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Rationale and Objectives Pathogenic mutations in some genes elevate women's breast cancer risk, necessitating risk-reduction strategies. Unfortunately, women are underscreened for cancer risk, and when identified as potentially high risk, women seldom pursue genetic counseling or testing. To improve cancer risk management, this project determined the feasibility of radiology-operated, proactive, same-day risk assessment and genetic testing programs to diagnose high-risk women undergoing breast imaging. Materials and Methods The Comprehensive Assessment, Risk & Education Program launched on June 5, 2019. Data was tracked through July 22, 2020. Women undergoing breast imaging completed questionnaires that calculated Tyrer-Cuzick risk and assessed genetic testing eligibility using National Comprehensive Cancer Network criteria. To encourage eligible women's genetic testing adherence, pretest counseling and saliva sample collection occurred that same day in the imaging center. Samples were tested by a 34-multigene panel. Genetic counselors called women with positive results. Women with negative results or variants of uncertain significance were mailed notifications. Summary statistics were calculated. Results A total of 3345 women completed questionnaires. 1080 (32.3%) met genetic testing criteria. 468/1080 (43.3%) submitted genetic samples, and 416/1080 (38.5%) completed testing. Of 416 completed tests, 269 (64.7%) tested negative, 109 (26.2%) had variants of uncertain significance, and 38 (9.1%) diagnosed pathogenic mutations. 13/38 (34.2%) women with pathogenic mutations implemented risk-reduction strategies at our institution. Conclusion Breast imaging centers can operate same-day cancer risk assessment and genetic testing programs, identifying high-risk women that conventional risk assessment methods may not have diagnosed. These proactive programs add value to radiology departments’ cancer care beyond traditional imaging services.

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Introduction Approximately one out of eight women are diagnosed with breast cancer in their lifetime. Women are recommended to begin annual mammograms at age 40 unless they are high-risk risk for breast cancer based on risk algorithms or positive germline mutations. Unfortunately, genetic testing and risk counseling are often not offered until a cancer diagnosis is already made. It is estimated that 5-10% of the general population has genetic predisposition to cancer. Purpose We established the Comprehensive Assessment, Risk & Education (CARE) Program at our mammogram center. Offered in partnership with Ambry Genetics, the CARE Program’s goal is to facilitate unaffected women in obtaining genetic testing and risk-counseling who otherwise may not have access to these services. Methods Patients undergoing a screening mammogram were given a tablet with a preprogrammed Progeny questionnaire. This questionnaire included questions on the patient’s gynecological history and family history. It calculates a Tyrer-Cuzick risk score and assesses National Comprehensive Cancer Network (NCCN) genetic testing criteria. Patients qualifying for genetic testing received pretest counseling by video and were offered genetic testing the same day as their mammogram appointment. Our genetic counselors performed follow-up counseling for patients receiving positive test results. Patients testing negative or inconclusive received a letter generated by Ambry. Our CARE program began on June 7th, 2019, and data was assessed through July 6th, 2020. Results 1,065 women met NCCN criteria for genetic testing. Of those women, 464 (43.6%) proceeded with testing, 387 (36.3%) declined testing and 214 (20.1%) were not able to obtain day-of genetic testing due to operational/personnel limitations. Of those who submitted tests, 403 (86.9%) completed testing and 61 tests were cancelled due to out of pocket costs or patient preference. Of the 403 patients who completed testing, 262 (65%) tested negative, 105 (26%) tested inconclusive and 35 (8.7%) tested positive. Positive test results were found in 15 genes (Table 1). Clinical Impact Over 13 months, we identified 35 patients at increased risk for cancer based on positive genetic test results. Based on these results, 6 (17%) patients were offered prophylactic surgeries, 16 (45.7%) were offered breast MRIs and enrollment in our high-risk breast clinic, 14 (40%) were offered increased colonoscopies and 9 (25.7%) were offered pancreatic screening based on family history. All patients were offered family variant testing. Conclusion Our experience integrating a screening questionnaire into our mammogram clinic shows that 44% of patients meeting NCCN criteria agree to do day of testing. Of those completing testing, 9% tested positive. This result is consistent with the national expected positive rate. Our CARE Program offers unaffected patients an opportunity to be tested in a comfortable low stress setting through the mammography suite. These patients and their families will now benefit from cancer prevention options that may not have been offered to them had they not been pre-emptively screened by our program. Table1. Positive test results for 35 patients.MutationNumber of patients identified (%)CHEK29 (25.7)MUTYH5 (14.2)HOXB134 (11.4)ATM3 (8.6)APC2 (5.7)BARD12 (5.7)PALB22 (5.7)BRCA21 (2.9)BRIP11 (2.9)MRE11A1 (2.9)MSH21 (2.9)MSH61 (2.9)RAD501 (2.9)RAD51D1 (2.9)TP531 (2.9) Citation Format: Lida Mina, Rebecca Luiten, Jennifer Siettmann, Vilert Loving. Identification of pathogenic mutations in otherwise unaffected patients through the CARE program [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-20.

