bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extended follow-up in the COGENT study: A randomized study of in-person versus telephone disclosure of cancer genetic test results.
Authors: Bradbury Angela R. , Patrick-Miller Linda J. , Egleston Brian L. , Domchek Susan M. , Olopade Olufunmilayo I. , Hall Michael J. , Daly Mary Beryl , Fleisher Linda , Grana Generosa , Ganschow Pamela , Fetzer Dominique ,   The COGENT Study Research Team
Published: September 2018

1504 Background: Alternative delivery models are needed in the era of Precision Medicine given a shortage of genetic providers and increasing utilization of genetic testing. Telephone disclosure (TD) of genetic test results, including multi-gene panel testing, is non-inferior to usual care in-person disclosure (IPD) for short-term distress but failed non-inferiority for knowledge. Longitudinal data including health behaviors are needed. Methods: 970 patients undergoing clinical genetic testing at 5 centers were randomly assigned to usual care IPD (n = 497) or TD (n = 473) of results in the COGENT Study (NCT01736345). Participants completed surveys after pre-test counseling, post-disclosure and at 6 and 12 months. We used non-inferiority tests for primary analyses and T-tests and logistic regressions for secondary analyses. Results: TD was not worse than IPD for anxiety both post-disclosure and at 6 months, but did not reach the non-inferiority threshold for knowledge at either time point. In secondary analyses there were no significant differences in anxiety, depression, or cancer worry between arms, but there was less knowledge gain at 6 (-0.41 v. +0.11 in IPD, p = 0.05) and 12 months (-0.34 v. +0.31 in IPD, p = 0.05) in the TD arm. In the TD arm, 195 (50%) returned for clinical follow-up with a physician to discuss medical management. Not returning for follow-up varied by site and was associated with a negative result, being male and non-white. Knowledge gain at 6 months was lower for those who did not return for follow-up (-0.77) compared to those who returned (-0.17, p = 0.08). There were no significant differences by arm at 6 and 12 months in performance of mammogram, breast MRI, colonoscopy or prophylactic surgeries. Conclusions: Distress is not unacceptably worse with TD, but knowledge failed the test for non-inferiority. Longitudinal knowledge declined more for those who did not return for medical follow-up, but uptake of screening and risk reducing behaviors did not differ by arm. Telephone disclosure of genetic test results, even MGPT, may be a reasonable alternative to in-person disclosure for patients who agree to return to meet with a provider for medical management recommendations. Clinical trial information: NCT01736345.
Survival outcomes of screening with breast MRI in high-risk women.
Authors: Bae Min Sun , Sung Janice S. , Han Wonshik , Bernard-Davila Blanca , Bara Filipe R. , Sutton Elizabeth J. , Comstock Christopher , Jochelson Maxine S. , Morris Elizabeth Ann 
Published: September 2018

1508 Background: Mammography is the only imaging modality proven to reduce mortality from breast cancer. Over the past decade, magnetic resonance imaging (MRI) screening of women with increased risk of breast cancer ( > 20% cumulative life time risk) has been recommended. However, there is little evidence that supplemental screening with MRI improves survival. The purpose of this study was to compare survival outcomes of combined screening with MRI and mammography to screening mammography alone in women at increased risk for breast cancer. Methods: A total of 3,002 women at increased risk underwent at least two screening rounds between 2001 and 2005, with at least 5 years of follow-up. 1,534 women had combined screening (MRI and mammography), and 1,468 had screening mammography alone. Cancer detection yield and survival were determined in the two groups. Results: 60 women were diagnosed with breast cancer, 38 patients in the combined screening group and 22 in the mammography-only group. Cancer yield was 24.8 per 1000 (95% CI, 17.6-33.8) combined screening and 15.0 per 1000 (95% CI, 9.4-22.6) mammography-only. No interval cancers occurred in women undergoing combined screening, while 9 interval cancers were found in women undergoing only mammography screening. During a median follow-up of 10.8 years (range, 0.7-15.2), a total of 11 recurrences and 5 deaths (4 breast cancer cause and 1 unknown cause) were found. Of the 11 recurrences, 6 were in the combined screening group and 5 were in the mammography-only group. All deaths were in the mammography-only group. The Kaplan-Meier estimate for disease-free survival showed no statistically significant difference between the two groups ( P = .325). However, patients in the combined screening group had a significantly better overall survival compared with patients in the mammography-only group ( P = .002). Conclusions: Combined screening with MRI and mammography in women with increased risk of breast cancer resulted in not only a higher cancer detection yield but also better overall survival.
Knowledge and understanding of genetic test results in men undergoing multigene testing for inherited prostate cancer.
Authors: Giri Veda N. , Hegarty Sarah , Obeid Elias , Hyatt Colette , Fang Carolyn Y , Leader Amy 
Published: September 2018

