Search

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

Purpose:To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and noncarriers with pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in eight genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared with patients testing negative for mutations in all 37 genes.Results:The 175 HRR mutation carriers and 2,730 noncarriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (median age at diagnosis: 63 vs. 66 years, P < 0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, P = 0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared with noncarriers [HR, 0.83; 95% confidence interval (CI), 0.70–0.97; P = 0.02]. Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared with patients without germline mutations in any of the 37 genes (HR, 0.72; 95% CI, 0.55–0.94; P = 0.01).Conclusions:This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared with noncarriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.

Supplementary Table from Classification of BRCA2 Variants of Uncertain Significance (VUS) Using an ACMG/AMP Model Incorporating a Homology-Directed Repair (HDR) Functional Assay

Genomic data/details, additional analyses

Purpose:The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory.Experimental Design:The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2.Results:Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS.Conclusions:Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

This file contains Supplementary Figure S1 (Correlation between downregulation of EGFR transcriptional target genes, and sensitivity to erlotinib at the high concentration after 6 hours); Supplementary Figure S2 (EGFR inhibitor and DNA damaging agents induce directionally opposing changes in EGR1 expression that are differentially associated with drug sensitivity); Supplementary Figure S3 (Representative 3D response surface plots for the gemcitabine-erlotinib combination in the indicated cell lines); Supplementary Figure S4 (Representative 3D response surface plots for the vorinostat-talazoparib combination in the indicated cell lines); Supplementary Table S1 (Validation of array-based measurements by qRT-PCR); Supplementary Table S2 (Genes with concerted changes in the same direction [upregulation or downregulation] 24 hours after treatment with each of the 15 drugs); and Supplementary Table S4 (Selected genes potentially mediating drug insensitivity to agents in the NCI TPW dataset).

The intracellular effects and overall efficacies of anticancer therapies can vary significantly by tumor type. To identify patterns of drug-induced gene modulation that occur in different cancer cell types, we measured gene-expression changes across the NCI-60 cell line panel after exposure to 15 anticancer agents. The results were integrated into a combined database and set of interactive analysis tools, designated the NCI Transcriptional Pharmacodynamics Workbench (NCI TPW), that allows exploration of gene-expression modulation by molecular pathway, drug target, and association with drug sensitivity. We identified common transcriptional responses across agents and cell types and uncovered gene-expression changes associated with drug sensitivity. We also demonstrated the value of this tool for investigating clinically relevant molecular hypotheses and identifying candidate biomarkers of drug activity. The NCI TPW, publicly available at https://tpwb.nci.nih.gov, provides a comprehensive resource to facilitate understanding of tumor cell characteristics that define sensitivity to commonly used anticancer drugs.Significance:The NCI Transcriptional Pharmacodynamics Workbench represents the most extensive compilation to date of directly measured longitudinal transcriptional responses to anticancer agents across a thoroughly characterized ensemble of cancer cell lines.

XLSX file - 713K, Excel sheet containing additional data for main Figure 4.

XLSX file - 271K, Excel sheet containing additional data for the main text.

PDF file - 880K, Volcano plots for 28 FDA approved cancer drugs of interest.

XLSX file - 337K, Excel sheet containing the list of compounds from Supplemental Figure 9.

PDF file - 3388K, Supplementary Figure 1: Variant filtering decision tree. Supplementary Figure 2: Distribution of variants by annotation. Supplementary Figure 3: The NCI-60 cell lines. Supplementary Figure 4: Distribution of variants by type. Supplementary Figure 5: Phylogenic conservation of POL epsilon-P286. Supplementary Figure 6: A snapshot of the WES dataset in Variant Analysis by Ingenuity Systems (http://www.ingenuity.com/NCI60_WES). Supplementary Figure 7: Pattern comparison for cell with wild-type TP53 status. Supplementary Figure 8: Receiver operating curves (ROC) for cross-validated drug predictors.

