bluuebunny/crossref_metadata_2025_split huggingface dataset:
Germline genetic testing in unselected pancreatic ductal adenocarcinoma (PDAC) patients.
Authors: Peters Mary Linton Bounetheau , Brand Randall , Borazanci Erkut Hasan , Stobie Lindsey , Dudley Beth , Karloski Eve , Moser A James , Colvin Arlene , Lim Cynthia , Bahary Nathan , Sun Weijing , Rhee John C. , Lembersky Barry C. , Stoller Ronald G. , LaDuca Holly , Dolinsky Jill S , Dalton Emily , Speare Virginia , Black Mary Helen , Tung Nadine M. 
Published: September 2018

1501 Background: The aim of this study is to assess the prevalence of known heritable germline mutations in unselected PDAC patients and to determine how well current guidelines for genetic testing identify mutation carriers. Methods: Consecutive, unselected patients with recently diagnosed PDAC from three centers were enrolled from May to December 2016 in an ongoing prospective study. A three-generation pedigree was obtained. Germline mutations in 12 genes associated with PDAC risk ( APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, PALB2, PMS2, STK11, TP53) and in 19 genes related to other cancer risks were screened for by NGS. American College of Gastroenterology and NCCN criteria for genetic testing for BRCA1/2, Lynch syndrome, and Familial Pancreatic Cancer (FPC) were assessed. Results: Among 183 patients, 46% are female, 79% are Caucasian and 10% are Ashkenazi Jewish, with median (IQR) age 68 (62,75) years at diagnosis. 41% of patients met ³1 criteria for genetic testing (35.5% BRCA1/2, 2.7% Lynch, 9.3% FPC). Twenty patients (11%) were found to have a total of 21 pathogenic mutations (table). Mutation status was not associated with age at diagnosis, sex, or personal history of cancer (all p > 0.05). Six mutation carriers (30% of positives) did not meet current criteria for genetic testing. Conclusions: Preliminary results show that 6.6% of unselected PDAC patients carry a germline mutation in a gene known to increase PDAC risk and 4.3% have a mutation in genes not previously linked to PDAC. Existing testing criteria did not identify 30% of carriers. Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk. Clinical trial information: NCT02790944. [Table: see text]
Lung cancer screening patient navigation for current smokers in community health centers: A randomized controlled trial.
Authors: Percac-Lima Sanja , Ashburner Jeffrey M , Rigotti Nancy , Park Elyse R. , Chang Yuchiao , Atlas Steven J 
Published: September 2018

1506 Background: Annual chest computed tomography (CT) can decrease lung cancer mortality in high risk individuals. Patient navigation (PN) has been shown to improve cancer screening rates in underserved populations. We evaluated the impact of PN on lung cancer screening (LCS) in current smokers in community health centers (CHC). Methods: Current smokers aged 55-77 receiving care in five CHC affiliated with an academic medical center were randomized to intervention (n = 400) or control (n = 800) groups. In the intervention arm, patient navigators (PNs) determined eligibility for LCS, provided brief smoking cessation counseling, introduced shared decision making about LCS, scheduled appointments with the primary care provider (PCP), reminded patients about appointments and PCPs to order CTs, and helped patients attend testing and follow-up any abnormal results. Control patients received usual care. The primary outcome was the proportion of patients in each group who had any chest CT during the study period. Secondary outcomes included proportion of patients receiving lung screening CTs and the number of lung cancers diagnosed in each group. Results: Baseline patient characteristics were similar between randomized groups. From March 2016-January 2017, PNs contacted 332 (83%) of intervention patients; 76 refused further participation. Of participating patients, 130 (51%) were eligible for LCS. Exclusions included insufficient smoking history (n = 117), competing comorbidities (n = 5), moved (n = 2), and died (n = 2). In intention-to-treat analyses, 124 intervention patients (31%) had chest CT vs. 138 control patients (17.3%, p < 0.01). Lung cancer screening CTs were performed in 94 intervention patients (23.5%) vs. 69 control patients (8.6%, p < 0.01). Eight lung cancers were diagnosed in intervention patients (2%) vs. 4 in controls (0.5%). Conclusions: A patient navigation program implemented in community health centers significantly increased lung cancer screening among current smokers. PNs may help underserved low-income current smokers complete LCS and improve equity in care while decreasing lung cancer mortality. Clinical trial information: 2015P002239.
Multigene hereditary cancer testing in sarcoma patients.
Authors: Jackson Sarah A. , Baxter Melanie D. , Mester Jessica , Susswein Lisa , Marshall Megan L. , Hruska Kathleen S. , Klein Rachel T. 
Published: September 2018