1516 Background: Genetic counseling (GC) for prostate cancer (PCA) risk is an emerging field, with limited insights regarding needs of males considering genetic testing (GT). Genetic Evaluation of Men is a prospective multigene testing study to identify inherited mutations linked to PCA, with testing following GC. We surveyed men pre-GT and post-GT on knowledge of cancer risk and genetics (KCRG) and understanding of personal GT results to identify GC needs. Methods: Eligibility for males affected or high-risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Demographic, clinical, and FH data were obtained from participants and medical records. Pre-GT survey included questions on KCRG (15 items) and health literacy/numeracy (6 items). Post-GT survey additionally included understanding of GT results (9 items). Personal and FH were categorized into three hereditary cancer syndromes (HCS) linked to PCA. Factors associated with baseline KCRG were assessed by univariable models followed by multivariable linear regression. McNemar’s test was used to assess concordance of understanding GT results vs. actual results. Results: Among 109 men (mean age 63 years, 81% White, 59% PCA diagnosis) who completed pre- and post-surveys, factors associated with higher pre-test KCRG included meeting HCS criteria (p = 0.006) and higher numeracy (p = 0.025). On multivariable analysis, HCS remained significantly predictive of higher KCRG (p = 0.040). However, of 101 men who responded definitively regarding understanding of personal GT results, 13 responded incorrectly on mutation status indicating significant disagreement with actual results (McNemar’s p < 0.001). Of these 13 men, 12 had > = 1 variant of uncertain significance (VUS). Additionally, 6 men were unsure whether they carried a mutation when their GT results found VUS but no mutations. Conclusions: This is the first report of knowledge and understanding of genetics and cancer risk in the context of multigene testing for PCA. While personal/FH of HCS was associated with higher KCRG, understanding of personal GT results was lacking, and warrants tailored GC strategies for multigene testing for inherited PCA.
The Angiosarcoma Project: Generating the genomic landscape of a rare cancer through a direct-to-patient initiative.
Authors: Painter Corrie , Dunphy Michael , Anastasio Elana , McGillicuddy Mary , Anderka Kristin , Larkin Katie , Lennon Niall , Chen Yen-Lin , Lander Eric , Golub Todd , Wagle Nikhil 
Published: September 2018