PDF file - 4628K, Volcano plots for 46 cancer genes of interest.

PDF file - 125K

Background: Understanding clot composition may allow for better technical planning and improved outcomes in mechanical thrombectomy (MT). We sought to correlate clot composition with reperfusion outcomes in MT. Methods: Clinical, imaging, and clot data from patients enrolled in the STRIP Registry from September 2016 to September 2020 were analyzed. Samples were fixed in 10% phosphate-buffered formalin and stained with hematoxylin and eosin and Martius Scarlett Blue. Percent composition, richness, and gross appearance were evaluated. Outcome measures included the rate of First-Pass Effect (mTICI2c/3, FPE) and the number of device passes. Results: A total of 1430 patients (mean age, 68.4±13.5years; median [IQR] baseline NIHSS,17.2 [10.5-23]; IV-tPA use, 36%; Stent-Retrievers [SR], 27%; Contact Aspiration [CA], 27%; Combined SR + CA, 43%) were included. The median [IQR] number of passes was 1 [1-2]. FPE was achieved in 39.3% of the cases. There was no association between percent histological composition or clot richness and FPE in the overall population. However, the combined technique resulted in lower FPE rates for RBC-rich (P Conclusion: Despite the lack of correlation between clot histology and FPE in the overall population, our study adds to the growing body of evidence supporting the notion that clot composition influences reperfusion treatment strategy outcomes. Additional studies are needed.

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Objective To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A 1c (HbA 1c ). Design Observational study. Setting OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants Adults with type 2 diabetes and HbA 1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures The primary outcome was time to HbA 1c ≥7.0%. Secondary outcomes were time to HbA 1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA 1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA 1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA 1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.

Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory. Experimental Design: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. Results: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. Conclusions: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

This purpose of this study is to correlate a new shear-wave elastography (SWE) parameter, mass characteristic frequency (fmass) and other elasticity measure with the prognostic histological factors and immunohistochemical (IHC) biomarkers for the evaluation of heterogeneous breast carcinomas. The new parameter, fmass, first introduced in this paper, is defined as the ratio of the averaged minimum shear wave speed taken spatially within regions of interest to the largest mass dimension. 264 biopsy-proven breast cancerous masses were included in this study. Mean (Emean), maximum (Emax), minimum (Emin) shear wave elasticity and standard deviation (Esd) of shear wave elasticity were found significantly correlated with tumor size, axillary lymph node (ALN) status, histological subtypes and IHC subtypes. The areas under the curve for the ALN prediction are 0.73 (95% confidence interval [CI]: 0.67-0.80) and 0.75 (95% CI: 0.69-0.81) for the combination of Emean with Breast Imaging Reporting and Data System (BI-RADS) score and Emax with BI-RADS score, respectively. fmass was significantly correlated with the presence of calcifications, ALN status, histological grade, the expressions of IHC biomarkers and IHC subtypes. To conclude, poor prognostic factors were associated with high shear wave elasticity values and low mass characteristic frequency value. Therefore, SWE provides valuable information that may help with prediction of breast cancer invasiveness.

Background Early prediction of tumor response to neoadjuvant chemotherapy (NACT) is crucial for optimal treatment and improved outcome in breast cancer patients. The purpose of this study is to investigate the role of shear wave elastography (SWE) for early assessment of response to NACT in patients with invasive breast cancer. Methods In a prospective study, 62 patients with biopsy-proven invasive breast cancer were enrolled. Three SWE studies were conducted on each patient: before, at mid-course, and after NACT but before surgery. A new parameter, mass characteristic frequency (fmass), along with SWE measurements and mass size was obtained from each SWE study visit. The clinical biomarkers were acquired from the pre-NACT core-needle biopsy. The efficacy of different models, generated with the leave-one-out cross-validation, in predicting response to NACT was shown by the area under the receiver operating characteristic curve and the corresponding sensitivity and specificity. Results A significant difference was found for SWE parameters measured before, at mid-course, and after NACT between the responders and non-responders. The combination of Emean2 and mass size (s2) gave an AUC of 0.75 (0.95 CI 0.62–0.88). For the ER+ tumors, the combination of Emean_ratio1, s1, and Ki-67 index gave an improved AUC of 0.84 (0.95 CI 0.65–0.96). For responders, fmass was significantly higher during the third visit. Conclusions Our study findings highlight the value of SWE estimation in the mid-course of NACT for the early prediction of treatment response. For ER+ tumors, the addition of Ki-67improves the predictive power of SWE. Moreover, fmass is presented as a new marker in predicting the endpoint of NACT in responders.

