bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of patients with multiple primary tumors.
Authors: Cadoo Karen Anne , Mukherjee Semanti , Khurram Aliya , Kemel Yelena , Tkachuk Kaitlyn , Liu Ying L , Carlo Maria Isabel , Walsh Michael Francis , Latham Alicia , Dubard-Gault Marianne E , Mandelker Diana , Wang Yuhan , Salo-Mullen Erin E. , Berger Michael F. , Ravichandran Vignesh , Stadler Zsofia Kinga , Joseph Vijai , Robson Mark E. , Seshan Venkatraman E. , Offit Kenneth 
Published: May 2020

1502 Background: 17% of patients (pts) with a cancer diagnosis in the U.S. have a prior malignancy. We sought to characterize pts with multiple (≥2) primary cancers (MPC) & identify potential drivers of cancer risk to guide management. Methods: Pts prospectively consented (1/2013-2/2019) to tumor-normal sequencing via custom targeted NGS panel. A subset consented to testing of >76 germline cancer predisposition genes. IARC 2004 rules for defining MPC were applied.Age adjusted gender specific standardized incidence ratios (SIR) for cancer event combinations occurring in at least 5pt were calculated using R statistical package. Results: Of 24417 pts sequenced, 4341 had MPC (18%). (Table) 3465 (80%) had 2, 4% had >4 cancers. Cancer pairs where SIR of 2nd cancer was higher than expected included: colon-colon, prostate-pancreas, bladder-prostate in men & lung-lung, breast-pancreas, thyroid-pancreas in women. 1580 (36%) pts had germline testing; 324 (21%) had 361 pathogenic/likely pathogenic (P/LP) variants (vts). Of these, 157 (48%), 66(20%), pts had high, moderate penetrance vts. The remainder had low penetrance, recessive or vts of uncertain utility. Of pts with high penetrance vt, 132 (84%) had at least one tumor type concordant with germline findings. Conclusions: 18% of pts in this cohort had MPC. There was a significant excess over expected incidence in some cancer combinations. Of pts with germline testing, 21% had a P/LP vt, with most (69%) being high or moderate penetrance. Assessment for loss of heterozygosity in tumor & germline sequencing of the full MPC cohort is ongoing. [Table: see text]
BARCODE 1: A pilot study investigating the use of genetic profiling to identify men in the general population with the highest risk of prostate cancer to invite for targeted screening.
Authors: Eeles Ros A. , ni Raghallaigh Holly ,   The BARCODE1 Study Group
Published: May 2020

1505 Background: Genetic profiling could be used to target population screening for prostate cancer (PrCa). Approximately 170 single nucleotide polymorphisms (SNPs) have been identified that associate with PrCa development. Although these confer a low to moderate risk of PrCa, the risk is cumulative with increasing number of risk alleles. BARCODE1 is the first study to prospectively investigate the use of a genetic profile in PrCa screening in the UK general population. Methods: A custom Eurek Genomics (EG) SNP assay was developed. Healthy males aged 55-69 were invited to participate via their General Practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using the EG assay and a polygenic risk score (PRS) was calculated for each participant. The PRS was calculated using the sum of the weighted alleles for 130 risk loci. Men in the top 10% of the genetic risk profile were invited for prostate MRI and biopsy at the Royal Marsden Hospital (RMH) in London. Results: Invitation letters were sent to 1434 men; overall uptake was 26% (range 13%-47%). 87% of responders were eligible for study entry. DNA was extracted from 303 samples and genotyped. Data were available for 285 men following QC. Mean PRS was 10.33 with a standard deviation of 0.64; twenty-five participants with a PRS above the 90th centile were identified for screening with MRI and prostate biopsy. Of these men (after exclusions due to medical comorbidity/invitations declined) 9 out of 20 had an abnormal MRI (45%) and 18 men underwent biopsy with 7 diagnoses of PrCa (38.8%). All cancers were low-risk with a mean PSA of 1.8 and were managed with Active Surveillance (AS). There were two adverse events following biopsy, both simple lower urinary tract infections managed with oral antibiotics. Average duration of follow-up is 4.5 months (range 1-11). Conclusions: Successful completion of recruitment has shown this community study to be feasible, with an average uptake of 26%. Approximately 70 GP sites have been identified to allow a transition to the full BARCODE-1 study which will recruit 5000 men. The use of genetic profiles to guide PrCa screening is attractive; it requires a one-off test utilising germline DNA which can be assessed for risk loci which are constant, unlike PSA which fluctuates. The results of the BARCODE1 study will be important in defining the role of genetic profiling in targeted PrCa population screening.
Complete human papillomavirus vaccination coverage over a 13-year period in a large population of privately insured U.S. patients.
Authors: Arriaga Yull Edwin , Rosario Bedda L , Scheufele Elisabeth , Rajmane Amol , South Brett , Kefayati Sarah , George Judy , Bullock Timothy , Jackson Gretchen Purcell , Rhee Kyu 
Published: May 2020