1519 Background: Angiosarcoma (AS) is a rare soft tissue sarcoma, with an incidence of 300/yr and a 5-year DSS of 30%. The low incidence has impeded large-scale research efforts that may lead to improved clinical outcomes. To address this, we launched a nationwide study, which seeks to empower patients (pts) to accelerate research by sharing their samples and clinical information remotely. Methods: With pts and advocacy groups we developed a website to allow AS pts to participate across the US. Pts are mailed a saliva and blood draw kit for germline and cell free (cf) DNA analysis. We then obtain medical records and stored tumor samples. Whole exome sequencing will be performed on tumor, cfDNA and saliva samples. Transcriptome analysis will be performed on tumor samples. A clinically annotated genomic database will be generated and shared widely to identify genomic drivers and mechanisms of response and resistance to therapies. Study updates will be shared with pts regularly. Results: We conducted a 3-week pilot study to test the feasibility of enrolling geographically dispersed AS pts through a direct-to-patient (DTP) approach. Through social media, we identified 100+ pts willing to participate, 90 within the first day of outreach. We enrolled 15 pts from 10 states to test our ability to remotely obtain pt reported data, online consent, and samples. The average age of pts is 48, ranging 23-71 yrs. Primary locations of AS are breast 6 pts (40%), cardiac 4 pts (27%), scalp 2 pts (13%), liver 1 pt (6%), bladder 1 pt (6%), forehead 1 pt (6%). 9 pts (60%) reported being disease free, 4 pts (27%) reported having AS spread to lung, lymph, bone, and hip. Requests for medical records and tissue samples are underway, and initial saliva samples have been received. We are now opening this study to all AS pts in the USA. Conclusions: A DTP approach enabled rapid identification of an initial cohort of AS pts willing to share tumors, saliva, blood and medical records. We were able to obtain detailed clinical experiences and samples to perform genomic analysis. This study serves as proof of principle that DTP genomics efforts can democratize cancer research for exceedingly rare cancers, which to date have been disproportionately understudied.
Baseline screening and psychosocial results from the UK SIGNIFY study: A whole-body MRI screening study in TP53 mutation carriers and matched controls.
Authors: Eeles Ros A. , Bancroft Elizabeth , Saya Sibel , Killick Emma , Whitehouse Richard W , Koh Dow-Mu , Sohaib Syed A , Walker Leslie ,   The SIGNIFY Study Steering Committee
Published: September 2018

1520 Background: In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. Some centres employ family specific screening with most centres having an “open-door” policy. Recent evidence suggests there may be a survival benefit with more intensive screening, including whole-body MRI. There are no published data on the psychological impact of such screening programmes. Methods: This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers aged over 18 years. Clinical and psychological endpoints were assessed. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. A series of questionnaires is used to assess the psychological impact of screening. Results: 44 TP53 mutation carriers and 44 population controls were recruited. In TP53 mutation carriers, six of 44 (13.6%, 95% CI: 5.2%-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1%, 95% CI: 20.5%-49.9%) and 7 controls (15.9%, 95% CI: 6.6%-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). To date, there is no evidence of clinically significant adverse psychosocial effects. Conclusions: The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. Clinical trial information: NCT01737255.
Prevalence of incidental germline pathogenic (PV) and likely pathogenic (LPV) variants in hereditary cancer-related genes identified in matched tumor/normal sequencing of advanced solid tumors.
Authors: Ileana Dumbrava Ecaterina Elena , Brusco Lauren , Daniels Molly S , Wathoo Chetna , Shaw Kenna Rael , Lu Karen H. , Zheng Xiaofeng , Strong Louise C. , Litton Jennifer Keating , Arun Banu , Eterovic Agda Karina , Routbort Mark , Piha-Paul Sarina Anne , Subbiah Vivek , Hong David S. , Kopetz Scott , Mendelsohn John , Mills Gordon B. , Chen Ken , Meric-Bernstam Funda 
Published: September 2018

