bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-time sharing of comprehensive clinical genomics sequencing data in St. Jude Cloud.
Authors: Newman Scott , McLeod Clay , Macias Michael , Birch Kirby , Gout Alexander , Foy Scott , Silkov Antonina , Kesserwan Chimene , Nakitandwe Joy , Shurtleff Sheila , Azzato Elizabeth M. , Wang Lu , Rusch Michael C , Nichols Kim , Gajjar Amar J. , Pappo Alberto S. , Mullighan Charles Grenfell , Ellison David W. , Zhang Jinghui , Downing James 
Published: May 2019

10019 Background: As tumor and germline genomic data from pediatric cancer patients is scarce in existing genomic databases, there is an urgent need for more comprehensive datasets. Such data will allow us to fully assess the actionable pediatric cancer genome, facilitate biomarker discovery, and identify new clinical associations. Methods: We sequenced 1002 tumor/normal pairs as part of a real-time clinical genomics service including whole genome, exome and transcriptome for 775 and exome/transcriptome for 227 samples. Tumor types were representative of the common and rare diseases treated at our institution (37% hematological, 31% brain and 32% solid tumors). A multidisciplinary team assessed every case, and after clinical reporting was complete, genomics data and basic clinical information (primary diagnosis, age, sex, ethnicity, primary/relapse/metastasis status), was made securely available online through St. Jude Cloud (www.stjude.cloud). Results: Based on analysis of 253 initial cases from the Genomes for Kids study, our multi-platform sequencing approach uncovered diagnostic, prognostic and/or therapeutically relevant findings in 78% of patients. We estimate 11-16% of clinically-relevant gene mutations could be missed by less comprehensive sequencing approaches. One quarter of patients had a potentially druggable mutation. This surprisingly high proportion was driven, in part, by BRAF fused low-grade gliomas and diverse JAK/STAT pathway alterations in B-Cell acute lymphoblastic leukemias. Whole genome/transcriptome sequencing allowed us to detect rare and novel gene fusions in 8% of cases and facilitated discovery of a new recurrent fusion gene in pediatric melanoma. All data is available online for others to mine and it is likely that additional clinically-relevant mutations can be uncovered. Conclusions: These data demonstrate the value of incorporating comprehensive sequencing into clinical diagnostics and patient care. We endeavor to make this large and richly annotated dataset available to others in real time rather than holding it back for months or years until publication. We anticipate adding approximately 500 additional cases per year at regular intervals, and as the resource grows, expect users to identify new targetable alterations that may be incorporated into patient care.
Participant hopes and expectations regarding outcomes of genomic sequencing research in pediatric oncology.
Authors: Marron Jonathan M , Quach Emily , Pikman Yana , Janeway Katherine A. , Mack Jennifer W. ,   the GAIN Consortium and LEAP Consortium Investigators
Published: May 2019

