0001). Perceived risk (p = 0.023) and self-efficacy (p = 0.035) mediated CGRA intentions in TCN. Conclusions Improvements in CGRA intentions and theorized mediators support the use of a tailored communication intervention among women at increased HBOC risk. (Clinicaltrials.gov: NCT03326713.) Trial registration: ClinicalTrials.gov identifier: NCT03326713.

Understanding Cancer Genetic Risk Assessment Intentions in a Tailored Risk Communication Intervention Randomized Controlled Trial

Background: Pathogenic variants in cancer predisposition genes increase second, hereditary cancer risk among women with breast and/or ovarian cancer, and primary cancers in their relatives. National guidelines recommend cancer genetic risk assessment (CGRA) (genetic counseling and/or genetic testing) for women at increased hereditary breast and ovarian cancer (HBOC) risk. Yet, less than half of high risk women, including rural dwellers and racial minorities have accessed CGRA. Purpose: The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE), a superiority trial, addressed this translational gap, testing the efficacy of a targeted print brochure (TP) vs tailored counseling and navigation (TCN) vs usual care (UC) on CGRA intentions. TCN targeted behavioral variables theorized to mediate CGRA intentions. We believe GRACE is the first study of its kind promoting guideline-based CGRA to women at increased HBOC risk. Methods: CGRA-eligible women were recruited from three state cancer registries (N=641), completed a baseline survey, and randomized to TCN, TP or UC. TP and TCN received the mailed educational brochure. TCN also engaged in a telephone-based decision coaching and navigation session using motivational interviewing and tailored materials based on the Extended Parallel Process Model and Health Action Process Approach. Participants completed a follow-up survey at one month. Results: TCN improved CGRA intentions compared to TP (0.64, p&amp;lt;0.001, CI 0.32, 0.97) and UC (0.69, p&amp;lt;0.001, CI 0.37, 1.02). Theoretical targets, perceived risk (0.77, p=0.02, CI 0.11, 1.44) and self-efficacy (0.67, p=0.04, CI 0.05, 1.28) mediated CGRA intentions in TCN. Stratification showed increases in CGRA intentions for TCN vs TP among non-Hispanic Whites, Hispanics, urban dwellers, and women with low health literacy and no family history of breast and/or ovarian cancer (FBOC). In TCN, perceived self-efficacy improved in women with no FBOC. Conclusions: Improvements in CGRA intentions and theorized mediators support use of tailored risk communication interventions in Hispanics and women with low health literacy and no FBOC. Further tailoring may improve CGRA intentions in Blacks, other minorities, rural dwellers, and women with high health literacy and FBOC.

TP53 pathogenic variants with low allele fraction in germline genetic testing.

10600 Background: Blood or saliva DNA generally considered to be representative of germline genome in genetic cancer risk assessment. However white blood cells from these samples may also include somatic origin DNA due to postzygotic variation or, most commonly, clonal hematopoiesis (CH). Low variant allele fraction (VAF) found in germline genetic testing suggest the possibility of somatic variant and may lead to misinterpretation of genetic risk. TP53, of which germline pathogenic variants are associated with Li-Fraumeni syndrome (LFS), is frequently mutated in CH. This analysis investigated characteristics of TP53 pathogenic variants with low VAF. Methods: We reviewed the prevalence and distribution of TP53 pathogenic variants(PVs) detected in 11,277 advanced cancer patients who underwent clinical testing with a clinical NGS pan-cancer panel. Potential somatic PVs were defined as variants with low VAF from 10% to 35%. The VAF were evaluated in matched tumor tissue samples if available. Results: TP53 pathogenic variants were detected in 36 (0.32%) patients from blood or saliva samples, VAF between 10% and 35% were identified in 8(22.22%) patients and 7 of them were performed NGS sequencing in matched tumor tissue samples. The average VAF of tissue samples were 9.31times lower than blood or saliva samples(21.69% vs 3.88%). Conclusions: TP53 pathogenic variants with low allele fraction in blood or saliva samples indicate the possibility of somatic variant, a reduced VAF in matched tumor tissue samples may contribute to confirmation for suspicion of somatic origin.

