bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiomyopathy risk among childhood cancer survivors of African ancestry and its molecular mechanisms.
Authors: Sapkota Yadav , Qin Na , Ehrhardt Matthew J. , Wang Zhaoming , Wilson Carmen Louise , Estepp Jeremie , Rai Parul , Hankins Jane E , Burridge Paul , Jefferies John L. , Zhang Jinghui , Hudson Melissa M. , Robison Leslie L. , Armstrong Gregory T. , Mulrooney Daniel A. , Yasui Yutaka 
Published: May 2020

10514 Background: Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial/ethnic disparities. Utilizing whole-genome sequencing data in the St. Jude Lifetime Cohort (SJLIFE), we previously identified two risk loci on chromosomes 1 (rs6689879) and 15 (rs9788776) for ejection fraction (EF) and cardiomyopathy in survivors of African ancestry. The rs6689879*C was associated with 4.2% reduction in EF and 21.6-fold risk of cardiomyopathy and the rs9788776*G was associated with 5.6% reduction in EF and 46.8-fold risk of cardiomyopathy. However, molecular mechanisms behind these genetic associations are unknown. Methods: We assessed the risk of clinically-assessed/graded (per the National Cancer Institute Common Terminology Criteria for Adverse Events) cardiomyopathy in childhood cancer survivors of African ancestry (n = 301) by comparing them with those of European ancestry (n = 1870), adjusting for known cardiovascular risk factors including hypertension, abnormal glucose metabolism, hypercholesteremia, hypertriglyceridemia, sedentary behavior, risky alcohol drinking and smoking. Molecular mechanisms underlying the chromosome 1 locus was investigated using DNA methylation data in 265 SJLIFE survivors of African ancestry and gene expression profiles in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of breast cancer patients. Results: Multivariable analysis showed survivors of African ancestry had 1.46-fold ( P= 0.067) and 2.43-fold ( P= 0.0039) higher risks of grade 2-4 and grade 3-4 cardiomyopathy. Results from DNA methylation data showed rs6689879*C was correlated with hypomethylation of a probe (cg16996019) located within the promoter region of PHTF1 (β = -0.10; P= 0.0014). Notably, the cg16996019 was also hypomethylated in survivors with cardiomyopathy (β = -0.15; P= 0.0028). These observations were further supported by upregulation (β = 0.45; P= 0.028) of PHTF1 in hiPSC-CMs samples derived from doxorubicin-exposed breast cancer patients with and without experiencing cardiotoxicity (n = 3 each). Conclusions: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry. Dysregulation of PHTF1 may represent the molecular mechanism underlying the rs6689879-cardiomyopathy association. These findings have potential implications for long-term cardiac surveillance as well as up front cancer care for patients of African descent.
Phase I study of tazemetostat, an enhancer of zeste homolog-2 inhibitor, in pediatric pts with relapsed/refractory integrase interactor 1-negative tumors.
Authors: Chi Susan N. , Bourdeaut Franck , Laetsch Theodore Willis , Fouladi Maryam , Macy Margaret E , Makin Guy WJ , Shukla Neerav Narendra , Wetmore Cynthia , Margol Ashley S. , Casanova Michela , Kilburn Lindsay Baker , Yi Joanna , Hargrave Darren R. , McCowage Geoffrey Brian , Pinto Navin R. , Ebb David , Robinson Giles W. , Sierra Laura , Merchant Melinda , Nysom Karsten 
Published: May 2020

10525 Background: Absence of integrase interactor 1 (INI1) expression is a defining molecular feature of rhabdoid tumors (RT), epithelioid sarcoma (ES), and chordomas, inducing dependence on enhancer of zeste homolog-2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the FDA for treatment of patients (pts) ≥16 yrs with metastatic or locally advanced ES ineligible for complete resection. Data from a Phase 1 (Ph1) pediatric dose-escalation study (Ph1a) of TAZ were previously reported; herein we report interim efficacy and safety from the Ph1 pediatric dose-expansion study (Ph1b). Methods: NCT02601937 is a Ph1, multicenter study in pts 6 months – 18 yrs evaluating TAZ administered BID at 1200 mg/m2 in Ph1b, per Ph1a recommendation. Ph1b cohorts enrolled pts based on tumor type: Atypical teratoid RT (ATRT), RT, and other INI1-negative tumors (including ES and chordoma). The Ph1b primary endpoint was overall