10020 Background: Tumor genomic sequencing is rapidly becoming more integrated into pediatric oncology, but for only a minority of individuals does sequencing identify new treatment options or impart an increased chance of cure. Retrospective data show that participants have high hopes for this promising technology, but patient/parent hopes and expectations for the outcomes of genomic sequencing have not previously been evaluated prospectively. Methods: Surveys were administered prospectively to eligible enrollees (young adult patients ≥18y with relapsed/recurrent cancer, rare cancers, and those with poor prognoses, or parents of patients < 18y) prior to return of sequencing results in two clinical sequencing studies through the GAIN (NCT02520713) and LEAP (NCT02670525) Consortia, across 18 pediatric cancer centers. Using previously validated measures, participants were queried about what they most hoped for and thought most likely to happen (most expected) as a result of participating in the sequencing study. Comparisons were made between hopes and expectations using McNemar’s test. Separate multivariate models assessed predictors of most hoping for, and most expecting, increased chance of cure as a result of participating. Models were adjusted for gender, race, disease (leukemia/solid tumor), highest education level achieved, and survey participant (patient/parent). We present interim survey results for 124 participants (67% response rate) who completed surveys between 10/15/17 (GAIN) or 9/1/16 (LEAP) and 1/15/19. Results: 58% (70/121) of respondents selected increased chance of cure as their greatest hope in participating; only 21% (25/119) reported cure as their greatest expectation (p < 0.005). 28% (34/121) most hoped their participation would help cure future patients, and 45% (54/119) most expected this result (p < 0.005). Only 8% (10/121) most hoped to learn more about their/their child’s cancer, but 21% (25/119) most expected this result (p = 0.006). In multivariate analyses, education beyond college level was associated with most hoping for cure as a result of sequencing (OR 2.7 95% CI [1.2, 5.8], p = 0.016). A solid tumor diagnosis was associated with most expecting cure in this setting (OR 2.7 [1.0, 7.2], p = 0.048). Conclusions: Participants derive great hope from participating in pediatric cancer genomic sequencing research, but expectations are more tempered. Some subgroups express heightened expectations of cure, however, potentially identifying target populations for educational intervention.
Subsequent neoplasm risk associated with rare variants in DNA repair and clinical radiation sensitivity syndrome genes: A report from the Childhood Cancer Survivor Study.
Authors: Morton Lindsay M. , Karyadi Danielle M , Hartley Steven , Frone Megan , Sampson Joshua N , Howell Rebecca M. , Neglia Joseph Philip , Arnold Michael A. , Dagnall Casey L , Hicks Belynda , Kristine Jones , Zhu Bin , Leisenring Wendy M. , Yasui Yutaka , Bhatia Smita , Robison Leslie L. , Tucker Margaret A. , Armstrong Gregory T. , Chanock Stephen J. 
Published: May 2019

10028 Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received > 0- < 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10-4), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10-4). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10-4) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10-4). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.
Phase II COLET study: Atezolizumab (A) + cobimetinib (C) + paclitaxel (P)/nab-paclitaxel (nP) as first-line (1L) treatment (tx) for patients (pts) with locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Brufsky Adam , Kim Sung-Bae , Zvirbule Zanete , Dirix Luc Yves , Eniu Alexandru E. , Carabantes Francisco , Izarzugaza Yann , Mebis Jeroen , Sohn Joohyuk , Wongchenko Matthew , Chohan Saibah , Amin Reena , McNally V. A. , Miles David , Loi Sherene 
Published: May 2019

1013 Background: COLET showed that the addition of C (MEK1/2 inhibitor) to P resulted in an increased ORR (38%; Brufsky, SABCS 2017); IMpassion130 demonstrated clinical benefit with the combination of PD-L1 inhibitor A and nP as 1L tx for pts with mTNBC (Schmid, N Engl J Med, 2018). We investigated the efficacy and safety of A + C + P/nP in pts with mTNBC, as this combination may target multiple cancer immune escape mechanisms simultaneously. Methods: In the multi-stage, multi-cohort Phase II COLET study, pts with histologically confirmed mTNBC were randomized 1:1 to receive 1L tx with A 840 mg IV (d1, d15) + C 60 mg qd (d3-d23) + P 80 mg/m2 IV (d1, d8, d15; cohort 2) or + nP 100 mg/m2 (d1, d8, d15; cohort 3) in 28-day cycles until progression or toxicity. The primary endpoint (EP) was confirmed ORR per investigator-assessed RECIST 1.1. Additional EPs were DOR, PFS, OS, safety and exploratory efficacy by PD-L1 status. Results: As of 10 Aug 2018 (6.5-mo median follow-up), 63 and 62 pts were evaluable for efficacy and safety, respectively. In cohorts 2 and 3, 21 pts (66%) and 20 pts (65%) had received neo/adjuvant taxane tx, 9 pts (28%) and 6 pts (19%) had a disease-free interval of ≤12 mo, respectively. All pts had ≥1 AE; 69% and 70% had Gr 3-5 AEs and 47% and 43% had serious AEs in cohorts 2 and 3, respectively. Efficacy data for all pts and by PD-L1 expression on tumor-infiltrating immune cells (IC ≥1%; PD-L1+) are summarized in the Table. Conclusions: ORRs were similar between the A + C + P arm and A + C + nP arm. Numerically higher ORR and PFS were observed in pts with PD-L1+ disease. The combination’s safety profile was consistent with the known individual safety profiles, and A did not increase toxicity. Clinical trial information: NCT02322814. [Table: see text]
Pembrolizumab (pembro) with paclitaxel (taxol) or capecitabine (cape) as early treatment of metastatic triple-negative breast cancer (mTNBC).
Authors: Page David B. , Chun Brie , Pucilowska Joanna , Kim Isaac , Sanchez Katherine , Redmond William L , Sun Zhaoyu , Wu Yaping , Feryn Alicia , Martel Maritza , Abaya Christina DiLauro , Wadell Dottie , Mellinger Staci L. , Moxon Nicole , Urba Walter John , McAndrew Philomena , El-Masry Maryliza , Basho Reva K. , Conlin Alison Katherine , McArthur Heather L. 
Published: May 2019