1511 Background: In the US, Human Papillomavirus (HPV) vaccination coverage is low, particularly in adolescents aged 13-15 years with respect to the Healthy People 2020 goal of 80%. There has been variability in the definition of measuring vaccination coverage in published studies. We examined complete HPV vaccination coverage in a population of privately insured individuals in the US. Methods: This retrospective study used IBM MarketScan Commercial Database, years 2006 to 2018. Inclusion criteria were ages 9 to 45 years and continuous enrollment from age 9 years or from 2006. Complete HPV vaccination coverage was defined as receipt of 2 doses (age 9-15 years) or 3 doses (age 16-45 years) within 12 months and stratified by year, demographics, and US region. Mean vaccination costs per dose were summarized by vaccine brand and health plan type. Results: The table summarizes complete HPV vaccination coverage by selected age groups for 2006 (n=12,221,938), 2010 (n=4,692,633), 2014 (n=2,808,132), and 2018 (n=1,662,148). From 2017 to 2018, the percentage of members who received HPV vaccine increased; for females ages 13-15 by 1% and 16-17 by 5% while for males ages 13-15 by 6% and 16-17 by 15%. In 2018, by region, the highest coverage was in females aged 18-26 at 53% and males aged 16-17 at 43% in the Northeast, and mean cost for each brand was $120 (-6% from 2017), $165 (-3%) and $220 (+5%) for Cervarix (n=151), Gardasil (n=8,201) and Gardasil 9 (n=139,356), respectively. The rate of utilization of Gardasil 9 increased from 33% (2015) to 94% (2018) of all vaccines. The lowest mean HPV vaccine cost by health plan type and brand was with Point-of-Service (POS) and Cervarix at $106, and the highest was with POS with Capitation and Gardasil 9 at $243. Conclusions: In a commercially insured US population, complete HPV vaccination coverage was lower than the Healthy People 2020 goal, but increased over time. Coverage varied according to health plan type and by region. In 2018, Gardasil 9 had the highest mean cost but was the most utilized vaccine, which may be related to broader coverage of HPV types. This study was limited by the transient nature of member enrollment and complexity of measuring complete vaccination coverage. These results should inform policy makers and practicing clinicians about the gap in vaccination coverage. [Table: see text]
The prevalence of germline mutations among patients with solid tumors with genomic alterations identified on tumor testing: Results from a tertiary care academic center molecular tumor board.
Authors: Watson Catherine , Tait Sarah , Soo Lindsay , Plichta Jennifer Kay , Zhang Tian , Castellar Edgardo , Armstrong Andrew J. , Previs Rebecca A. , Strickler John H. , Green Michelle , Datto Michael , Marcom Paul Kelly , Menendez Carolyn S. 
Published: May 2020