1524 Background: Next-generation sequencing (NGS) for tumor molecular profiling can reveal germline incidental mutations in hereditary cancer-related genes. The American College of Medical Genetics and Genomics (ACMG) has recommended that laboratories performing clinical sequencing seek and report PV and LPV in 56 genes. We assessed the prevalence of incidental germline LPV and PV in other cancer-related genes among patients undergoing hybrid capture sequencing of 201 cancer-related genes. Methods: Matched tumor and germline DNA NGS of a targeted panel of 201 genes was performed in 1000 patients (pts) with advanced or metastatic solid tumors enrolled in a molecular testing protocol (NCT01772771) in a research laboratory. We previously reported germline alterations in the putative most actionable genes as designated by ACMG (PMID: 26787237). We assessed the germline LPV and PV in 54 additional cancer-related genes. Results: Among the 1000 patients who underwent tumor and normal DNA sequencing, 37 patients (3.7%) were found to have a germline PV or LPV in the following genes: ATM (4); BAP1 (1); CDH1 (1); CDKN2A (1); CHEK1 (2); CHEK2 (10); EGFR (1); ERCC3 (4); ERCC5 (1); HNF1B (1); HRAS (1); MLL3 (1); NF1 (3); PKHD1 (4); PTCH1 (1) and SMARCA4 (1). Eight pts (22%) had previous genetic counseling and testing for various reasons, but only 3 pts (8%) had previously identified alterations (all with NF1 mutations). After discussion in our return of germline results board, it was decided to return the findings in established hereditary cancer predisposition genes with high penetrance: BAP1 (p.Y401X), CDH1 (p.C688X), CDKN2A (p.G101W), EGFR (p.T790M) and SMARCA4 (p.S332FfsX55) after validation in a CLIA laboratory. Conclusions: Return of the previously unrecognized germline LPV or PV in patients with advanced or metastatic cancers who undergo somatic profiling is of great interest. The exact genes for which the germline results should be returned is controversial. Broader genomic testing is likely to identify additional incidental germline alterations with potential clinical utility to patients and their relatives.
NGS-based multi-gene panel analysis in BRCA1/2-negative breast and ovarian cancer families.
Authors: Pohl Esther , Hauke Jan , Horvath Judit , Dworniczak Bernd , Gehrig Andrea , Niederacher Dieter , Arnold Norbert , Sutter Christian , Smogavec Mateja , Just Walter , Weber Bernhard H.F. , Hentschel Julia , Faust Ulrike , Hackmann Karl , Schmidt Gunnar , Gross Eva , Ramser Juliane , Rhiem Kerstin , Hahnen Eric , Schmutzler Rita K. 
Published: September 2018

1526 Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic mutations in the BRCA1 or BRCA2 genes. The population-specific mutation prevalence of non- BRCA1/2 genes associated with familial BC and/or OC is largely unknown and was determined in a large German cohort. Methods: Here, we present next-generation sequencing (NGS) data established from TruRisk (GC-HBOC-designed) or TruSight cancer gene panels. A cohort of 6,507 BRCA1/2-negative index cases fulfilling the inclusion criteria of the GC-HBOC for germline testing was analyzed. Illumina sequencing platforms were used and data analysis was carried out at each individual center using different analysis pipelines. Analysis of copy number variations (CNV) was not included in the present data evaluation. Results: By focusing on 8 confirmed BC/OC risk genes ( ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53), the 6,507 cancer patients revealed 165 different deleterious variants in 378 unrelated mutation carriers (5.8%). We found a high prevalence of CHEK2 (n = 150, 2.3%), ATM (n = 89, 1.4% ), and PALB2 (n = 72, 1.1%) mutations while RAD51C (n = 21, 0.3%), TP53 (n = 16, 0.2%), NBN (n = 15, 0.2%), CDH1 (n = 10, 0.2%), and RAD51D (n = 5, 0.1%) were less frequently mutated. Conclusions: The high frequency of pathologic mutations in the genes ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53, together accounting for almost 6% of familial BC/OC risk, highlights the importance of these genes to be included in BC/OC routine diagnostics. The relevance of these mutations in a clinical setting for early detection of breast and ovarian cancer needs to be established.
Clinical implementation of whole genome multi-omics analyses for patients with refractory cancers.
Authors: Radovich Milan , Kiel Patrick , Ratcliff Katie , Geiser Andrew , Jones Shannon , Hunter Cynthia , Finder Rebecca , Moller Teresa , Spradlin Allison , Koselke Elizabeth , Jones Thomas , Ibrahim Sulfikar , Schneider Bryan Paul 
Published: September 2018