1015 Background: Atezolizumab (anti-PD-L1) plus nab-paclitaxel was shown to improve outcomes in mTBNC in a phase III clinical trial. Subjects were required to be > 12 months from curative-intent therapy in this trial. It remains unknown whether non-taxane chemo + anti-PD-1/L1 will be beneficial in mTNBC, or whether this approach is effective in rapidly-progressing patients ( < 12 mo from curative-intent therapy). Methods: mTNBC patients were enrolled in a phase Ib study of anti-PD-1 (pembro, 200mg IV q3w) plus physician’s choice chemo (cape: n = 14, 2000mg BID, 7d on/7d off; or taxol: n = 14, 80mg/m2 q1w). Primary/secondary objectives were to evaluate safety/tolerability (primary) and RECIST1.1 response (w12). The exploratory objective was to explore for differences in immunomodulation according to chemo choice. Mixed effects models were employed to compare the longitudinal effects of chemo on peripheral immune cells (flow cytometry) and T-cell diversity (Immunoseq assay). Results: Enrollment of the trial is complete (n = 28), with 100% of evaluable patients tolerating therapy (n = 22) as of 2/1/2019. Cape ORR was 43% (5 PR, 1 CR, 2 SD) with median PFS = 155d. Taxol ORR was 25% (1 CR, 1 PR, 3 SD) with median PFS = 99d. Subjects enrolled < 12 months from curative-intent therapy had numerically lower response (ORR = 27%, 1 CR, 2 PR, 3 SD) than subjects without rapid progression (ORR = 45%, 1 CR, 4 PR, 2 SD). No significant differences in immunomodulation were observed according to chemo type, however both cape & taxol were associated with declines in T-cell quantity (CD4 p < .02, CD8 p < .04) and Immunoseq T-cell fraction over time. Conclusions: Pembro plus cape or taxol is safe with encouraging efficacy, however activity may be lower in the setting of rapid progression following curative-intent chemo. Cape+pembro efficacy is favorable with no measurable differences in immunomodulation, and therefore cape may be preferred as a chemo backbone in selected patients. Both cape and taxol are associated with iatrogenic declines in T-cell quantity, which may explain the observed dropoff in anti-PD-1/L1 activity in later lines. Clinical trial information: NCT02734290.
Characterization of mutational processes in ER+ metastatic breast cancer.
Authors: Buendia-Buendia Jorge , Cohen Ofir , Kim Dewey , Jain Esha , Winer Eric P. , Lin Nancy U. , Wagle Nikhil 
Published: May 2019

