Citations

Abstract 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 < .05). In case-control studies, BARD1 PVs were associated with high risks (odds ratio > 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.

Abstract 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.

PurposeIn quantitative susceptibility mapping (QSM) using magnetic resonance imaging, image reconstruction methods usually aim at suppressing streaking artifacts. In this study, a streaking detection method is proposed for evaluating and optimizing quantitative susceptibility maps.MethodsNine healthy subjects participated in this study and underwent three‐dimensional multi‐echo gradient echo scans. Regularized iterative algorithm was used for reconstruction of tissue susceptibility maps in all subjects. Streaking detection was applied to evaluate streaking artifact in tissue susceptibility maps. In addition, an optimization process for QSM reconstruction by streaking detection was applied and was compared with matching noise level method.ResultsIt is shown that the proposed streaking detection technique effectively delineates streaking artifact in tissue susceptibility maps. In QSM reconstruction, optimization by streaking detection successfully determines the regularization factor that balances between streaking artifact suppression and tissue texture preservation. ROI analyses of brain tissue susceptibility show that optimization by streaking detection achieves results in good agreement with that from matching noise level method.ConclusionsStreaking detection enables direct visualization of streaking patterns in tissue susceptibility maps. It can be applied both for evaluating QSM reconstruction quality and for comparing different reconstruction algorithms. Furthermore, streaking detection can be incorporated into an optimization process of QSM reconstruction. Therefore, we conclude that the proposed method will add value to reconstruction of QSM.

ABSTRACTBACKGROUND AND PURPOSEThere is a relative paucity of radiology literature on spinal cord cavernous malformations (SCMs). We hypothesized that the classic MRI features of cavernous malformations are not highly prevalent. The purpose was to review MR imaging findings of SCMs with a focus on prevalence of hemorrhagic features, including adjacent intramedullary hemorrhage at initial presentation.METHODSIn this single‐institution study, 78 SCMs in 76 patients diagnosed on imaging/pathology were retrospectively evaluated for size, location, cord expansion, exophytic component, popcorn morphology, signal characteristics, including T1 weighted (T1w) and T2w rims, blood‐fluid levels, and adjacent intramedullary hemorrhage. Intramedullary hemorrhage was defined as centrally and/or eccentrically located linear or flame shaped non‐edematous signal abnormality extending longitudinally away from SCMs, distinct from lesional rim.RESULTSSixty‐three percent (49/78) of SCMs measured <1 cm in length, 78% (61/78) extended to the cord surface, 65% (51/78) were expansile, and 32% (25/78) were exophytic. Popcorn morphology was seen in 15% (12/78) on T1w and 22% (17/78) on T2w. Internal blood‐fluid levels were evident in 4% (3/78). Sixty‐nine percent (54/78) showed T2w hypointense rims; the T2w rim was complete/near‐complete in 37% (29/78). A rim on T1w was visible in 49% (38/78); this was hyperintense in 58% (22/38). Adjacent intramedullary hemorrhage was seen in 45/78 (58%), was most commonly bidirectional in 67% (30/45) and eccentric in 68% (30/44). Cord edema was seen in 22% (17/78); 53% (9/17) also demonstrated intramedullary hemorrhage with edema.CONCLUSIONSThe classically described popcorn morphology, internal blood‐fluid levels, and complete/near‐complete T2w hypointense rims are often absent on MRIs in SCMs. Adjacent intramedullary hemorrhage is frequently present, often eccentric and bidirectional.