Retrospective analysis of non-BRCA gene pathogenicity variation in Chinese patients with ovarian cancer.

10584 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer. Pathogenic (harmful) variants（PV) in BRCA1 and BRCA2 are the strongest hereditary risk factors for the development of ovarian cancer. To date, there is little information regarding the frequency of non- BRCA gene PV in Chinese women with OC that undergo genetic cancer risk assessment. In this study we analyzed wild-type BRCA1/2 OC patients (pts) registered in our database. Methods: Peripheral blood of 766 women, diagnosed with ovarian cancer, were taken from the recruited cases with the consent of performing germline genetic testing. Germline mutations including SNV, small INDEL were analyzed by next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 766 OC pts, 460 pts (60%) underwent BRCA1/2 testing only, while 306 pts (40%) consented in multigene panel testing (MGPT). BRCA1/2 detection rate was 16.8% (129/766), while the detection rate for non- BRCA genes was 7.5% (23/306). There was a significant statistical difference in average age that the non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group (62 vs. 57, p=0.018). Wild-type B RCA1/2 OC pathogenic variants (PV), were diagnosed in BLM (n=4, 17.4%), ERCC5 (n=2, 8.7%), MUTYH (n=2, 8.7%), RAD51C (n=2, 8.7%), RAD51D (n=2, 8.7%), ATM (n=1, 4.4%), BRIP1 (n=1, 4.4%), CDH1 (n=1, 4.4%), CHEK2 (n=1, 4.4%), ERCC4 (n=1, 4.4%), LZTR1 (n=1, 4.4%), MSH3 (n=1, 4.4%), PALB2 (n=1, 4.4%), PMS2 (n=1, 4.4%), RAD50 (n=1, 4.4%) and SLX4 (n=1, 4.4%) genes. Of all the 23 non- BRAC gene pathogenicity variations, 57% (13/23) lay in the Homologous Recombination Repair (HRR) pathways. Moreover, a 48-year-old woman with ovarian cancer with two pathogenic variants of the [ BRCA2- MUTYH] genes was detected in the retrospective cohort study. Conclusions: BLM, ERCC5, MUTYH, RAD51C and RAD51D genes are the main contributors to hereditary wild-type BRCA1/2 OC in our cohort. The average age of non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group. Therefore, multi-gene PANEL detection is recommended for ovarian cancer patients, especially for older patients.

Cross-sectional clinical cancer genomics community of practice survey analysis of provider attitudes and beliefs regarding the use of deceased family member tissue to guide living family member genetic cancer risk assessment.

Next-generation tumor tissue sequencing techniques may result in the detection of putative germline pathogenic variants (PVs), raising the possibility that germline cancer predisposition could be identified from archival medical tissue samples of deceased relatives. The approach, termed traceback, is designed to inform risk management recommendations for living family members. Provider perspectives regarding traceback testing have not yet been explored, so we conducted a cross-sectional survey of Clinical Cancer Genomics Community of Practice providers regarding their attitudes and beliefs toward traceback testing. Self-reported demographics, provider characteristics, attitudes and perceived barriers were collected. We evaluated responses in the context of whether providers had previous experience with traceback testing. Data were analyzed using chi-square and Fisher's exact testing. Among 207 respondents (of 816 eligible), most were women (89.4%), white (85.5%), and not Hispanic or Latino (89.7%). US-based providers represented the majority of respondents (87.4%). Relatively, few providers 32 of 207 (15.5%) had previous experience with traceback. Among the individuals without experience in traceback, 84.0% thought there would be barriers to implementation; however, only 68.8% of individuals with previous traceback experience agreed (p=.04). Respondents in both groups thought that traceback would be valuable in their practice (82.6%, p=.22) and that they would feel comfortable discussing the concept (83.6%, p=.83), interpreting the results (72.2%, p=.24), and discussing the results with their patients (80.7%, p=.38). Patient interest and cost were seen as less of a barrier by those with experience with traceback testing. Recurrent themes obtained in open-ended responses are also presented. Overall, providers believe that traceback would be a valuable tool in their practice. Individuals with previous experience identified less barriers with implementation of this testing, highlighting an area for future research and education.