response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), and survival. Results: Ph1b has enrolled 47 pts who received TAZ oral suspension. Across all tumor types, ORR was 17% (Table). Responses were observed in ATRT (4/21), chordoma (2/4), and ES (2/7); 1 pt dosed at 520mg/m2 and 7pts at 1200mg/m2. In the ATRT cohort, 19% of pts responded to TAZ with a median DOR of 6.5 months. The median DOR has not yet been reached in the other cohorts, with ongoing responses in 3 pts. TAZ was generally well tolerated with no drug-related deaths. Most common adverse events (AE) include vomiting, nausea, and cough. During Ph1b enrollment, 1 pt with chordoma (dosed at TAZ 900 mg/m2 for 15 months in Ph1a) developed a secondary malignancy (T-cell lymphoblastic lymphoma). In response, the pediatric recommended Ph2 dose was revised to limit exposure in pts without CNS involvement to 520 mg/m2 TAZ (maximum dosing of 1 yr after response, pts to go off-treatment until disease progression). Conclusions: Interim results indicate TAZ is generally well tolerated in children with an AE profile similar to adults. Pt enrollment in the non-ATRT, INI1-negative cohorts is ongoing. TAZ shows promising anti-tumor activity in a subset of pediatric tumors, including ATRT, chordoma, and ES. Clinical trial information: NCT02601937. [Table: see text]
Assisted reproductive technology outcomes in childhood cancer survivors: A report from the Childhood Cancer Survivor Study.
Authors: Keefe Kimberly W. , Lanes Andrea , Stratton Kayla , Green Daniel M. , Chow Eric Jessen , Oeffinger Kevin C. , Barton Sara , Diller Lisa , Yasui Yutaka , Leisenring Wendy M. , Armstrong Gregory T. , Ginsburg Elizabeth S. 
Published: May 2020

10528 Background: Some treatment exposures for childhood cancer reduce ovarian reserve. Registry-based evaluation has not been conducted for assisted reproductive technology (ART) outcomes of female survivors. Methods: The Childhood Cancer Survivor Study, a retrospective cohort of five-year survivors and siblings, was linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS), which captures nationwide, CDC-required reporting of ART outcomes. We assessed live birth rate and relative risk (RR, 95% CI) as a function of treatment exposure, using generalized estimating equation to account for multiple ovarian stimulations per subject. Results: Among 9885 female survivors, 137 (1.4%; median age at diagnosis 10 years, range 0-20; 11 years of follow-up, 2-11) underwent 243 ART cycles (mean 1.8 cycles) and among 2419 siblings, 33 (1.4%) underwent 60 ART cycles (mean 1.8). Median age at autologous egg retrieval was 30 years (19-44) for survivors and 34 (24-43) for siblings. In the subset using autologous eggs (Table), 99 survivors underwent 155 ovarian stimulation cycles that resulted in 113 embryo transfers and 49 live births for a live birth rate of 32% per ovarian stimulation and 43% per transfer. Sibling live birth rate was 38% (p = 0.39 compared to survivors) per autologous ovarian stimulation and 53% (p = 0.33) per transfer. 38 survivors and 1 sibling underwent egg donor ovarian stimulation cycles. Two survivors used autologous eggs with gestational carriers and one cycle resulted in live birth. Cranial radiation therapy (RT) [RR 0.48 (0.27-0.87) p = 0.02] and pelvic RT [0.30 (0.14-0.66) p = 0.002], compared with no RT, resulted in lower RR of live birth in survivors. The likelihood of live birth after ART in survivors was not impacted by alkylator exposure [CED < 8000 mg/m2 vs. none: 1.14 (0.65-2.02); CED >8000 mg/m2 vs none: 1.07 (0.06-1.91)]. Conclusions: While live birth rates among survivors were lower compared with siblings, differences were not statistically significant. Pelvic and cranial RT were associated with a decreased likelihood of live birth, with no association with alkylator exposure identified. [Table: see text]
Overall survival (OS) in patients (pts) with advanced breast cancer (ABC) with visceral metastases (mets), including those with liver mets, treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA (ML) -3 and -7 trials.
Authors: Yardley Denise A. , Nusch Arnd , Yap Yoon Sim , Sonke Gabe S. , Bachelot Thomas , Chan Arlene , Neven Patrick , Slamon Dennis J. , Wheatley-Price Paul , Lteif Agnes , Sondhi Manu , Rodriguez-Lorenc Karen , Gaur Anil , Chia Stephen K. L. 