1518 Background: In multi-gene hereditary cancer testing, multiple syndromes may be interrogated simultaneously, increasing the likelihood of detecting an underlying cancer predisposition. We characterized the yield and distribution of pathogenic or likely pathogenic variants (PV/LPV) in patients with a personal history of sarcoma undergoing panel testing through our clinical diagnostic laboratory. Methods: We retrospectively reviewed panel test results, demographic data, and personal/family history information from patients reporting a personal history of sarcoma. Patients included in this study underwent panel testing (NGS and del/dup) of up to 61 genes at this laboratory and concurrent or prior TP53 analysis at this or an outside laboratory. Chi-square and Fisher’s exact tests were used to compare groups. Results: Among 374 sarcoma patients, 53 (14.2%) harbored one or more PV/LPV in 14 genes: TP53, BRCA2, CHEK2, BRCA1, ATM, MSH6, MLH1, NBN, BAP1, BRIP1, FLCN, MSH2, PTEN, and RB1. Thirty-nine (10.4%) individuals reported both a personal and family history of sarcoma; however, PV/LPV were not more likely to be detected among this group than those with personal history alone (p = 1.0). PV/LPV were most often detected in BRCA1/2 (15/374, 4.0%) or TP53 (12/374, 3.2%). Notably, four probands with BRCA1/2 PV/LPV reported a family history of sarcoma, including one kindred in which the variant was present in two brothers, both affected with sarcoma. Additionally, seven patients were found to have PV/LPV (1.9%) in genes causative for Lynch syndrome. Among patients with PV/LPV in genes other than TP53, nearly half (17/41, 41.5%) met National Comprehensive Cancer Network TP53 testing criteria. Conclusions: The majority of PV/LPV were identified in genes for which association with sarcoma risk is not well-established. While several of these genes have been implicated in somatic pathways related to sarcoma development, it is unclear whether these germline findings are causative, play no role, or modify sarcoma risk. Although these data do not inherently associate non- TP53 genes with sarcoma risk, they suggest a potential clinical benefit can be gained from performing hereditary cancer risk assessment and multi-gene panel testing in sarcoma patients.
Performance of mutation risk prediction models in a racially diverse multi-gene panel testing cohort.
Authors: Idos Gregory , Roth Katherine G , Naghi Leah , Ricker Charite Nicolette , Culver Julie , Sturgeon Duveen , Kingham Kerry , Koff Rachel , Chun Nicolette M. , Rowe-Teeter Courtney , Hartman Anne-Renee , Allen Brian , Evans Brent , Mills Meredith , Hong Christine , McDonnell Kevin , Ladabaum Uri , Ford James M. , Gruber Stephen B. , Kurian Allison W. 
Published: September 2018