Abstract P2-09-11: Uptake of risk-reducing strategies and related challenges among carriers of breast cancer-associated germline pathogenic variants in Mexico

Abstract Background: Genetic cancer risk assessment is a multidisciplinary approach that enables the invaluable opportunity to recommend measures aimed at decreasing the risk of recurrence and new cancer diagnoses in individuals with inherited cancer predisposition. However, different challenges may limit the uptake of risk-reducing (RR) strategies among patients in underserved settings. This study describes the implementation of RR surgeries or surveillance studies and related barriers among carriers of breast cancer-associated germline pathogenic variants (PV). Methods: PV carriers were identified at two referral cancer centers in Mexico ≥6 months after receiving test results and genetic counseling. From October 2020 to June 2021, participants were invited to answer a multiple-choice survey assessing their uptake rate of RR measures according to NCCN guidelines by type of PV, as well as the challenges that had hindered this uptake. Descriptive statistics and Chi-squared or Fisher’s exact tests were used for data analysis. Results: In total, 162 carriers (median age: 42.5 years [range 21-73]) answered the survey. Most were women (89%), lived in an urban setting (91%), were married/in domestic partnership (72%), had at least high school education (69%), and were employed (51%). Monthly household income was lower than the minimum wage in 25% of cases and most patients had public (53%) or no (32%) healthcare coverage. Overall, 105 (65%) had a personal history of cancer, most commonly unilateral (77%) or bilateral (13%) breast cancer. PV were found in BRCA1/BRCA2 (75%), CHEK2 (11%), PALB2 (6%), ATM (4%), RAD51C (3%), and less frequently (3%) in TP53, NF1 or PTEN. Carriers underwent at least one of the recommended RR surgeries and surveillance studies in 61% and 69% of cases, respectively. Specifically, 52/124 (42%) of female BRCA1/BRCA2, PALB2, PTEN or TP53 PV carriers had undergone RR mastectomy, while 45/77 (58%) of eligible BRCA1/BRCA2 or RAD51C PV carriers had RR salpingo-oophorectomy. As for surveillance studies, carriers performed all, some and none of the recommended examinations according to their PV in 34%, 35% and 31% of cases, respectively. When an annual mammogram was recommended, 69/109 (63%) underwent the study in the previous year; in the case of breast MRI, only 23/103 (22%) had performed it in the last year. Notably, 132 (81%) carriers reported ≥1 challenge that hindered the uptake of RR strategies (median: 2 [range 0-10]). The main barriers were lack of insurance coverage of the recommended interventions (60%), financial limitations (50%), belief that their physician had not requested the studies or procedures (36%), and fear (25%). Uptake of RR strategies was not associated with carriers’ age, education level, employment status, income, place of residence, or type of mutation (high-risk vs moderate- or low-risk PV). Significant associations are reported in the Table. Conclusion: An important proportion of PV carriers in this resource-constrained setting underwent all or some of the recommended RR strategies, with the most cited uptake challenges being financial barriers and lack of endorsement by their physician. Targeted interventions to reduce out-of-pocket expenses and improve patient-physician communication and patients’ understanding of the implications of carrying a genetic mutation are warranted to enhance the uptake of RR surgeries and surveillance strategies among PV carriers. Variables associated with the uptake of RR strategiesVariableUnderwent ≥1 RR surgeryDid not undergo any RR surgeryp-valueVariableUnderwent all or some surveillance studiesDid not undergo any surveillance studiesp-valueMarital status.012Gender&amp;lt;.001Married/Domestic partnership6532Female10133Single/Divorced/Widowed1419Male313Personal cancer history&amp;lt;.001Personal cancer history.002Yes6923Yes7521No1028No2925Attendance to follow-up appointments&amp;lt;.001Attendance to follow-up appointments&amp;lt;.001Yes6225Yes7916No1726No2530Knowledge that a genetic mutation conveys a greater risk of new cancer diagnoses.001Knowledge that a genetic mutation conveys a greater risk of cancer recurrence.012Yes7336Yes7423No615No3023Knowledge of carrier status.044Yes9436No1010Recent cancer diagnosis in a relative.017Yes2922No7524 Citation Format: Cynthia Villarreal-Garza, Fernanda Mesa-Chavez, Yanin Chavarri-Guerra, Dione Aguilar y Mendez, Andrea Becerril-Gaitan, Bryan F Vaca-Cartagena, Salvador G Santiesteban, Alejandro Aranda-Gutierrez, Daniela Obregon-Leal, Melina Miaja-Avila, Maria F Ochoa Chavez, Andres Rodriguez-Faure, Hermes J Franco Jimenez, Jeffrey N Weitzel. Uptake of risk-reducing strategies and related challenges among carriers of breast cancer-associated germline pathogenic variants in Mexico [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 P2-09-11.