1516 Background: The proportion of germline versus somatic mutations identified on genomic tumor testing of solid malignancies is not well characterized. We compared somatic and germline testing results in patients with breast, ovarian, pancreatic or prostate cancer with a genomic alteration identified on tumor testing. Methods: Retrospective chart review was performed using a tertiary care academic center’s database of somatic tumor testing results obtained via FoundationOne and Guardant testing. Patients with breast, ovarian, pancreatic or prostate cancer who had a genomic alteration identified on tumor testing, including pathogenic and VUS variants, in BRCA1or BRCA2, CHEK2, ATM, BRIP1, RAD51C, RAD51D, PALB2and CDH1and who had also received germline testing were identified. Analysis was performed to assess prevalence of germline results. The association between mutant allele fraction (MAF) and germline mutation status was also assessed. Results: Results: 124 patients with breast, ovarian, pancreatic or prostate cancer were identified who had a genomic alteration of interest also tested for via germline testing. 54 (32.5%) of tumor mutations were also identified on germline testing. Proportion of genomic results that were germline was wide, ranging from 0-85.7% depending on the gene and variant classification (Table). Germline mutations were present in 36.4% of breast, 25% of ovarian, 53.3% of pancreatic, and 20.9% of prostate cancer patients who had a tumor alteration present. Alterations that were found to be concordant in both somatic and germline testing had an average MAF of 0.54, and alterations identified on somatic testing only had an average MAF of 0.30. Conclusions: Our findings suggest that approximately one-third of genomic alterations on tumor testing will be of germline origin. However, concordance rates may be gene and variant dependent. Higher MAF may be associated with germline alteration status, but further evaluation is needed. Thus, while information provided by genomic tumor testing may be suggestive of a correlating germline mutation, no single alteration type or MAF value is reliably predictive. [Table: see text]
Prevalence and clinical characterization of MMR-D/MSI extra-colonic cancers among germline PMS2 mutation carriers.
Authors: Latham Alicia , Salo-Mullen Erin E. , Catchings Amanda , Ranganathan Megha , Fiala Elise , Kemel Yelena , Konner Jason A. , Soslow Robert A. , Momeni-Boroujeni Amir , Shia Jinru , Mandelker Diana , Birsoy Ozge , Hechtman Jaclyn Frances , Berger Michael F. , Carlo Maria Isabel , Walsh Michael Francis , Robson Mark E. , Offit Kenneth , Stadler Zsofia Kinga , Cadoo Karen Anne 
Published: May 2020

1527 Background: PMS2-associated Lynch syndrome (LS) may have a more modest phenotype than that associated with other mismatch repair (MMR) genes ( MLH1, MSH2, MSH6, EPCAM). Recent studies suggest limited extra-colonic cancers, and modified risk-reducing measures can be provided. Understanding the spectrum of risk is of critical importance as some LS-associated cancers do not have effective screening, requiring risk-reducing surgery (endometrial, ovarian). As MMR-deficiency (MMRD)/ microsatellite instability (MSI) is associated with LS pan-cancer, we sought to characterize PMS2-associated malignancies according to MMR/MSI status. Methods: Review of cancer patients (pts) consented to an IRB-approved protocol of tumor/germline next-generation sequencing (NGS) identified 43 germline heterozygous PMS2 mutation carriers. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via immunohistochemical staining (IHC). Clinical variables were correlated with MMR/MSI status, comparing via Chi-square or standard T-test. Results: There were > 10 tumor types; 69.8% (30/43) were extra-colonic cancers (endometrial (n = 4), ovarian (n = 6), small bowel (n = 3), urothelial (n = 2), pancreas (n = 3), prostate (n = 3), breast (n = 3), brain (n = 3), biliary (n = 1), spindle cell sarcoma (n = 1), and hepatoblastoma (n = 1)). 46.5% (20/43) of tumors were MMRD/MSI. 61.5% (8/13) of colorectal cancers (CRC) were MMRD/MSI, compared to 40% (12/30) of extra-colonic tumors. All endometrial and small bowel cancers were MMRD/MSI. Of 6 ovarian cancers, 3 were clear-cell, 1 endometrioid, and 2 high-grade serous (HGS). The only MMRD/MSI ovary tumor was HGS. 73.9% (17/23) of pts with MMRP/MSS tumors had recurrent/metastatic disease vs 30% (6/20) of pts with MMRD/MSI tumors ( p= 0.004). Mean age at diagnosis did not differ significantly between MMRP/MSS and MMRD/MSI groups (49 vs. 57, respectively, p= 0.146). 11.6% (5/43) of pts had a prior cancer, with only one patient having prior CRC. Pts with extra-colonic tumors were less likely to meet clinical pt and family history LS testing criteria than those with CRC (63.3% (19/30) vs. 7.7% (1/13); p< 0.001). Conclusions: While PMS2-related LS may have a more modest clinical phenotype, in this single-institution study, 60% (12/20) of patients with MMRD/MSI tumors presented with extra-colonic cancers. We caution counseling pts with PMS2-associated LS about reduced extra-colonic risk until more complete information about penetrance, spectrum, and age distribution of cancer is available.
ATM mutation carriers and family history of pancreatic cancer.
Authors: Klavanian Jeannie , Zakalik Dana , Konde Anish S , Rangarajan Tara 
Published: May 2020

