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PURPOSE: Increasing usage of multigene panel testing has identified more patients with pathogenic or likely pathogenic (P or LP) variants in low-moderate penetrance genes or variants of uncertain significance (VUS). Our study evaluates the association between genetic test results and contralateral prophylactic mastectomy (CPM) among patients with breast cancer. METHODS: We conducted a retrospective cohort study among women diagnosed with unilateral stage 0-III breast cancer between 2013 and 2020 who underwent genetic testing. We examined whether genetic test results were associated with CPM using multivariable logistic regression models. RESULTS: Among 707 racially or ethnically diverse women, most had benign or likely benign (B or LB) variants, whereas 12.5% had P or LP and 17.9% had VUS. Racial or ethnic minorities were twice as likely to receive VUS. Patients with P or LP variants had higher CPM rates than VUS or B or LB (64.8% v 25.8% v 25.9%), and highest among women with P or LP variants in high-penetrance genes (74.6%). On multivariable analysis, P or LP compared with B or LB variants were significantly associated with CPM (odds ratio = 4.24; 95% CI, 2.48 to 7.26). CONCLUSION: Women with P or LP variants on genetic testing were over four times more likely to undergo CPM than B or LB. Those with VUS had similar CPM rates as B or LB. Our findings suggest appropriate genetic counseling and communication of cancer risk to multiethnic breast cancer survivors.

Supplementary Table 1 shows number of TAP cases per site

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20–33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair–deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.

Supplementary Table 3 shows types of surgical resection

Supplementary Table 2 shows individual case-level data (clinical history, genetic testing, secondary cancers)

Background: Contralateral prophylactic mastectomy (CPM) is a risk-reducing surgery offered to women with unilateral breast cancer intended to reduce the risk of contralateral breast cancer. The rate of CPM among women with unilateral early-stage breast cancer has risen in the United States over the past two decades, despite limited evidence for a survival benefit in the majority of patients. We evaluated sociodemographic and clinical factors, including receipt and results of BRCA1/2 genetic testing or multigene panel testing, associated with CPM among young women with unilateral early-stage breast cancer. Methods: We conducted a retrospective cohort study of women diagnosed with unilateral stage 0-III breast cancer at age ≤ 50 years between January 2007 and December 2017 at Columbia University Irving Medical Center (CUIMC) in New York, NY. Patients with bilateral breast cancer, male breast cancer, metastatic disease, or missing breast surgery information were excluded from the analysis. Demographics (age, race/ethnicity, marital status, primary health insurance) and clinical information (stage and year of diagnosis, family history of breast cancer) were collected from the electronic health record (EHR) and New York Presbyterian Hospital (NYPH) Tumor Registry. We also determined receipt of genetic testing (yes/no) and results (pathogenic/likely pathogenic [P/LP], variant of uncertain significance [VUS], negative). The primary outcome of interest was receipt of CPM. Multivariable logistic regression models were used to assess the association between demographic and clinical factors, including receipt and results of genetic testing, and CPM. Results: Among the 1207 women who met inclusion criteria, median age was 42.9 years (standard deviation [SD], 5.7 years), and 43% identified as non-Hispanic white, 27% Hispanic, 13% non-Hispanic black, 10% Asian, and 7% other. Nearly half (49.5%, N=597) underwent germline genetic testing for cancer susceptibility genes, and of those tested, 12.6% had P/LP variants (of which 69.3% were in BRCA1/2), 14.2% had VUSs, and 73.2% had negative results. Over one-quarter (27.7%, N = 334) underwent CPM, 29.8% had a unilateral mastectomy and 42.5% had lumpectomy. In multivariable analysis, women with a younger age at diagnosis, more advanced stage disease, and a family history of breast cancer were more likely to undergo CPM. There were no differences in CPM rates by primary health insurance. Asian women were less likely to undergo CPM compared to non-Hispanic white women (odds ratio [OR]=0.56, 95% confidence interval [CI]=0.34-0.95). Compared to women who did not undergo genetic testing, CPM rates were higher among those who had a P/LP variant (OR=5.12, 95% CI=2.94-8.89), those who had a VUS (OR=1.94, 95% CI=1.23-3.36) or negative results (OR=1.51, 95% CI=1.09-2.09). From 2007 to 2017, rates of genetic testing uptake in the study population increased from 17.9% to 67.1%, and CPM rates increased from 15.2% to 30.0%. Conclusions: Among young women with unilateral early-stage breast cancer, CPM rates were relatively high and increased over time. Women with P/LP variants were over 5 times more likely to undergo CPM compared to those who did not undergo genetic testing, however, even those with VUS or negative results were over 50% more likely to undergo CPM. The American Society of Breast Surgeons now recommends genetic testing for hereditary breast cancer among all women diagnosed with breast cancer. As multigene panel testing is increasingly utilized among women with breast cancer, further evaluation of its role in decisions regarding risk-reducing surgery such as CPM is warranted, particularly given the unclear implications of moderate-risk pathogenic variants and VUS results on contralateral breast cancer risk. Citation Format: Julia E McGuinness, Boya Guo, Meghna S Trivedi, Tarsha Jones, Wendy K Chung, Roshni Rao, Elana Levinson, Carrie Koval, Donna Russo, Ilana Chilton. Association between genetic testing for hereditary breast cancer and contralateral prophylactic mastectomy among young women diagnosed with early-stage breast cancer [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 P6-08-11.