Published: May 2020

1054 Background: In the Phase III ML-3 (NCT02422615) and ML-7 (NCT02278120) trials, RIB + ET demonstrated a significant OS benefit (ML-3: HR, 0.72, P = 0.00455; ML-7: HR, 0.71, P = 0.00973) over placebo (PBO) + ET in pts with HR+/HER2- ABC (Im et al. N Engl J Med. 2019; Slamon et al. N Engl J Med. 2019). The presence of visceral mets generally portends a poor prognosis, which is especially poor in pts with liver mets (He et al. Ann Oncol. 2019). Here we report OS in pts with visceral mets with a focus on those with liver mets in ML-3 and ML-7. Methods: In ML-3, postmenopausal pts were randomized 2:1 to receive RIB + fulvestrant (FUL) or PBO + FUL as first- (1L) or second-line (2L) treatment. In ML-7, premenopausal pts were randomized 1:1 to receive RIB + ET or PBO + ET (this analysis included only pts who received an NSAI as ET partner to match approved indication). Results: Visceral mets were identified in 293 pts (60.5%) in the RIB arm and 147 (60.7%) in the PBO arm in ML-3 and 150 (44.8%) and 142 pts (42.1%), respectively, in ML-7. In ML-3, the median age of pts with visceral mets was 63 and 65 years in the RIB and PBO arms, and in ML-7 it was 42.5 and 45.0 years, respectively. In ML-3, 214 pts with visceral mets received 1L therapy (RIB, n = 137; PBO, n = 77), while 219 pts received 2L therapy or had early relapse (RIB, n = 151; PBO, n = 68). Lung and liver were the most common sites of visceral mets for pts in ML-3 (49.8% and 44.8%, respectively) and ML-7 (51.4% and 58.2%, respectively). OS HRs in pts with visceral mets were consistent with the benefit in the overall pt populations and suggested a particularly substantial OS benefit in pts with liver mets (HR for liver mets group in ML-3, 0.629 [95% CI, 0.421-0.942]; HR in ML-7, 0.531 [95% CI, 0.321-0.877]; Table). No new safety signals were observed. Conclusions: Approximately half of the pts in ML-3 and ML-7 had visceral mets. The OS data in these pts are consistent with the benefit observed with RIB in the overall populations of each trial. In pts with liver mets, a group with an especially poor prognosis, RIB + ET demonstrated a substantial OS benefit compared with PBO + ET. Clinical trial information: NCT02422615; NCT02278120 . [Table: see text]
Phase II study of alisertib as a single agent in recurrent or progressive atypical teratoid rhabdoid tumors.
Authors: Upadhyaya Santhosh , Campagne Olivia , Robinson Giles W. , Onar-Thomas Arzu , Orr Brent , Billups Catherine A , Tatevossian Ruth G , Broniscer Alberto , Kilburn Lindsay Baker , Baxter Patricia Ann , Smith Amy A. , Crawford John , Partap Sonia , Ellison David W. , Stewart Clinton F. , Patay Zoltan , Gajjar Amar J. 
Published: May 2020

10542 Background: We conducted a Phase II study of alisertib, small-molecule inhibitor of Aurora A kinase, as single-agent treatment in patients < 22 y with recurrent or progressive atypical teratoid rhabdoid tumors (ATRT) (NCT02114229). Methods: Patients received alisertib once daily [80 mg/m2 (enteric-coated tablets) or 60 mg/m2 (liquid)] on Days 1–7 of a 21-day cycle for 2 y or until progressive disease (PD). Therapy was considered promising if ≥10 patients were without PD by MR imaging at 12 wk. Molecular groups were determined using Infinium Methylation EPIC BeadChips and the Heidelberg classifier. Alisertib plasma concentrations were measured in cycle 1, on Days 1 (single dose) and 7 (steady state) and analyzed using population-based modeling. Results: Data from 30 patients representing all 3 molecular groups [SHH (10/26), MYC (10/26), TYR (6/26), unknown (4/26)] was analyzed. One patient remains on therapy. The study did not meet the efficacy end point as only 8/29 patients were without PD after 12 wk, including 1 with partial response. Progression-free survival (PFS) was 31%±8.2% at 6 months and 15.8%±6.5% at 1 y. One- year overall survival (OS) was 42.1%±9.2%. One patient remained on treatment for > 12 months, and another for > 18 months. The median treatment duration was 44 days (range, 2–653 days). There was no difference in OS (p = 0.096) or PFS (p = 0.98) by molecular groups. Neutropenia was the most common adverse effect (77%). After single-dose alisertib, we observed higher mean maximum concentration (Cmax) 10.1±3.0 µM and faster time to Cmax (Tmax = 1.2±0.7 h) in the 22 patients who received liquid formulation than those who received tablets (Cmax = 5.7±2.4 µM, Tmax = 3.4±1.4 h). Drug exposure did not differ between the formulations (AUC0-∞ = 58.6±25 h·µM). Average apparent oral clearance was 2.32 L/h per m2, which was about half that reported in adults. Serial CSF samples were collected in 2 patients; the CSF/plasma AUC ratios were 1.2%-2.7%. Conclusions: Although the study did not meet the efficacy end point, alisertib was well tolerated as a single agent in children with recurrent ATRT. A third of the patients demonstrated disease stabilization for > 6 months. Treatment response beyond 1 y was seen in 2 patients Clinical trial information: NCT02114229.