1523 Background: Mutation carrier prediction models are clinically useful tools for identifying candidates for genetic counseling and testing. Consensus guidelines recommend germline genetic testing for those with a carrier probability (CP) of approximately 5% or higher. However, prediction models may perform less well among racial/ethnic minorities. Our hypothesis is that pathogenic mutations (PM) are identifiable in a clinically meaningful fraction of racially/ethnically diverse patients with a CP of < 5%. Methods: We conducted a multicenter prospective clinical trial of patients undergoing cancer-risk assessment using a 25 gene panel, which include APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were recruited from August 2014 to November 2016 at three centers. Patients were enrolled if they met standard clinical criteria for genetic testing or were predicted to have a ≥2.5% probability of inherited cancer susceptibility using validated prediction models. We evaluated the CP of patients with a PM in BRCA1, BRCA2, and/or a mismatch repair (MMR) gene using the following models: (1) BRCApro, (2) MMRpro and (3) PREMM1,2,6. Results: Of 2000 patients enrolled in this cohort, 80.6% are female (n = 1612). Regarding race/ethnicity, the cohort is 40.1% Non-Hispanic White (n = 802), 37.4% Hispanic (n = 748), 11.5% Asian (n = 230), 3.9% Black (n = 78), and 7.1% Other (n = 142). Among 241 (12.1%) patients who tested positive for a pathogenic mutation, 76 (31.5%) patients had a BRCA1 or BRCA2 mutation. Of those, 52 (68.4%) patients had a BRCApro CP of < 5%. Thirty-eight (15.8%) patients had a pathogenic mutation in an MMR gene: 19 (50.0%) had an MMRpro CP of < 5%, while 13 (34.2%) had a PREMM1,2,6 CP of < 5%. The racial/ethnic distribution of BRCA1/2 or MMR mutation carriers is similar to that of the whole cohort. Conclusions: In a diverse cohort of patients undergoing 25-gene multiple-gene panel testing, half or more carriers of BRCA1/2 or MMR mutations had a CP of < 5%, the consensus guideline-recommended cutoff for genetic testing. These results support a lower threshold for genetic testing guidelines. Clinical trial information: NCT02324062.
PALB2 mutations in high-risk women with breast or ovarian cancer.
Authors: Metcalfe Kelly A. , Akbari Mohammad R , Narod Steven , Lerner-Ellis Jordan 
Published: September 2018

1527 Background: In Canada, genetic testing for BRCA1 and BRCA2 is available free of charge to women who meet eligibility criteria, based on personal and family history of cancer. Less than 10% of women are identified with a BRCA mutation, despite features of hereditary cancer. PALB2 has been identified as a moderate penetrance gene in various populations. In the current study, we examined the frequency of PALB2 mutations in women with breast or ovarian cancer who met criteria for genetic testing for BRCA1 and BRCA2and tested negative. Methods: DNA samples from women with breast or ovarian cancer, who met criteria for provincial BRCA1 and BRCA2 genetic testing and tested negative between the years of 2007 and 2014 were included in this study. All 13 coding exons of PALB2 plus 20 base pairs from the exon boundaries were amplified using Wafergen SmartChip technology. The amplified DNA were paired-end sequenced at 2x250 cycles using an Illumina MiSeq sequencer. Results: 2,225 women with breast cancer and 429 women with ovarian cancer were tested for PALB2 mutations. No PALB2 mutations were found in women with ovarian cancer. Seventeen deleterious PALB2 mutations were detected in women with breast cancer (0.8%). The frequency of PALB2 mutations was significantly higher in women with bilateral breast cancer (2.4%) compared to women with unilateral breast cancer (0.6%) (p = 0.01). There was no significant difference in age at diagnosis between those with and without a PALB2mutation (50.9 years vs 53.8 years; p = 0.34). Conclusions: Genetic testing for PALB2 should be considered for high-risk women with breast cancer, especially those who present with bilateral breast cancer. However, PALB2 does not appear to contribute to ovarian cancer which has implications for counselling women who are identified with a PALB2 mutation.
Association of baseline plasma levels of 25OH vitamin D and breast cancer risk in a chemoprevention trial.
Authors: Bonanni Bernardo , Serrano Davide , Gandini Sara , Johansson Harriet Ann , Macis Debora , Aristarco Valentina , Guerrieri-Gonzaga Aliana , De Censi Andrea 
Published: September 2018