Abstract Background: Pathogenic variants detected in multi-gene cancer predisposition panels are increasingly used to counsel women regarding their risk for breast cancer. However, the clinical implications of moderate penetrance genes (e.g. CHEK2, ATM) remain unclear. Breast MRI is indicated for women with a lifetime risk of breast cancer of &gt;20%, and polygenic risk scores (PRS) based on common variants discovered in recent genome-wide association studies (GWAS) may identify women with pathogenic variants in CHEK2 and ATM who are above or below this level of risk. PRS may also stratify carriers with substantially elevated lifetime risks of breast cancer. Previous work found that PRS modified breast cancer risk in carriers of pathogenic variant in BRCA1 or BRCA2, but the joint effects of pathogenic variants and PRS have not been studied in samples drawn from the general population. There is also no published study evaluating the effect of PRS among women with pathogenic variants in genes other than BRCA1/2 and CHEK2. Here, we evaluated the joint effects of PRS and pathogenic variants in ten established breast cancer predisposition genes in a population-based case-control sample. Method: We analyzed 43,144 non-Hispanic European-ancestry individuals (20,988 controls and 22,120 cases) drawn from 7 cohorts and 2 population-based case-control studies in the CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium. Targeted sequencing was performed using a dual bar-coded QIAseq panel of breast cancer predisposition genes. Variant calling was conducted with Haplotype Caller and Vardict. The PRS was calculated based on 106 common variants using effect estimates from the largest published breast cancer GWAS. Genetic status was evaluated for 10 breast cancer predisposition genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NF1, PALB2 and TP53. Lasso Penalized regression was performed to assess the combined effect on overall breast cancer of pathogenic variants and common variants (including main and interaction effects between age, family history, carrier status and PRS). The fraction of women at &gt;2-fold increased risk (which is associated with approximately 20% lifetime risk of breast cancer) was calculated for pathogenic variant carriers and non-carriers of different family history and age groups (&lt;40, 40-50, 50-60, 60-70, &gt;70yrs old). Results: Among non-carriers, one standard deviation change in the PRS was associated with a 1.63x change in odds of breast cancer. The best-fitting risk model did not include any PRS-by-carrier interaction terms, implying the relative risk gradient associated with PRS among women with pathogenic variants is similar to that among non-carriers. For carriers of pathogenic variants in moderate penetrance genes with no family history of breast cancer, the PRS can identify 60.6% of ATM pathogenic variant carriers and 30% of CHEK2 pathogenic variant carriers that have less than 2-fold risk of breast cancer; when carriers have a family history of breast cancer, the PRS can identify 30% of ATM pathogenic variant carriers and 11.8% of CHEK2 pathogenic variant carriers with less than 2-fold risk of breast cancer. Conclusion: In our large, population-based case-control study, the effect of the PRS among pathogenic variant carriers was not significantly different than among non-carriers. However, the PRS may be particularly important for estimating breast cancer risk among carriers of pathogenic variants in moderate penetrance genes such as CHEK2 and ATM, enabling a more precise approach for MRI screening strategy and breast cancer risk management. Citation Format: Chi Gao, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Kun Y. Lee, Jie Na, Nicholas J. Boddicker, Raed Samara, Paul Auer, Leslie Bernstein, Mia Gaudet, Amy Trentham-Dietz, Song Yao, Christopher Haiman, Janet E. Olson, Susan Neuhausen, Jeffrey N. Weitzel, David E. Goldgar, Susan Domchek, Katherine L. Nathanson, Fergus J. Couch, Peter Kraft, on behalf of the CARRIERS consortium. Polygenic risk scores provide clinically meaningful risk stratification among women carrying moderate penetrance pathogenic variants in breast cancer predisposition genes: Results from the CARRIERS study [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 PD3-02.