1529 Background: Multigene panel testing (MGT) is commonly utilized in patients with a personal or family history of cancer. One of the more common gene mutations identified is in the ATM gene, associated with a moderately increased risk of breast and other cancers. There are reports of an association with pancreatic cancer, however the exact risks are unclear. The aim of this study is to describe the family history of pancreatic cancer in a cohort of ATM mutation carriers, and to evaluate possible genotype/phenotype correlation. Methods: Patients who underwent MGT, between ‘13 and ‘19, and tested positive for a pathogenic/likely pathogenic ATM mutation were included in this study. Family history, with a focus on pancreatic cancer, and genetic testing results were analyzed. Results: A total of 114 patients were identified to carry an ATM mutation. Twenty-two (19.3%) individuals had a family history of pancreatic cancer in a close relative, and of those, 13 (11.4%) had an affected first degree relative, and 11 (9.6%) had an affected second degree relative. Among the families with pancreatic cancer, 20 close relatives had a personal history of pancreatic cancer, with the youngest diagnosed at age 40, the oldest diagnosed at age 91, and a mean age of diagnosis of 66.5 years. Thirteen unique variants were identified: 4 splice site, 3 missense, 3 frameshift, 1 nonsense, and 1 silent. Two families had the known high-penetrance ATM mutation, c.7271T > C (p.V2424G). Conclusions: This study describes the association of pancreatic cancer in individuals found to carry pathogenic ATM mutations. A significant proportion (19.3%) of patients had a family history of pancreatic cancer in a close relative, diagnosed as young as age 40. The mean age of diagnosis was slightly younger than the average age in the general population (age 70). As pancreatic cancer screening continues to improve, this information will be an important component to help guide cancer risk assessment and future screening recommendations for ATM mutation carriers. Additional larger studies are needed to further characterize pancreatic cancer risks in patients with ATM gene mutations.
Cancer risk management and family communication of genetic test results among women with inherited breast cancer genes.
Authors: Pal Tuya , Weidner Anne , Tezak Ann , Clouse Kate , Cragun Deborah 
Published: May 2020

1532 Background: Identification of inherited breast cancer may guide care, with benefits amplified through family testing. Methods: Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about cancer risk management, family communication of genetic test results, and family testing. Comparisons were made across genes. Results: The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and 61% had a prior breast cancer diagnosis. For women with P/LP variants in BRCA1/2, PALB2, and ATM/CHEK2, bilateral mastectomy rates were 79%, 61%, and 52%, respectively; and risk-reducing oophorectomy rates were 89%, 30%, and 37%, respectively. All women with PALB2 and ATM/CHEK2 P/LP variants with a bilateral mastectomy had a personal or family history of breast cancer; however, only 27% of those with a risk-reducing oophorectomy had a family history of ovarian cancer. Family communication of genetic test results and family testing rates were higher for those with P/LP variants in BRCA1/2 compared to others. Conclusions: Bilateral mastectomy and risk-reducing oophorectomy were relatively common among women with PALB2 and ATM/CHEK2 P/LP variants in our study, suggesting overtreatment through risk-reducing surgery. Furthermore, strategies to improve family communication of genetic test results and family testing are needed to amplify testing benefits.
Genome Wide Association Study (GWAS) of cognitive impairment after blood or marrow transplantation (BMT) for hematologic malignancy.
Authors: Sharafeldin Noha , Singh Purnima , Bosworth Alysia , Ojesina Akinyemi I , Zhang Jianqing , Chen Yanjun , Patel Sunita K. , Wang Xuexia , Francisco Liton , Forman Stephen J. , Wong F. Lennie , Bhatia Smita ,   NeuroCog-COH
Published: May 2020