Prediabetes and progression to diabetes among adult survivors of childhood cancer in the St. Jude Lifetime Cohort.
Authors: Dixon Stephanie , Lu Lu , Wilson Carmen Louise , Jefferies John L. , Merchant Thomas E. , Howell Rebecca M. , Ness Kirsten K. , Srivastava Deo Kumar , Hudson Melissa M. , Robison Leslie L. , Chemaitilly Wassim , Armstrong Gregory T. 
Published: May 2020

10548 Background: Cardiac death among survivors of childhood cancer occurs at > 10 times the rate expected in the general population. Modifiable cardiovascular risk factors, including diabetes, increase risk for major cardiac events in a near multiplicative fashion. Thus, prevention of progression from prediabetes to diabetes could improve long-term cardiac morbidity and mortality. However, little is known about prediabetes in survivors. Methods: Prevalence of prediabetes (fasting glucose 100-125 mg/dL or HbA1c 5.7-6.4%) and diabetes were assessed in 3529 5+ year survivors ≥18 years of age and compared to 450 community controls stratified by age and matched for race/ethnicity, sex, and BMI using Chi-squared statistics. Logistic regression estimated risk factors for prediabetes and cox proportional hazards regression for progression from prediabetes to diabetes among survivors with multiple visits, reported as odds (OR) and hazard ratio (HR), respectively, with 95% confidence intervals (CI). Results: Among 3529 survivors (median age 30 years, range 18-65), the prevalence of prediabetes overall was 29.2% (95% CI 27.7-30.7) and diabetes was 6.5% (5.7-7.3). In each age strata, survivors had significantly higher prevalence of prediabetes and diabetes than controls with over 50% of middle-aged survivors (35-44 years) having prediabetes or diabetes (Table). In a multivariable model, therapy-related risk factors for prediabetes included high pancreatic tail dose (≥20 Gy: 2.9 [1.8-4.8]) and moderate prescribed cranial radiation dose (OR [95% CI] > 0- < 20 Gy: 1.4 [1.1-1.8], 20- < 30 Gy: 1.4 [1.0-1.9]) independent of age, sex, race/ethnicity and BMI. Among 695 survivors with prediabetes and longitudinal follow-up, median 5.1 years, 68 (10%) progressed to diabetes. After adjustment for age, sex, race/ethnicity and BMI, risk of progression from prediabetes to diabetes was increased by the presence of insulin resistance (HR 4.9 [95% CI 2.3-10.6]) or prior treatment with hematopoietic cell transplant (HR 2.9 [1.1-7.7]) or total body irradiation (HR 4.6 [1.6-13.5]). Conclusions: Survivors of childhood cancer have a high prevalence of prediabetes and high rates of progression to diabetes. Strategies that prevent progression to diabetes should be considered to decrease diabetes risk and subsequent cardiac morbidity and mortality in this high-risk population. [Table: see text]
Cell-free DNA comparative analysis of hormone receptor-positive, first-line metastatic breast cancer genomic landscape in the United States and China.