BackgroundWe retrospectively evaluated the composition of retrieved clots from ischemic stroke patients to study the association between histological composition and stroke etiologyMethodsConsecutive patients enrolled in the Stroke Thromboembolism Registry of Imaging and Pathology (STRIP) were included in this study. All patients underwent mechanical thrombectomy and retrieved clots were sent to a central core lab for processing. Histological analysis was performed using martius scarlet blue (MSB) staining, and quantification for red blood cells (RBCs), white blood cells (WBCs), fibrin and platelets was performed using Orbit Image Software. A Wilcoxon test was used for continuous variables and χ2test for categorical variables.Results1350 patients were included in this study. The overall rate of Thrombolysis In Cerebral Infarction (TICI) 2c/3 was 68%. 501 patients received tissue plasminogen activator (tPA) (37%). 267 patients (20%) had a large artery atherosclerosis (LAA) source, 662 (49%) a cardioembolic (CE) source, 301 (22%) were cryptogenic, and the remainder had other identifiable sources including hypercoagulable state or dissection. LAA thrombi had a higher mean RBC density (46±23% vs 42±22%, p=0.01) and a lower platelet density (24±18% vs 27±18%, p=0.03) than CE thrombi. Clots from dissection patients had the highest mean RBC density (50±24%) while clots from patients with a hypercoagulable state had the lowest mean RBC density (26±21%).ConclusionsOur study found statistically significant but clinically insignificant differences between clots of CE and LAA etiologies. Future studies should emphasize molecular, proteomic and immunohistochemical characteristics to determine links between clot composition and etiology.

Summary Determination of the clinical relevance of rare germline variants of uncertain significance (VUSs) in the BRCA2 cancer predisposition gene remains a challenge as a result of limited availability of data for use in classification models. However, laboratory-based functional data derived from validated functional assays of known sensitivity and specificity may influence the interpretation of VUSs. We evaluated 252 missense VUSs from the BRCA2 DNA-binding domain by using a homology-directed DNA repair (HDR) assay and identified 90 as non-functional and 162 as functional. The functional assay results were integrated with other available data sources into an ACMG/AMP rules-based classification framework used by a hereditary cancer testing laboratory. Of the 186 missense variants observed by the testing laboratory, 154 were classified as VUSs without functional data. However, after applying protein functional data, 86% (132/154) of the VUSs were reclassified as either likely pathogenic/pathogenic (39/132) or likely benign/benign (93/132), which impacted testing results for 1,900 individuals. These results indicate that validated functional assay data can have a substantial impact on VUS classification and associated clinical management for many individuals with inherited alterations in BRCA2.

Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p< 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was >20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was < 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [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 GS4-04.

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants. METHODS: In a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed. RESULTS: Pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer. CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)

Medical segmentation is an important but challenging task with applications in standardized report generation, remote medicine and reducing medical exam costs by assisting experts. In this paper, we exploit time sequence information using a novel spatio-temporal recurrent deep learning network to automatically segment the thyroid gland in ultrasound cineclips. We train a DeepLabv3+ based convolutional LSTM model in four stages to perform semantic segmentation by exploiting spatial context from ultrasound cineclips. The backbone DeepLabv3+ model is replicated six times and the output layers are replaced with convolutional LSTM layers in an atrous spatial pyramid pooling configuration. Our proposed model achieves mean intersection over union scores of 0.427 for cysts, 0.533 for nodules and 0.739 for thyroid. We demonstrate the potential application of convolutional LSTM models for thyroid ultrasound segmentation.