1546 Background: Observational studies have shown a correlation of higher serum 25-hydroxyvitamin D (25OHD) concentrations and reduced cancer risk, including breast cancer (BC). We assessed the association of 25OHD and Vitamin D Receptor (VDR) polymorphisms (SNPs) with breast cancer events within a chemoprevention trial in premenopausal women at risk for BC. Methods: Premenopausal women with history of intraepithelial neoplasia (IEN) or at risk women according to the Gail model were included in a 4 arm phase II prevention trial (low dose tamoxifen vs fenrerinide vs their combination vs placebo). Level of 25OHD were measured at baseline. VDR SNPs ( FokI, BsmI, TaqI, ApaI, and Cdx2) were determined using the Applied Biosystems’ Taqman Allelic Discrimination Assay according to manufacturer’s instructions. Survival analysis for breast cancer events was performed using competing risk models, adjusted for BMI, age, season and risk strata. Results: Plasma samples were available for 228 subjects. At baseline the median plasma 25OHD concentrations were slightly higher in 53 unaffected women, 19.6 ng/ml (IQR 12.7-27.3 ng/mL) than in 175 women with IEN, 18.8 ng/ml (11.7-25.8). After a median follow up of 15 years, 79 women developed a breast cancer event, 12 had different neoplastic events. The median level of 25OHD was 19.7 ng/ml (IQR 12.8-26.1) in subjects free from oncological events and 17.8 ng/ml (9.7-23.9) in subjects with breast events. Women in the lowest 25OHD quartile (≤12 ng/ml) had an increased risk of breast cancer events: HR = 1.79 (95%CI, 1.07-2.99, p = 0.03). Considering all cancer events, the associations with 25OHD were confirmed (P = 0.005). Among the VDR SNPs the ApaI variant in homozygote or heterozygote versus wild type showed an HR of 1.83 (95%CI, 1.04-3.21 p = 0.03). Conclusions: Our results support a role of plasma vitamin D levels in breast cancer risk. Subjects in the lowest quartile had a two-fold increased risk of a cancer event. Our findings support trials of 25OHD supplementation to prevent breast cancer in 25OHD insufficient subjects.
Prospective randomized biomarker study of metformin and lifestyle intervention for prevention in obese postmenopausal women at increased risk for endometrial cancer.
Authors: Yates Melinda S. , Basen-Engquist Karen , Zhang Qian , Schmandt Rosemarie , Medepalli Meena , Nebgen Denise R , Soletsky Beth , Levy Erma J , Fellman Bryan M. , Urbauer Diana L , Lu Karen H. 
Published: September 2018

1551 Background: Obesity significantly increases risk of endometrial cancer (EC) through systemic metabolic effects and local tissue action, driven by estrogen and dysregulated insulin signaling. EC is most commonly diagnosed in postmenopausal women. Metformin, an antidiabetes drug, and lifestyle intervention were evaluated for effects on endometrial proliferation and serum biomarkers, in parallel with weight loss. Methods: Obese postmenopausal women were randomized into 4 groups for a 16 week intervention using a 2 (metformin 1700 mg/day vs placebo) x 2 (lifestyle intervention vs no lifestyle intervention) factorial design based on the Diabetes Prevention Program. Pre- and post-intervention endometrial biopsies were assessed for proliferation (% Ki67+). Body weight and serum markers were measured pre- and post-intervention (estrone, FSH, DHEA-S, SHBG, IGF-1, adiponectin, omentin, insulin, glucose, A1C, ALT, triglycerides, and others). Results: Of 576 women approached for the study, 29 women were randomized and 26 completed the study. Similar adherence was seen for placebo and metformin, with 88% and 94% of doses taken, respectively. Adverse events were grade 1 or 2, most commonly flatulence, headache, and diarrhea. Metformin+lifestyle group lost the most weight (-7.4%), followed by lifestyle (-5.2%), metformin only (-3.1%), and placebo (+0.1%). Endometrial proliferation was not changed. Overall proliferation was low (7.1% at baseline) with substantial variability even in this postmenopausal cohort. Biopsies produced limited endometrium, precluding evaluation of other tissue markers. Metformin significantly increased serum DHEA (p = 0.002). SHBG increased (p = 0.031) and insulin decreased with lifestyle intervention (p = 0.035) but were not statistically significant after multiple comparisons correction. Conclusions: Metformin and lifestyle intervention produced positive changes in serum markers and weight loss. While it is known that obese postmenopausal women are at increased risk for EC, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Clinical trial information: NCT01697566.
Breast cancer screening in transgender patients: Findings from the 2014 BRFSS survey.
Authors: Narayan Anand , Morris Elizabeth Ann , Lebron Lizza 
Published: September 2018