Pathogenic variants among Mexican patients with colorectal cancer referred for genetic cancer risk assessment.

69 Background: Lynch syndrome (LS) is the most frequent hereditary cancer syndrome among patients with colorectal cancer. Screening tests such as immunohistochemistry (IHC) for mismatch repair (MMR) proteins and PREMM5 model help to identify patients at risk of germline pathogenic variants (PVs). However, there has been a disparity in that evaluation of these screening tools and their correlation with pathogenic variants (PVs) has been limited in Hispanic populations. Methods: Patients with colorectal cancer referred for genetic cancer risk assessment were enrolled in the Clinical Cancer Genomics Community Research Network (CCGCRN) registry from October 2017 to February 2021 at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Genetic testing was performed by full sequencing of the MMR genes ( MLH1, PMS2, MSH2, MSH6 and EPCAM) and other cancer-associated genes ( APC, BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, BRIP1) and multiplex ligation dependent probe amplification to detect copy number variants (CNV) was performed for selected genes. Demographic, clinical characteristics and IHC results were obtained from clinical records. MMR PV probability was calculated using PREMM5. Results: Sixty-nine patients with colorectal cancer were included; mean age at diagnosis was 50 (26-82) years and 39/69 (56%) were women. A MMR gene PV was identified in 23/69 patients (33%); most frequently in MLH1 n = 14, followed by MSH2 n = 2, MSH6 n = 2 and PMS2 n = 1. Four recurrent PVs in MLH1 and MSH2 represented 22% of PVs. CNVs were identified in 4/23 (17.4%) patients with LS. PVs in other genes were identified in 8.6% of the cases: 2 ATM, 1 APC, 1 PALB2, 1 BRIP1 and 1 BRCA1. IHC results were available in 52/69 cases (75.4%) and MMR protein deficiency was found in 16/17 (94%) carriers and in 14/31 (45%) non-carriers (sensitivity 94.1% and specificity 54.8%). The area under the ROC curve for PREMM5 score was 0.94 (95% CI 0.88-0.99) with a mean score 31.6 (2.4-50) in patients with LS and 4.1 (0.9-50) in non-carriers. The diagnosis of a second primary colon cancer was more frequent among LS (30% vs 2.5%; p &lt; 0.01). Conclusions: We found a high frequency of MMR gene PVs among patients referred for GCRA with personal history of colon cancer, and only a small proportion with PVs in other genes. Our results showed a good performance of PREMM5 model and a high sensitivity of MMR IHQ in a Mexican population, indicating that these are tools that can be used to prioritize patient selection for germline testing.