Purpose:To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and noncarriers with pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in eight genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared with patients testing negative for mutations in all 37 genes.Results:The 175 HRR mutation carriers and 2,730 noncarriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (median age at diagnosis: 63 vs. 66 years, P < 0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, P = 0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared with noncarriers [HR, 0.83; 95% confidence interval (CI), 0.70–0.97; P = 0.02]. Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared with patients without germline mutations in any of the 37 genes (HR, 0.72; 95% CI, 0.55–0.94; P = 0.01).Conclusions:This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared with noncarriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.

OBJECTIVESTo emulate the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) trial using real-world data prior to its publication. GRADE is the first comparative effectiveness study to directly compare second-line glucose-lowering medications with respect to their ability to lower hemoglobin A1c (HbA1c).DESIGN AND SETTINGIn this observational cohort study, we applied GRADE trial criteria to claims and laboratory data from OptumLabs® Data Warehouse (OLDW), a U.S. nationwide claims database, between 1/25/2010 and 6/30/2019.PARTICIAPNTSAdults with type 2 diabetes with hemoglobin A1c (HbA1c) 6.8-8.5% on metformin monotherapy, identified according to GRADE trial specifications.INTERVENTIONSGlimepiride, liraglutide, sitagliptin, and insulin glargine.MAIN OUTCOME MEASURESThe primary outcome was time to HbA1c ≥7.0% and secondary outcomes were other metabolic, microvascular, macrovascular, and safety outcomes specified by GRADE. Propensity scores were estimated using the gradient boosting machine method and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression.RESULTSWe identified 8252 patients (19.7% of adults starting the study drugs in OLDW) meeting GRADE eligibility criteria (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses due to small sample size. Median times to HbA1c ≥7.0% were 442 (95% CI, 394-480) days for glimepiride, 764 (95% CI, 741-NA) days for liraglutide, and 427 (95% CI, 380-483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared to glimepiride (HR 0.57 [95% CI, 0.43-0.75]) and sitagliptin (HR 0.55 [95% CI, 0.41-0.73]). Results were consistent for the secondary outcome of time to HbA1c >7.5%. There were no significant differences among treatment groups for the remaining secondary outcomes.CONCLUSIONSIn this emulation of the GRADE trial, liraglutide was significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. There is value in generating timely evidence on medical treatments using real-world data as a complement to prospective trials.SUMMARY BOXESWhat is already known about this topic?Real-world data is an important source of information about clinical practice, comparative effectiveness and safety, and health outcomes and has the potential to generate timely, pragmatic evidence on medical treatments as a complement to prospective clinical trials.Multiple classes of second-line glucose-lowering medications have been approved for the management of type 2 diabetes, with limited evidence of their comparative effectiveness with respect to glycemic control.What this study adds?We emulated the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) randomized clinical trial using data from a U.S. nationwide administrative claims database to identify the strengths and limitations of using real-world data to emulate prospective comparative effectiveness trials, particularly when examining medications in contexts that may not be the standard of care.Liraglutide is more effective than glimepiride and sitagliptin at lowering HbA1c, supporting its preferential use when substantial glycemic reduction is needed.Advanced causal inference analytic methods applied to observational data can be used to efficiently and effectively emulate clinical trials.