Abstract Germline mutations in several cancer predisposition genes included in hereditary multigene testing panels have been associated with increased breast cancer risk. However, estimates of breast cancer risks for each gene have in large part been derived from studies of high-risk populations enriched for family history of breast and ovarian cancer, young age of breast cancer diagnosis, or founder mutations. The breast cancer risks associated with mutations in many of these genes in the general population remain to be clearly defined. As clinical hereditary cancer genetic testing is already provided to many women at increased risk and may soon be offered to all breast cancer patients, population-based risk estimates associated with predisposition gene mutations will be needed for appropriate clinical management of mutation carriers. The “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium of 17 cohort-based case-control, population-based case-control, and family studies focused on estimation of population-based breast cancer risks and penetrance analysis for mutations in known and candidate breast cancer predisposition genes. Germline DNA from 39486 breast cancer cases and 35868 matched controls was subjected to dual bar-coded QIAseq multiplex amplification of 1733 target regions in 37 predisposition genes. Products from sets of 768 samples were pooled and sequenced in each lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Verdict. High quality sequence data was obtained for 99.3% of target regions. Here we report on results from 34741 population-based breast cancer cases and 32728 matched unaffected controls. The mean age of breast cancer diagnosis for cases was 61.2 years and mean age for controls was 61.1 years. Overall, 20.9% of cases and 14.3% of controls had a family history of breast cancer. Furthermore, 74.3% of cases and 75.8% of controls were non-Hispanic white, whereas 13.3% of cases and 15.3% of controls were African American. Among cases with tumor information available, 81.7% were ER-positive and 7.7% were triple negative breast cancers (TNBC). We assessed mutation frequencies in 24 genes including 12 established breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, andTP53). The overall mutation frequency was 6.2% in cases and 2.7% in controls. Case-control association analysis after adjusting for study, age, family history of breast cancer, and race/ethnicity showed that BRCA1(OR=7.45; 95%CI:5.24-10.95) and BRCA2(OR=5.31; 95%CI:4.15-6.88) were associated with high risks of breast cancer in the general population. However, PALB2mutations were only associated with moderate risks (OR=3.63; 95%CI:2.57-5.26). ATMmutations conferred attenuated risks (OR=1.83; 95%CI:1.47-2.28) relative to studies of high-risk families or young onset breast cancers. NBNmutations were not associated with increased breast cancer risk. Mutations in BARD1, RAD51C, RAD51Dand XRCC2were specifically significantly associated with moderate risks of ER-negative breast cancer and TNBC, whereas mutations in ATM, CDH1and CHEK2were specifically significantly associated with ER-positive disease. On the basis of these findings age-related absolute breast cancer risks for commonly mutated genes were estimated. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in enriched populations including high-risk families and young onset, bilateral, or multiple primary cases. We anticipate that the results from this study will inform cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J Couch, Chunling Hu, Steven N Hart, Rohan Gnanaolivu, Kun Y Lee, Jie Na, Chi Gao, Nicholas J Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Christine B Ambrosone, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia M Gaudet, Christopher Haiman, Esther M John, Susan Neuhausen, Janet E Olson, Tuya Pal, Julie R Palmer, Dale P Sandler, Jack A Taylor, Amy Trentham-Dietz, Celine M Vachon, Clarice Weinberg, Song Yao, Jeffrey N Weitzel, David E Goldgar, Susan M Domchek, Katherine L Nathanson, Peter Kraft, Eric C Polley. Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study [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 PD3-01.