1019 Background: Diverse mutational processes are active at different stages of cancer development and cause the mutational burden in cancer cells. These processes leave distinctive signatures, characterized by varying frequencies of nucleotide substitutions and their flanking base-pairs. Mutational signatures found in early stage breast cancer have been described, but less is known about the mutational processes in metastatic breast cancer (MBC). Methods: We performed whole exome sequencing (WES) on 209 metastatic tumor biopsies from patients with ER+ MBC. In a subset of patients, we obtained and performed WES on the matched primary biopsy (n = 62). Decomposition of mutational signatures was done by determining the linear combination of 30 previously reported mutational signatures (Alexandrov et al., 2013) that most accurately reconstructs the mutational profile of each tumor sample. For comparison, signature decomposition was also performed on 695 treatment-naïve primary ER+ breast cancers form The Cancer Genome Atlas (TCGA). Results: Cohort-level comparison of signature activity between our cohort of MBC biopsies versus the primary ER+ breast cancers from TCGA demonstrated enrichment of Signature 13 in MBC samples (q = 0.002), attributed to activity of the APOBEC family of cytidine deaminases and implicated in resistance to endocrine therapies. Activity of Signature 22, associated to activity of the nucleotide-excision repair mechanism, was depleted in MBC tumors relative to TCGA ER+ breast tumors (q = 0.02). Decomposition of mutational signatures at the clone level in the subset of patients with both metastatic and matched primary samples allowed us to infer signatures acquired in the metastatic setting. Among mutations in acquired clones, we found enrichment of APOBEC signatures (Sig. 2, q = 0.018; Sig. 13, q = 0.003). Conversely, activity of Signature 1, attributed to the normal aging process, was enriched in mutations shared between primary and MBC samples (q = 0.004). This suggests that mutations developed early in tumor evolution may be driven primarily by natural processes, while later mutations may reflect selective pressures imposed by therapies and cellular defects acquired during disease progression. Conclusions: The profile of somatic mutations in MBC differs from early stage breast cancer. APOBEC-related mutations arising late during tumor evolution are one possible mechanism for this difference. Further studying the associations between clinical features and therapies to mutational processes could inform design of clinical trials and management of MBC.
Effect of HER2/neu 655 polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.
Authors: Blancas Isabel , Martín Celia , Legerén Marta , Martos Michel , Sequero Silvia , Mut-Salud Nuria , Gallardo Emma , Garrido Jose Manuel , Rodríguez-Serrano Fernando 
Published: May 2019

1025 Background: HER2 overexpression in breast cancer is associated with a poor outcome, high risk of metastasis and a reduced overall survival. The introduction of Trastuzumab in the treatment scheme improved the prognosis of these patients. Nevertheless, around 20% of patients develop cardiotoxicity. The purpose of this study is to analyze the association of the HER2 Ile655Val A > G polymorphism with trastuzumab-induced cardiotoxicity and with survival. Methods: The study included 93 patients recruited from San Cecilio University Hospital in Granada (Spain) who were treated intravenously with Trastuzumab. The cardiotoxicity was diagnosed during the treatment follow-up considering a decrease of the left ventricular ejection fraction (LVEF) from baseline or clinical manifestation of congestive heart failure. HER2 655 A > G was genotyping using TaqMan SNP technology. Results: Genotype frequencies of HER2/neu 655 met Hardy-Weinberg equilibrium ( p= 0.363). We did not find differences in baseline LVEF in patients who developed cardiotoxicity vs those who did not. However, in cardiotoxicity group, the symptomatic patients had a baseline LVEF significantly lower than non-symptomatic patients (57.7 vs 66.1, p < 0.028). Logistic regression analysis adjusted by hormonal status and anthracycline treatment showed significant differences between AG and AA (OR = 3.00, CI95% 1.07-8.41, P= 0.037) or AG and AA+GG (OR = 3.21, CI95% 1.15-8.96, P= 0.026). However, we did not find association between Her2/neu Ile655Val polymorphism and disease-free survival or global survival. Conclusions: HER2 655 A > G polymorphism is significantly associated with higher risk of trastuzumab-induced cardiotoxicity but is not associated to a differential survival rate.
Disparities in treatment patterns and overall survival (OS) in hormone receptor-positive HER2+ metastatic breast cancer (MBC): A National Cancer Database Analysis.
Authors: Statler Abby , Gupta Annie , Blake Cassann N. , Wei Wei (Auston) , Hobbs Brian P , Nahleh Zeina A. 
Published: May 2019