To evaluate the racial and ethnic differences in prevalence of germline pathogenic variants (PVs) and the effect of race and ethnicity on breast cancer (BC) risk among carriers, results of multigene testing of 77 900 women with BC (non-Hispanic White [NHW] = 57 003; Ashkenazi-Jewish = 4798; Black = 6722; Hispanic = 5194; and Asian = 4183) were analyzed, and the frequency of PVs in each gene were compared between BC patients (cases) and race- and ethnicity-matched gnomAD reference controls. Compared with NHWs, BRCA1 PVs were enriched in Ashkenazi-Jews and Hispanics, whereas CHEK2 PVs were statistically significantly lower in Blacks, Hispanics, and Asians (all 2-sided P 4.00) of BC in Blacks, Hispanics, and Asians; ATM PVs were associated with increased risk of BC among all races and ethnicities except Asians, whereas CHEK2 and BRIP1 PVs were associated with increased risk of BC among NHWs and Hispanics only. These findings suggest a need for personalized management of BC risk in PV carriers based on race and ethnicity.

Background The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies. Methods Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer. Results Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer. Conclusions The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing.

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

Purpose Despite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include. Methods To inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT. Results We identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria. Conclusion Opportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.

Objectives The purpose of this study is to retrospectively evaluate the presence of screening digital breast tomosynthesis (DBT) correlates for suspicious lesions detected on pre-operative staging magnetic resonance imaging (MRI) in patients with newly diagnosed breast cancer. Methods After approval from the institutional review board (IRB), screening DBTs on breast cancer patients with BI-RADS 4 or 5 staging MRI exams between 8/1/17 and 8/1/18 were assessed for presence of DBT correlates for suspicious MRI findings. The pathology of the index lesion, type of additional MRI finding (mass, non-mass enhancement, or focus), correlative finding on tomosynthesis (mass, asymmetry/focal asymmetry, distortion, or calcifications), size on MRI and tomosynthesis, breast density, and pathology of the additional lesion were recorded. The chi-square test of association was used unless otherwise specified. Confidence intervals for proportions were estimated using the Wilson's score method. Results 17/70 (24%) of additional lesions seen on pre-operative MRI exams in patients with newly diagnosed cancer had a mammographic correlate on corresponding screening DBT. There was no significant relationship between the presence of a mammographic correlate and the type of MRI finding (mass, NME, or focus), breast density, size of lesion, pathology of index cancer, or pathology of the additional lesion (p≥ 0.05). Conclusions 76% of additional lesions seen on pre-operative staging MRI in patients with newly diagnosed breast cancer are not seen retrospectively on screening DBT. Since about 24% of MRI-detected additional lesions may have a DBT correlate, DBT exams should be reviewed in patients recalled for further workup of findings seen on pre-operative MRI since this may facilitate DBT-guided biopsy of suspicious lesions, which is preferable to MRI-guided biopsy for cost and patient comfort reasons.

Objectives To overcome the limitations of power Doppler in imaging angiogenesis, we sought to develop and investigate new quantitative biomarkers of a contrast-free ultrasound microvasculature imaging technique for differentiation of benign from malignant pathologies of breast lesion. Methods In this prospective study, a new high-definition microvasculature imaging (HDMI) was tested on 521 patients with 527 ultrasound-identified suspicious breast masses indicated for biopsy. Four new morphological features of tumor microvessels, microvessel fractal dimension (mvFD), Murray’s deviation (MD), bifurcation angle (BA), and spatial vascularity pattern (SVP) as well as initial biomarkers were extracted and analyzed, and the results correlated with pathology. Multivariable logistic regression analysis was used to study the performance of different prediction models, initial biomarkers, new biomarkers, and combined new and initial biomarkers in differentiating benign from malignant lesions. Results The new HDMI biomarkers, mvFD, BA, MD, and SVP, were statistically significantly different in malignant and benign lesions, regardless of tumor size. Sensitivity and specificity of the new biomarkers in lesions > 20 mm were 95.6% and 100%, respectively. Combining the new and initial biomarkers together showed an AUC, sensitivity, and specificity of 97% (95% CI: 95–98%), 93.8%, and 89.2%, respectively, for all lesions regardless of mass size. The classification was further improved by adding the Breast Imaging Reporting and Data System (BI-RADS) score to the prediction model, showing an AUC, sensitivity, and specificity of 97% (95% CI: 95–98%), 93.8%, and 89.2%, respectively. Conclusion The addition of new quantitative HDMI biomarkers significantly improved the accuracy in breast lesion characterization when used as a complementary imaging tool to the conventional ultrasound. Key Points • Novel quantitative biomarkers extracted from tumor microvessel images increase the sensitivity and specificity in discriminating malignant from benign breast masses. • New HDMI biomarkers Murray’s deviation, bifurcation angles, microvessel fractal dimension, and spatial vascularity pattern outperformed the initial biomarkers. • The addition of BI-RADS scores based on US descriptors to the multivariable analysis using all biomarkers remarkably increased the sensitivity, specificity, and AUC in all size groups.