1531 Background: Relative lack of prior success of genomic technology has been a function of suboptimal target detection and poor timely implementation. We set out to improve patient access to targeted therapy through use of whole genome sequencing (WGS) to optimize targets and operational implementation to identify clinical trials and secure off-label drugs. Methods: We performed a retrospective analysis of our first 100 patients (Feb-Nov 2016) with metastatic disease whose tumors and matched blood were analyzed using whole genome (WGS) and transcriptome sequencing, as well as targeted proteomic analysis in a CLIA setting (NantOmics). Most common tumor types were Colorectal (20%), Breast (15%), and Ovarian (10%). Patients were seen in dedicated precision genomics clinics with results reviewed by a multi-disciplinary molecular tumor board. A dedicated service line with staff to match patients to clinical trials, medication acquisition, and genetic counseling for germline findings was provided. Results: 85% of patients had a finding either on WGS or proteomic analysis that pointed to an FDA approved drug or clinical trial. Common findings included: mutations in the PI3K pathway (15%), BRCA1&2/ATM (15%), and cell cycle genes (11%). Other markers of note include: HER2, TMB/MSI for immune checkpoint therapy, IDH1/2, and MET. WGS also enabled identification of rare actionable findings, particularly translocations, and viral integration for trials requiring HPV-positivity. Cancer predisposition germline findings were observed in 3 patients. Of the 85 patients with actionable findings, 22 went on to be treated with a genomically-directed agent, 13 did not follow recommendations or were sent to hospice, 4 were lost to follow-up, and 46 still remain on their therapy prescribed prior to sequencing. Conclusions: A higher proportion of patients in our program went on to be treated with a genomically-directed agent than previously reported in the literature secondary to comprehensive whole genome multi-omics profiling and a clinical service line dedicated to medication acquisition and matching to clinical trials.
Underutilization of multigene panels among Ashkenazi Jewish patients.
Authors: Fields Jessica , Nasioudis Dimitrios , Zhou Zhen Ni , Carlson Ann , Frey Melissa Kristen , Holcomb Kevin , Chapman-Davis Eloise 
Published: September 2018

1533 Background: Approximately one in forty Ashkenazi Jewish (AJ) individuals carry a BRCA1/2 mutation and genetic screening in this population has largely focused on these two genes. With the recent rapid uptake of multigene panel testing for cancer genetic assessment, we sought to explore multigene panels in our cohort which is comprised of AJ and non-AJ patients. Methods: The results of all patients with known ancestry who underwent genetic testing and counseling at the hereditary breast and ovarian cancer center at a single institution between 7/1/2013-12/31/2016 were reviewed. Results: One thousand six hundred and fifty patients with known ancestry underwent genetic testing over the study period, including 681 AJ patients. The median age was 49 (range 20-86). AJ patients were more likely to undergo targeted testing than non-AJ patients (74% vs. 61 %, P<0.001). The use of multigene panels in AJ patients increased over time (2013 – 3.2%, 2014 – 18.7%, 2015 – 27.4%, 2016 – 48.4%, P<0.001). Mutations were more common in AJ patients (75, 11% vs. 66, 7%, P=0.003). Variants of uncertain significance (VUS) were less common in AJ patients (40, 6% vs. 124, 13%, P<0.001), even when excluding patients with single gene testing (32, 19% vs. 98, 27%, P=0.05). Among all patients, mutations in BRCA1/2 were most common (75%). The majority (69%) of non- BRCA1/2 mutations were identified on multigene panels. Rates of mutations in non- BRCA1/2 genes were the same among AJ and non-AJ patients (16, 21% vs. 20, 30%, P=0.3, Table 1). Conclusions: AJ patients have equivalent rates of non- BRCA1/2 mutations and on multigene panels have lower rates of VUS compared to non-AJ patients. However, the majority of AJ patients underwent targeted gene testing. These findings suggest consideration of a change in paradigm for genetic assessment of AJ patients with a focus on BRCA and non- BRCAassociated cancer genes through multigene panel testing. [Table: see text]