A Multidisciplinary Precision Medicine Service in Primary Care.

A need for accessible genomic services is growing with the rise of commercial genetic testing. Because of this, primary care clinicians may increasingly encounter genetic cancer risk assessment, pharmacogenomics, and direct-to-consumer genetic testing in routine clinical care. Such a rapid increase

Renin-Angiotensin System Single Nucleotide Polymorphisms Are Associated with Bladder Cancer Risk.

The renin-angiotensin system (RAS), besides being a major regulator of blood pressure, is also involved in tumor angiogenesis. Emerging evidence suggests a correlation between the use of pharmacologic RAS inhibitors and a delay in urothelial bladder cancer (BC) progression. However, it is unknown whether RAS gene variants may predispose to the development of BC. This study examined the association of RAS single nucleotide polymorphisms (SNPs) including AT1R rs5186, AT2R rs11091046, REN rs12750834, ANG rs4762, and ANG rs699 with the risk of developing non-invasive BC. Peripheral blood samples from 73 patients with T1 urothelial BC (66 men, seven women) and an equal number of healthy subjects (control group) were collected. The TT genotype of the REN rs12750834 SNP (OR: 2.8 [1.3–6.05], p = 0.008) and to a lesser extent the presence of the T allele (OR: 2.3 [1.2–4.48], p = 0.01) conferred a higher risk of BC. The highest risk for BC within SNP carriers of the RAS system was associated with the presence of the CC genotype (OR: 17.6 [7.5–41.35], p < 0.001) and C allele (OR: 17.7 [8.8–35.9], p < 0.001) of the ANG rs699 SNP. The presence of the AT2R rs11091046 SNP, particularly the AA genotype, was associated with a protective effect against developing BC (OR: 0.268 [0.126–057], p < 0.001). In conclusion, these results support the clinical utility of RAS gene SNPs AT2R rs11091046, REN rs12750834, and ANG rs699 in the genetic cancer risk assessment of patients and families with BC.

Breast cancer in West Africa: molecular analysis of BRCA genes in early-onset breast cancer patients in Burkina Faso

BackgroundBreast cancer (BC) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among women in Africa after cervical cancer. Even if the epidemiological data are now aligned with those relating to industrialized countries, the knowledge concerning breast cancer in Africa, particularly in Western Africa, still lack clinical data, medical treatments, and the evaluation of genetic and non-genetic factors implicated in the etiology of the disease. The early onset and the aggressiveness of diagnosed breast cancers in patients of African ancestry strongly suggest that the genetic risk factor may be a key component, but so far, very few studies on the impact of germ line mutations in breast cancer in Africa have been conducted, with negative consequences on prevention, awareness and patient management. Through Next Generation sequencing (NGS), we analyzed all of the coding regions and the exon–intron junctions of BRCA1 and BRCA2 genes—the two most important genes in hereditary breast cancer—in fifty-one women from Burkina Faso with early onset of breast cancer with or without a family history.ResultsWe identified six different pathogenic mutations (three in BRCA1, three in BRCA2), two of which were recurrent in eight unrelated women. Furthermore, we identified, in four other patients, two variants of uncertain clinical significance (VUS) and two variants never previously described in literature, although one of them is present in the dbSNP database.ConclusionsThis is the first study in which the entire coding sequence of BRCA genes has been analyzed through Next Generation Sequencing in Burkinabe young women with breast cancer. Our data support the importance of genetic risk factors in the etiology of breast cancer in this population and suggest the necessity to improve the genetic cancer risk assessment. Furthermore, the identification of the most frequent mutations of BRCA1 and BRCA2 in the population of Burkina Faso will allow the development of an inexpensive genetic test for the identification of subjects at high genetic cancer risk, which could be used to design personalized therapeutic protocols.