Although systemic antibiotics are critical in controlling infections and reducing morbidity and mortality, overuse of antibiotics is presumed to contribute to negative repercussions such as selection of antimicrobial-resistant organisms and collateral damage to commensal microbes. In a prospective, randomized study of four clinically relevant antibiotic regimens [doxycycline (20mg or 100mg), cephalexin, or trimethoprim/sulfamethoxazole], we investigated microbial alterations on skin after administration of systemic antibiotics to healthy human volunteers. Samples from different skin and oral sites as well as stool were collected before, during, and up to 1 year after antibiotic use, and shotgun metagenomic sequencing was performed. Taxonomic analysis showed that subjects receiving doxycycline 100mg and trimethoprim/sulfamethoxazole (TMP/SMX) exhibited greater changes to their skin microbial communities, as compared to those receiving other regimens, or untreated controls. Oral and stool microbiota also demonstrated fluctuations after antibiotics. Bacterial culturing in combination with whole-genome sequencing revealed specific emergence, expansion, and persistence of antibiotic-resistant staphylococci harboring tetK or tetL and dfrC or dfrG genes in all subjects who received doxycycline 100mg or TMP/SMX, respectively. Last, analysis of metagenomic data revealed an increase of genes involved in gene mobilization, indicating stress responses of microbes to antibiotics. Collectively, these findings demonstrate direct, long-lasting effects of antibiotics on skin microbial communities, highlighting the skin microbiome as a site for the development and persistence of antibiotic resistance and the risks of overprescribing.

Introduction: The relationship between germline pathogenic variants (PVs) in cancer predisposition genes and ductal carcinoma in situ (DCIS) is not well established. The objective of this study is to determine the risks of DCIS and contralateral breast cancer among women with DCIS associated with germline PVs in cancer predisposition genes. Methods: Associations between pathogenic variants in 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) and DCIS were determined in case control analyses of a population-based cohort of 3876 women with DCIS and age-matched unaffected women, and in a clinical cohort of 9887 DCIS cases undergoing clinical genetic testing at Ambry Genetics and unaffected reference controls. The incidence of contralateral breast cancer risk in BRCA1, BRCA2, and PALB2 PV carriers with DCIS was also evaluated in a time-to-event analysis. Results: The mean age at diagnosis of DCIS was 50 years in the clinical testing cohort and 59 years in the population-based cohort. The frequency of PVs in 11 predisposition genes among DCIS cases was 6.9% in the clinical testing cohort and 4.9% in the population-based cohort. PVs in ATM, BRCA1, BRCA2, CHEK2, MSH6, PALB2, and RAD51D were associated with significantly increased risks (Odds Ratio (OR) >2) of DCIS in the clinical testing cohort whereas only PVs in BRCA1, CHEK2, PALB2, and ATM were associated with significantly increased risks of DCIS in the population-based cohort. The cumulative incidence of contralateral breast cancer among BRCA1, BRCA2, and PALB2 PV carriers with DCIS was 11% in 5-years and 20% in 15-years. Conclusions: This study provides new insights into PVs that predispose to DCIS. In addition, it establishes an increased risk of contralateral breast cancer risk among women with DCIS who are carriers of PVs in BRCA1, BRCA2, or PALB2. These findings will guide surveillance and risk reducing strategies in germline PV carriers with DCIS. Citation Format: Huaizhi Huang, Ronan E. Couch, Holly LaDuca, Siddhartha Yadav, Eric C. Polley, Nicholas J. Boddicker, Jie Na, Rohan D. Gnanaolivu, David E. Goldgar, Tina Pesaran, Steven N. Hart, Jill S. Dolinsky, Julie R. Palmer, Lauren Teras, Alpa V. Patel, Kathryn J. Ruddy, Janet E. Olson, Celine M. Vachon, Peter Kraft, Song Yao, Amy Trentham-Dietz, Katherine L. Nathanson, Jeffrey N. Weitzel, Susan M. Domchek, Fergus J. Couch, Chunling Hu. Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A003.