Introduction: Approximately one out of eight women get breast cancer in their lifetime, and the National Cancer Institute estimates 268,600 new diagnoses in 2019. About 5-10% of breast cancers can be attributed to a genetic predisposition. Identifying women with genetic predispositions is significant because they qualify for more intense breast cancer screening or risk reducing strategies. Unfortunately, genetic testing is often not offered until cancer is diagnosed. This traditional genetic testing model is reactive rather than proactive, and it fails to identify a large proportion of unaffected genetic mutation carriers in the United States. Purpose: Our goal was to create a proactive system for identifying women at high risk for breast cancer. We integrated an online family history software, Progeny, into our mammography center to screen unaffected women for high-risk status (Tyrer-Cuzick (TC) score ≥ 20%) and National Comprehensive Cancer Network (NCCN) genetic testing criteria. Methods: Patients undergoing breast imaging were given a computer tablet with a preprogrammed Progeny questionnaire. Progeny collects the patient’s gynecological and family history, calculates a TC risk score, and assesses NCCN genetic testing criteria. Progeny was integrated into the mammography center on 1/10/2019 and this preliminary data was collected through 6/6/2019. Summary statistics were tabulated. Results: A total of 3,129 patients were invited to complete the questionnaire. 2,474 (79.1%) completed the questionnaire and 540 (21.8%) met NCCN genetic testing criteria. The average age of those meeting NCCN criteria was 60.3 years (range: 21-94). Of the patients who completed the questionnaire, 148 (6.0%) patients were found to be high-risk due to a TC score ≥20%. Clinical Impact: We found 540 patients who qualified for genetic counseling/testing. Under the previous, reactive genetic testing model, most of these patients would not have been selected for testing unless they received a cancer diagnosis. We recommended pretest genetic counseling to all these high-risk patients. Typical oncology genetic counselors see 10.2 new patients a week and our clinic can see 15 new patients per week. It would take 36 weeks with our current clinic system for all the patients identified during the initial questionnaire trial period to see a genetic counselor for pretest counseling. This demand alone would require two full time genetic counselors to accommodate. Conclusion: Our initial experience integrating a genetic screening questionnaire into our mammography center shows that 22% of patients need genetic testing and 6% need follow-up in a high-risk breast cancer clinic. Given current staffing constraints, it would take about 9 months to genetic test and counsel the patients identified after just 6 months of screening. This estimate does not include the demand placed on genetic counselors from current referral sources, so actual wait times could be longer than 9 months. This long wait time could increase anxiety for patients and dissatisfaction for patients and providers. A new approach to offering genetic testing and counseling to these patients is needed. Future Directions: In response to this increased clinical demand, we are partnering with Progeny and Ambry Genetics to create a novel program that allows patients to receive preliminary genetic education by video and genetic testing the same day as their mammogram appointment. Ultimately, the hope is that this new, high volume, proactive high-risk prevention program will allow a larger proportion of women with a genetic predisposition to receive diagnoses of their mutations and to initiate risk reducing and life-saving treatments. With this partnership, we will better accommodate the increased patient demand for genetic testing and avoid long wait times for counseling. Citation Format: Rebecca C Luiten, Vilert A Loving, Jennifer Siettmann, Beverly Reyes, Lida A Mina. Creation of a high volume, proactive high-risk breast cancer prevention program [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-03.

Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.

Individuals with hypertrophic cardiomyopathy (HCM) and long QT syndrome (LQTS) are advised to avoid certain forms of exercise to reduce their risk of sudden death. Cardiovascular genetic counselors facilitate both adaptation to, and decision-making about, these exercise recommendations. This study describes decision-making and experiences of active adults who exercise above physicians' recommendations. Purposive sampling was used to select adults with HCM and LQTS who self-identified as exercising above recommendations. Semi-structured interviews explored participants' decision-making and the psychological impact of exercise recommendations. Fifteen individuals were interviewed (HCM: 10; LQTS: 5; mean age: 40). Transcripts were coded and analyzed for underlying themes. Despite exercising above recommendations, nearly all participants made some modifications to their prior exercise regimen. Often these decisions changed over time, underscoring the importance of shared decision-making conversations beyond the initial evaluation. The importance of exercise was frequently cited as a reason for continued exercise, as were perceptions of sudden death risk as low, acceptable, or modifiable. Many participants reported that family and friends supported their exercise decisions, with a minority having family or friends that expressed significant reservations. Genetic counselors, cardiologists, and nurses can use these data to inform their counseling regarding exercise recommendations.

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

Summary The ability to identify single-nucleotide mutations is critical for probing cell biology and for precise detection of disease. However, the small differences in hybridization energy provided by single-base changes makes identification of these mutations challenging in living cells and complex reaction environments. Here, we report a class of de novo-designed prokaryotic riboregulators that provide ultraspecific RNA detection capabilities in vivo and in cell-free transcription-translation reactions. These single-nucleotide-specific programmable riboregulators (SNIPRs) provide over 100-fold differences in gene expression in response to target RNAs differing by a single nucleotide in E. coli and resolve single epitranscriptomic marks in vitro. By exploiting the programmable SNIPR design, we implement an automated design algorithm to develop riboregulators for a range of mutations associated with cancer, drug resistance, and genetic disorders. Integrating SNIPRs with portable paper-based cell-free reactions enables convenient isothermal detection of cancer-associated mutations from clinical samples and identification of Zika strains through unambiguous colorimetric reactions., Graphical Abstract, Highlights • SNIPRs are riboregulators with single-nucleotide-specific RNA detection capabilities • They operate in live cells and in paper-based cell-free reactions • Automated in silico design allows SNIPRs to detect many different harmful mutations • Isothermal SNIPR tests enable portable human genotyping and viral strain detection, The development of high-specificity RNA toehold-based sensors allows for the discrimination of point mutations and RNA base modifications and enables genotypic diagnosis for E. coli, human samples, and Zika virus strains

Objective We examined the extent and nature of the psychological difficulty experienced by athletic adults with hypertrophic cardiomyopathy (HCM), correlates of that difficulty and coping mechanisms. Methods A survey assessed athletic history and psychological impact of exercise restrictions. LASSO penalised linear regression identified factors associated with psychological difficulty. Semistructured interviews provided deeper insight into the nature and origins of psychological difficulty. Results 54 individuals (33% female, mean age 55.9) completed the survey. The majority were recreational athletes at the time of restriction (67%). There was a drop in athleticism after diagnosis, including time spent exercising (p=0.04) and identification as an athlete (p=0.0005). Most respondents (54%) found it stressful and/or difficult to adjust to exercise restrictions. Greater psychological morbidity was associated with history of elite or competitive athletics, athletic identity and decrease in time spent exercising. 16 individuals (44% female, mean age 52.4) were interviewed. Long-term effects included weight gain and uncertainty about exercising safely. The role of exercise in interviewees' lives contracted significantly after restriction, from multiple functions (eg, social, stress relief, fitness) to solely health maintenance. Interviewees reported a unique form of social support: having family and friends participate with them in lower intensity exercise. Lack of understanding from family or friends and avoiding exercise completely were detrimental to coping. Conclusions Athletic adults with HCM experience multifaceted, lasting difficulty adjusting to exercise recommendations. These data can guide clinicians in identifying patients at highest risk for distress and in helping to bolster coping and adaptation.