1564 Background: Transgender patients undergoing transitions often receive cross sex hormonal therapies, placing them at uncertain risk for developing breast cancer. There is limited population-based information about the extent to which transgender patients undergo mammography screening. Our purpose was to determine the extent to which transgender patients undergo mammography screening using nationally representative survey data. Methods: Transgender participants in the 2014 Behavioral Risk Factor Surveillance System survey were included. Proportions undergoing mammography screening in the last year or two years were calculated stratified by age category and transition status (male to female(MtF), female to male(FtM), non-conforming(people who do not follow societal notions how they should look or act based on the sex they were assigned at birth)). For each transition status, predictors of mammography screening (demographics, indices of access to health care) were calculated using logistic regression. Results: 656 transgender patients were included (343 were MtF, 203 were FtM and 110 classified themselves as gender non-conforming). For MtF respondents, 61.5% of women underwent mammography screening within the last year (71.9% within last two years). For FtM respondents, 66.1% underwent mammography screening within the last year (74.2% within the last two years). For gender non-confirming transgender patients, 57.9% underwent mammography screening within the last year (74.4% within the last two years). For all transgender patients, income category (OR 1.16, 0.82 - 1.64), higher education category (OR 1.09, 0.31 - 3.86) and health insurance (OR 0.38, 0.10 - 1.41) were not associated with increased adherence to mammography screening. Adjusted for age, education, race and income, transgender patients were comparably likely to undergo mammography screening compared with non-transgender patients (OR 0.97, 0.58 – 1.62). Conclusions: High proportions of transgender survey respondents undergo mammography screening (57.9 – 66.1% within the last year, 71.9 – 74.4% within the last two years), proportions comparable to non-transgender survey respondents.
The epidemiology of metaplastic breast cancer: A review of 2,500 cases from the national cancer database.
Authors: Campbell Brittany Morgan , Thomas Samantha Marie , Ong Cecilia Tuongquang , Greenup Rachel Adams , Plichta Jennifer Kay , Rosenberger Laura Horst , Force Jeremy Meyer , Hyslop Terry , Hwang Eun-Sil Shelley , Fayanju Oluwadamilola Motunrayo 
Published: September 2018

1570 Background: Metaplastic breast cancer (MBC) is a rare, aggressive, sarcomatoid breast cancer that was first described in 1973 but only became recognized as a histologically distinct entity in 2000. Given the paucity of data on the epidemiology of MBC, we performed a population-based analysis to delineate sociodemographic and clinicopathological characteristics associated with increased likelihood of MBC diagnosis. Methods: Adult female breast cancer patients with stage I-III MBC and non-MBC histology diagnosed between 2010 and 2013 were identified in the National Cancer Database (NCDB). Multivariate logistic regression was used to identify factors associated with diagnosis of MBC, and Cox proportional hazards modeling was used to estimate the effect of MBC on overall survival. Results: 2,451 MBC and 568,057 non-MBC patients were identified. After adjusting for receptor status (ER, PR, HER2), age, stage, grade, and treatment variables, MBC patients had worse survival than non-MBC patients (HR 1.45, p < 0.001). Compared to non-MBC patients, a higher proportion of MBC patients were non-Hispanic black (16.7% vs 10.5%), had an annual income < $35k (29.0% vs 25.5%), had lower high school completion rates (36.7% vs 33.9%), were treated at academic centers (35.5% vs 30.8%), and had government-sponsored insurance (48.8% vs 43.7%, all p < 0.01). MBC diagnosis was more likely in patients with triple-negative breast cancer (OR 20.71), higher clinical T stage (cT4 vs cT1: OR 6.18), and lower clinical N stage (cN1 vs cN0: OR 0.38, all p < 0.001). MBC patients were also more likely to be diagnosed based on pathology from their first operation rather than preoperatively (OR 1.41, p < 0.001). Conclusions: Black women and women of low socioeconomic status were at increased risk for diagnosis with MBC. Though MBC was more likely to be treated at academic centers, MBC was less likely to be diagnosed prior to surgical intervention. Many of the sociodemographic factors associated with MBC have also been associated with triple-negative breast cancer. Additional research is needed to determine the contribution of sociodemographic factors to the epidemiology of MBC independent of receptor status.
A phase I study of convection enhanced delivery (CED) of 124I-8H9 radio-labeled monoclonal antibody in children with diffuse intrinsic pontine glioma (DIPG).
Authors: Souweidane Mark M. , Kramer Kim , Pandit-Taskar Neeta , Zanzonico Pat , Zhou Zhiping , Donzelli Maria , Lyashchenko Serge K. , Haque Sofia , Thakur Sunitha B , Cheung Nai-Kong V. , Larson Steven M. , Dunkel Ira J. 
Published: September 2018

2010 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm3. The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.