Key Points Question Can real-world data regarding the use of degarelix and leuprolide be used to emulate the forthcoming PRONOUNCE trial, a phase 3b trial comparing the cardiovascular safety of degarelix vs leuprolide among patients with prostate cancer and cardiovascular disease? Findings In this cohort study of 2226 propensity score–matched men with prostate cancer taking degarelix or leuprolide, no significant difference was observed in the risk of a major adverse cardiovascular event. Meaning These findings suggest that real-world data are increasingly available and useful for medical product evaluation, including for emulating clinical trials to understand products’ use in clinical practice and the associated benefits and harms of treatment., This cohort study uses electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial, which compares the cardiovascular safety of degarelix and leuprolide in men with cardiovascular disease and advanced prostate cancer., Importance With a growing interest in the use of real-world evidence for regulatory decision-making, it is important to understand whether real-world data can be used to emulate the results of randomized clinical trials. Objective To use electronic health record and administrative claims data to emulate the ongoing PRONOUNCE trial (A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease). Design, Setting, and Participants This retrospective, propensity-matched cohort study included adult men with a diagnosis of prostate cancer and cardiovascular disease who initiated either degarelix or leuprolide between December 24, 2008, and June 30, 2019. Participants were commercially insured individuals and Medicare Advantage beneficiaries included in a large US administrative claims database. Exposures Degarelix or leuprolide. Main Outcomes and Measures The primary end point was time to first occurrence of a major adverse cardiovascular event (MACE), defined as death due to any cause, myocardial infarction, or stroke, analogous to the PRONOUNCE trial. Secondary end points were time to death due to any cause, myocardial infarction, stroke, and angina. Cox proportional hazards regression was used to evaluate primary and secondary end points. Results A total of 32 172 men initiated degarelix or leuprolide for prostate cancer; of them, 9490 (29.5%) had cardiovascular disease, and 7800 (24.2%) met the PRONOUNCE trial eligibility criteria and were included in this study. Overall, 165 participants (2.1%) were Asian, 1390 (17.8%) were Black, 663 (8.5%) were Hispanic, and 5258 (67.4%) were White. The mean (SD) age was 74.4 (7.4) years. Among 2226 propensity score–matched patients, no significant difference was observed in the risk of MACE for patients taking degarelix vs those taking leuprolide (10.18 vs 8.60 events per 100 person-years; hazard ratio [HR], 1.18; 95% CI, 0.86-1.61). Degarelix was associated with a higher risk of death from any cause (HR, 1.48; 95% CI, 1.01-2.18) but not of myocardial infarction (HR, 1.16; 95% CI, 0.60-2.25), stroke (HR, 0.92; 95% CI, 0.45-1.85), or angina (HR, 1.36; 95% CI, 0.43-4.27). Conclusions and Relevance In this emulation of a clinical trial of men with cardiovascular disease undergoing treatment for prostate cancer, degarelix was not associated with a lower risk of cardiovascular events than leuprolide. Comparison of these data with PRONOUNCE trial results, when published, will help enhance our understanding of the appropriate role of using real-world data to emulate clinical trials.