Abstract Purpose: To determine the sensitivity of germline hereditary cancer genetic testing recommendations for detection of pathogenic mutations in breast cancer predisposition genes in an unselected cohort of breast cancer patients. Patients and Methods: The study population included patients enrolled in a prospective breast cancer registry after being seen at Mayo Clinic for newly diagnosed breast cancer between 2004 and 2016. All patients were subjected to germline mutation testing for 12 known breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D and TP53). Results from testing of all breast cancer patients according to American Society of Breast Surgeons (ASBrS) genetic testing recommendations and patients meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing, based on age at diagnosis and personal and family history of cancer, were compared. Results: Among the 4516 patients in the cohort, the median age at diagnosis of breast cancer was 57 years, 80.5% had estrogen receptor positive tumors, and 43% had a family history of breast cancer. All patients in the cohort met ASBrS criteria for hereditary cancergenetic testing, 2050 (45.4%) met NCCN criteria, 1892 (41.9%) did not meet NCCN criteria, and 574 (12.7%) patients could not be fully evaluated for NCCN testing criteria due to missing data. The frequencies of pathogenic variants in the cohort are shown in Table 1. Patients meeting NCCN criteria were more likely to carry a pathogenic variant compared to those who did not (9.8% vs. 3.8%, p&lt;0.001, Table 1). However, 72 (26.5%) out of the 272 patients with mutations in 12 breast cancer predisposition genes and 15 (12.4%) out of 121 with mutations in BRCA1/2 were overlooked when NCCN selection criteria alone were applied. When testing was expanded to include all patients with breast cancer diagnosed at age ≤65 and/or meeting NCCN testing criteria, only 20 (7.4%) out of 272 mutation carriers in 12 breast cancer genes and 2 (1.6%) out of 121 BRCA1/2 mutation carriers were overlooked. However, this increased the number tested to detect one mutation carrier on average from 17 to 25 for BRCA1/2 and from 9 to 12 for the 12 breast cancer predisposition genes. In total, this age cutoff led to an increase in the number of patients tested by 28% while the number of patients in the cohort that need not undergo germline genetic testing was 20%. Conclusions: Although NCCN criteria for BRCA1/2 germline genetic testing detect the majority of predisposition gene mutation carriers, a significant number of carriers are missed in an unselected cohort of breast cancer patients using these criteria. Expanding the current NCCN criteria to include all women with breast cancer diagnosed ≤ 65 years of age, will substantially improve the sensitivity of mutation testing, without the need for evaluation of all breast cancer patients. Table 1: Comparison of frequency of germline mutations between patients who met and did not meet NCCN guidelines for germline genetic testing#Total, Meets ASBrS guidelines N=3942Meets NCCN guidelines, N=2050Did not meet NCCN guidelines, N=1892P-value€ NCCN vs non-NCCNPercent mutation carriers missed by NCCN criteria* BRCA1/2121 (3.1%)106 (5.2%)15 (0.8%)&lt;0.00112.4%6 High risk genes$150 (3.8%)120 (5.8%)30 (1.6%)&lt;0.00120.0%12 Breast cancer genes:272 (6.9%)200 (9.8%)72 (3.8%)&lt;0.00126.5%ATM45 (1.1%)32 (1.56%)13 (0.69%)28.9%BARD16 (0.2%)5 (0.24%)1 (0.05%)16.7%BRCA158 (1.5%)53 (2.59%)5 (0.26%)8.6%BRCA263 (1.6%)53 (2.59%)10 (0.53%)15.9%CDH16 (0.2%)3 (0.15%)3 (0.16%)50.0%CHEK267 (1.7%)41 (2.00%)26 (1.36%)38.8%NF10 (0.0%)0 (0.00%)0 (0.00%)0.0%PALB216 (0.4%)7 (0.34%)9 (0.48%)56.3%PTEN1 (0.0%)1 (0.05%)0 (0.00%)0.0%RAD51C6 (0.2%)6 (0.29%)0 (0.00%)0.0%RAD51D4 (0.1%)2 (0.10%)2 (0.11%)50.0%TP537 (0.2%)3 (0.15%)4 (0.21%)57.1%#: Patients who did not meet NCCN criteria excluded from analysis$: BRCA1, BRCA2, CDH1, PALB2, PTEN and TP53;€: Fisher exact test comparing frequency of germline mutations between those who met NCCN guidelines and those who did not;*: Denominators for percentages are the total mutation carriers in respective categories. Citation Format: Siddhartha Yadav, Chunling Hu, Steven N. Hart, Nicholas Boddicker, Eric C. Polley, Jie Na, Rohan Gnanaolivu, Kun Y. Lee, Janet E. Olson, Kathryn J. Ruddy, Fergus J. Couch. Comparison of recommendations for germline genetic testing in an unselected cohort of patients with 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 P6-08-01.

Abstract 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 &gt;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.

Abstract Background Using synthetic antibiotic‐eluting envelope (ABE) is an effective intervention for prevention of cardiovascular implantable electronic device (CIED) infection. The biologic extracellular‐matrix envelope (ECME), may offer potential advantages over the synthetic ABE. To further minimize the risk of infection, the ECME can be hydrated in gentamicin prior to CIED implantation. We aimed to evaluate the efficacy and pharmacokinetics (PK) of gentamicin containing ECME in an animal model. Methods For all experiments, the ECME was hydrated in gentamicin (40 mg/Ml) (treatment) for 2 min. In vitro antimicrobial efficacy against six different bacterial species was assessed. In vivo experiments were conducted using a rabbit model of CIED pocket infection. Serum and ECM gentamicin concentrations were measured. Five different organisms were inoculated into the device pocket of control (ECME hydrated in 0.9% saline) and treatment groups. Macroscopic appearance and colony forming units from CIED, ECME, and tissue were determined. Results No bacteria were recovered from any culture after 12 h of exposure to the gentamicin containing ECME. Serum gentamicin levels dropped below the limit of quantification at 15 h after implant. Gentamicin concentration in the ECME remained relatively stable for up to 7 days. Signs of clinical infection were observed in the control but not in the treatment group. In the presence of gentamicin, statistically significant reduction was demonstrated across all tested bacterial species. Conclusions In this preclinical animal infection model, gentamicin containing ECME was highly effective in reducing bacterial burden in the implant pocket, while systemic exposure after implantation remained low.