1032 Background: Determinants of variation in therapy utilization and OS are unclear for patients diagnosed with hormone receptor+, human epidermal growth factor 2 positive (HER2+) MBC. This study aimed to identify if there are disparities in first-line treatment patterns and outcomes for this subpopulation of MBC patients. Methods: We analyzed MBC patients included in the National Cancer Database diagnosed with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) and HER2+ disease (i.e. triple positive) treated with endocrine therapy or chemotherapy between 2010 and 2015. Analyses describe the distribution of treatments administered in the first-line setting. Kaplan-Meier method was used to estimate distributions of OS, which were compared among patient cohorts using the log-rank test. Results: Of the 6215 patients diagnosed with triple positive MBC, the majority were 50-70 years old (n=3414 [55%]), female (n= 6122 [98%]), and white (n=4478 [72%]). Four distinct treatment patters were identified; hormonal therapy was the most common (n= 2289 [37%]), followed by hormonal therapy + anit-HER2 (n=1471 [24%]), chemotherapy (1280 [20%]), and chemotherapy + anit-HER2 (n=1175 (19%)). Significant differences in demographic, socioeconomic, and disease characteristics were identified across groups. Disparities in OS were also observed; the unadjusted 5-year OS was substantially lower among older patients, African Americans (AA), those with government insurance, and lower income (Table). Conclusions: This is the first study to report disparities in treatment patterns and OS among real-world triple positive MBC patients. Further investigation is required to determine if there are independent causal associations between poor prognosis and the identified demographic and socioeconomic characteristics. [Table: see text]
Genetic predisposition to breast cancer among African American women.
Authors: Palmer Julie R , Hu Chunling , Hart Steven , Gnanaolivu Rohan David , Gao Chi , Anton-Culver Hoda , Trentham-Dietz Amy , Bernstein Leslie , Weitzel Jeffrey N. , Domchek Susan M. , Goldgar David , Nathanson Katherine , Pal Tuya , John Esther M , Gaudet Mia , Haiman Christopher , Yao Song , Kraft Peter , Polley Eric , Couch Fergus 
Published: May 2019

104 Background: The identification of pathogenic mutations in breast cancer susceptibility genes through clinical genetic testing leads to focused screening and prevention strategies for women at increased risk of cancer. However, the frequency of mutations and the risks of cancer associated with breast cancer predisposition genes has not been established for the African American population. Methods: Germline DNA samples from African American women (5,054 breast cancer cases and 4,993 age-matched unaffected controls) from 10 U.S. studies were tested for mutations in 20 established breast cancer predisposition genes using a QIAseq multiplex amplicon panel as part of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study. The frequency of mutations in each gene and associations between mutations and breast cancer risk, adjusted for study design, age, and first-degree family history of breast cancer, were evaluated. Results: The mean age at diagnosis of breast cancer cases was 54.4 years and the mean age of controls was 55.2 years. 18.2% of cases and 10.8% of controls reported a first-degree family history of breast cancer. Pathogenic mutations in any of the 20 breast cancer predisposition genes were identified in 7.6% of breast cancer cases and 2.4% of controls. In multivariable analyses, mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (odds ratio (OR) > 5.0). Mutations in CHEK2 were associated with moderate risks of breast cancer (OR > 2.0), whereas mutations in ATM had lower clinical relevance (OR = 1.8). Mutations in BRCA1, BRCA2, PALB2, and RAD51D, but not CHEK2 or ATM, were associated with increased risks of estrogen receptor negative breast cancer. Conclusions: Cancer predisposition genes confer similar risks of breast cancer in the African American population as in non-Hispanic Whites. These studies provide important insights into the risks of breast cancer associated with predisposition gene mutations in the African American population.