The unique situational challenges of the COVID‐19 pandemic have demanded creative modifications to the delivery of genetic services. Institutions across the country have adapted workflows to continue to provide quality care while minimizing the need for physical visits. As the first epicenter of the pandemic in the country, New York City healthcare workers and residents had to make rapid, unprecedented changes to their way of life. This article describes the workflow adaptations of genetic counselors across various clinical settings at New York Presbyterian/Columbia University Irving Medical Center, the largest provider of genetics care in New York City, during the height of the COVID‐19 pandemic. The authors observe how the adaptations impacted clinical care and the genetic counselors. Our lived experience and account can provide guidance for others during the current and future pandemics.

Recent advances in next generation sequencing have enabled panel gene testing, or simultaneous testing for mutations in multiple genes for a clinical condition. With more extensive and widespread genetic testing, there will be increased detection of genes with moderate penetrance without established clinical guidelines and of variants of uncertain significance (VUS), or genetic variants unknown to either be disease-causing or benign. This study surveyed 232 patients who underwent genetic counseling for hereditary breast and ovarian cancer to examine the impact of panel gene testing on psychological outcomes, patient understanding, and utilization of genetic information. The survey used standardized instruments including the Impact of Event Scale (IES), Multidimensional Impact of Cancer Risk Assessment (MICRA), Satisfaction with Decision Instrument (SWD), Ambiguity Tolerance Scale (AT-20), genetics knowledge, and utilization of genetic test results. Study results suggested that unaffected individuals with a family history of breast or ovarian cancer who received positive results were most significantly impacted by intrusive thoughts, avoidance, and distress. However, scores were also modestly elevated among unaffected patients with a family history of breast and ovarian cancer who received VUS, highlighting the impact of ambiguous results that are frequent among patients undergoing genetic testing with large panels of genes. Potential risk factors for increased genetic testing-specific distress in this study included younger age, black or African American race, Hispanic origin, lower education level, and lower genetic knowledge and highlight the need for developing strategies to provide effective counseling and education to these communities, particularly when genetic testing utilizes gene panels that more commonly return VUS. More detailed pre-test education and counseling may help patients appreciate the probability of various types of test results and how results would be used clinically, and allow them to make more informed decisions about the type of genetic testing to select.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death; approximately 5–10% of PDAC is hereditary. Self-administered health history questionnaires (HHQs) may provide a low-cost method to detail family history (FH) of malignancy. Pancreas Center patients were asked to enroll in a registry; 149 with PDAC completed a HHQ which included FH data. Patients with FH of PDAC, or concern for inherited PDAC syndrome, were separately evaluated in a Prevention Program and additionally met with a genetic counselor (GC) to assess PDAC risk (n = 61). FH obtained through GC and HHQ were compared using Wilcoxon signed-rank sum and generalized linear mixed models with Poisson distribution. Agreement between GC and HHQ risk-assessment was assessed using kappa (κ) statistic. In the Prevention Program, HHQ was as precise in detecting FH of cancer as the GC (all p > 0.05). GC and HHQ demonstrated substantial agreement in risk-stratification of the Prevention Program cohort (κ = 0.73, 95% CI 0.59–0.87.) The sensitivity of the HHQ to detect a patient at elevated risk (i.e., moderate- or high-risk) of PDAC, compared to GC, was 82.9% (95% CI 67.3–92.3%) with a specificity of 95% (95% CI 73.1–99.7%). However, seven patients who were classified as average-risk by the HHQ were found to be at an elevated-risk of PDAC by the GC. In the PDAC cohort, 30/149 (20.1%) reported at least one first-degree relative (FDR) with PDAC. The limited sensitivity of the HHQ to detect patients at elevated risk of PDAC in the Prevention Program cohort suggests that a GC adds value in risk-assessment in this population. The HHQ may offer an opportunity to identify high-risk patients in a PDAC population.

Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD.A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure.Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP-GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P.001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans.These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information.

BACKGROUND Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. METHODS Patients in a high-risk PDAC prevention and genetics program or those with a personal history of PDAC who were referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. RESULTS A total of 37 patients without PDAC underwent BRCA1/2 testing at the study institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six patients carried Ashkenazi Jewish founder mutations (3 with BRCA1 and 3 with BRCA2), and 1 patient was found to have a BRCA2 mutation on comprehensive testing. Thirty-two patients with PDAC underwent BRCA1/2 genetic testing. Five patients had Ashkenazi Jewish founder mutations (2 with BRCA1 and 3 with BRCA2), and 2 patients were found to have BRCA2 mutations on comprehensive testing. The diagnostic yield was 7 of 32 patients (21.9%). CONCLUSIONS BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation-positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer. Cancer 2014;120:1960–1967. © 2014 American Cancer Society.

Background In view of the increasing availability of commercial internet-based Personal Genome Testing (PGT), this study aimed to explore the reasons why people would consider taking such a test and how they would use the genetic risk information provided. Methodology/Principal Findings A self-completion questionnaire assessing public awareness and interest in PGT and motivational reasons for undergoing PGT was completed by 4,050 unselected adult volunteers from the UK-based TwinsUK register, aged 17 to 91 (response rate 62%). Only 13% of respondents were aware of the existence of PGT. After reading a brief summary about PGT, one in twenty participants (5%) were potentially interested at current prices (£250), however this proportion rose to half (50%) if the test was free of charge. Nearly all respondents who were interested in free PGT reported they would take the test to encourage them to adopt a healthier lifestyle if found to be at high genetic risk of a disease (93%). Around 4 in 5 respondents would have the test to convey genetic risk information to their children and a similar proportion felt that having a PGT would enable their doctor to monitor their health more closely. A TwinsUK research focus group also indicated that consumers would consult their GP to help interpret results of PGT. Conclusions/Significance This hypothetical study suggests that increasing publicity and decreasing costs of PGT may lead to increased uptake, driven in part by the general public's desire to monitor and improve their health. Although the future extent of the clinical utility of PGT is currently unknown, it is crucial that consumers are well informed about the current limitations of PGT. Our results suggest that health professionals will inevitably be required to respond to individuals who have undergone PGT. This has implications for health service providers regarding both cost and time.