1536 Background: Cognitive impairment is prevalent in hematologic malignancy patients treated with BMT (autologous: 18.7%; allogeneic: 35.7%; Sharafeldin JCO; 2018). Given the inter-individual variability in risk of cognitive impairment in this population, we investigated the role of genetic susceptibility using a genome-wide single nucleotide polymorphism (SNP) array platform to identify novel genetic associations. Methods: Discovery: Cognitive function was assessed objectively in 239 adult BMT recipients at pre-specified timepoints: pre-BMT and at 6 mo, 1y, 2y, and 3y post-BMT. A global deficit score (GDS - a summary score of 14 standardized neuropsychological tests) was computed for each patient; a higher score indicated greater cognitive impairment. SNPs passing standard quality control filters ( > 1.4M) were used for analysis. Linear mixed effects models used GDS as the outcome, adjusted for age, sex, BMT type, baseline cognitive reserve, and the first four principal components. We used additive, codominant, and genotype models and an adjusted genome-wide significance threshold of 1.25 x 10−8. Replication: An independent cohort of 544 BMT survivors (192 cases with self-endorsed cognitive problems and 352 controls without) was used for replication. Results: Discovery: Median age at BMT was 51.3y; primary diagnoses: 47% leukemia, 32% lymphoma, 21% multiple myeloma; 57% males; 69% non-Hispanic whites: 50% allogeneic BMT, median GDS score = 0.22 (range 0-2). Forty-four SNPs were significantly associated with increased GDS (additive model: 3 SNPs; codominant model: 20 SNPs; genotype model: 21 SNPs). Estimates ranged from increase in GDS score by 0.28 points for each additional copy of risk allele, p = 1.07 x 10−8 to increase in GDS score by 1.82 points for two copies of risk allele, p = 2.3 x 10−11. Replication: Median age at BMT was 44y; primary diagnoses: 32% leukemia, 49% lymphoma, 19% multiple myeloma; 54% males; 80% non-Hispanic whites: 34% allogeneic BMT. Three SNPs were successfully replicated: rs116334183 resides within lncRNA-SEMA6D-2, which facilitates neuronal migration; rs13286152 86kb downstream of TLE-1, which promotes neuronal survival; and rs12486041 0.36Mb downstream from lncRNA-SPTSSB-1, which regulates sphingolipid production in neuronal axons and 0.36Mb upstream from TOMM22P6 linked to neural repair. Conclusions: In this first GWAS of cognitive impairment post-BMT, we identify 3 SNPs with plausible links to genes implicated in neuronal integrity. Functional studies are currently underway.
Germline alterations other than BRCA in triple negative breast cancer (TNBC) patients who underwent neoadjuvant therapy (NAT) on a prospective clinical trial.
Authors: Arun Banu , Zhao Li , Bassett Roland L. , Thompson Alastair Mark , White Jason B , Layman Rachel M. , Gutierrez Barrera Angelica , Valero Vicente , Ueno Naoto T. , Litton Jennifer Keating , Zhang Jianhua , Ravenberg Elizabeth , Candelaria Rosalind P , Rauch Gaiane M , Tripathy Debu , Moulder Stacy L. 
Published: May 2020

1546 Background: Previous studies have related germline BRCA mutations to pathologic complete response (pCR) in TNBC cohorts. However, prospective data is lacking on the frequency of non- BRCA germline mutations and pCR in TNBC patients who received neoadjuvant therapy (NAT). The aim of this study was to describe germline alterations in comparison with pCR in a prospective cohort of TNBC receiving NAT. Methods: Pre-NAT blood was drawn from patients enrolled in a clinical trial of genomically tailored NAT (ARTEMIS: NCT: 02276443, per eligibility patients had to have negative clinical BRCA tetsing). Germline DNA was extracted and sequenced on a HiSeq4000 sequencer (Illumina, coverage 60X). Reads were aligned to human reference hg19. Variants were filtered against public databases of normal cohorts: esp6500, 1000 genome, ExAC with a frequency cutoff at 1% in any ethnicity. Two integrative scores were used to evaluate the deleteriousness of the missense variants and the variants predicted to be damaging by both scores were included in the analyses. A 105 pan-cancer susceptibility gene panel was selected based on literature data and commercially available gene panels. NAT included anthracycline and taxane based chemotherapy +/- targeted therapy based on tumor genomic expression. Univariate logistic regression models were used to fit pCR for individual mutations, excluding genes mutated in fewer than three patients. All statistical analyses were performed using R version 3.6.1. with a significance of p=0.05. Results: Germline results and pCR were available for 152 patients. Median age was 55 yrs (range: 24-77). 7.9% were stage (st) I, 65.8% st II, 26.3% st III. 55 pts (36%) had pan-cancer associated germline mutations, whereas 33 (21%) had a breast-cancer associated mutation. Greater than 1% mutations were seen in seventeen genes (Table). There was no significant difference in pCR rate after NAT among pts with different germline mutations versus without mutation. Conclusions: Breast cancer related germline mutations other than BRCA in TNBC are relatively common supporting at least a breast panel (not only BRCA1/2) testing. Treatment implications of different germline mutations and their impact on pCR is ongoing on an extended series. [Table: see text]