Authors: Li Huiping , Davis Andrew A. , Liu Xiao-ran , Xie Feng , Gui Xin-Yu , Chen Yi-Fei , Zhang Qiang , Gerratana Lorenzo , Zhang Youbin , Shah Ami N. , Behdad Amir , Wehbe Firas , Huang Yong , Yu Jian-Jun , Du Peter , Jia Shi-Dong , Cristofanilli Massimo 
Published: May 2020

1059 Background: Metastatic breast cancer (MBC) is a heterogeneous disease associated with known somatic mutations of variable biological value in different subtypes. Furthermore, the clinical evolution of the disease demonstrates clonal evolution resulting in disease resistance more accurately detected using blood-based sequencing. Few studies have explored differences in genomic features of tumors across populations. Here, we performed circulating tumor DNA (ctDNA) sequencing to compare the genomic landscape of patients with hormone-receptor positive MBC at time of first recurrence or de-novo metastatic diagnosis in the United States (US) and China. Methods: Twenty-three US patients from Northwestern University and 65 Chinese patients from Peking University had ctDNA sequencing from plasma performed using the harmonized CLIA-certified, 152-gene PredicineCARE assay in laboratories in the US and China, respectively. The data analysis was conducted in China. Institutional Review Boards at each site approved the study. Fisher’s exact test was performed to compare mutational frequencies across populations. Results: Median age of patients at MBC diagnosis was 51 in the US cohort and 55 in the Chinese cohort. 87% of US patients and 82% of Chinese patients had received prior therapy for primary breast cancer, including endocrine therapy. Mutations were detected in 17 of 23 (74%) US patients and 59 of 65 (91%) Chinese patients. CNAs were observed in 57% of US patients and 58% of Chinese patients. The most common mutations detected in US patients were TP53 (26%), PIK3CA (22%), AKT1 (22%), CDH1 (17%), PTEN (13%), and ESR1 (9%) vs. PIK3CA (46%), TP53 (35%), ESR1 (12%), and BRCA2 (11%) in Chinese patients. Frequency of AKT1 and CDH1 mutations were significantly higher in the US population (P < 0.05), while PIK3CA mutations were higher in the Chinese population (P < 0.05). CNA gains in CCND3 and CDK4 were significantly higher in the US cohort, and FGFR1 was significantly more common in the Chinese cohort (all P < 0.05). Conclusions: To our knowledge, this is a first cross-regional comparison study in HR+ MBC patients in the US and China using a harmonized cfDNA NGS platform. At a population level, there were notable differences observed in somatic variants in two cohorts. Future sequencing efforts and clinical trials should include patients of diverse ethnic backgrounds to explore the impact of differences in genomic landscape on probability of benefit from treatments. A larger validation cohort is required to confirm these findings.
Meta-analysis of cyclin-dependent kinase (CDK) 4/6 inhibitors with endocrine therapy versus endocrine therapy alone on progression-free survival (PFS) and overall survival (OS) for metastatic breast cancer (MBC).
Authors: Kunwor Ranju , Baniya Ramkaji , Abu-Khalaf Maysa M. 
Published: May 2020

1060 Background: CDK 4/6 inhibitors with Endocrine therapy (ET) are the preferred first line treatment for Hormone Receptor positive and Human Epidermal Growth factor receptor 2 negative (HR+/HER2-) MBC. Over the last few years multiple trials have shown benefit in PFS. Only two studies evaluating Ribociclib and Abemaciclib showed an OS benefit while no statistically significant OS benefit has been reported in any of the studies evaluating Palbociclib raising the possibility that this benefit may be drug specific rather than applicable to all CDK 4/6 Inhibitors. This updated meta-analysis of randomized controlled trials (RCTs) aims to assess the PFS and OS of all three CDK 4/6 inhibitors in HR+/HER2- MBC. Methods: We performed a systematic search for RCTs using Cochrane Library, PubMed, Embase, and Web of Science. Only the phase II and III RCTs comparing CKD 4/6 inhibitors plus ET with ET alone were eligible for this meta-analysis. The pooled analysis of Hazard Ratio (HR) was performed with Review Manager 5.3 using random effect model. Results: A total of 8 RCTs including 4338 patients with HR+/HER2- MBC were included in this meta-analysis (table). The pooled HR for PFS was 0.55 (95% confidence interval (CI), 0.50-0.59; P < .00001) and the pooled HR for OS was 0.75 (95% CI, 0.68-0.84; P < .00001). Conclusions: The result of our meta-analysis confirms the previously reported PFS benefit from CDK 4/6 inhibitors plus ET and shows an OS benefit when including RCTs of all 3 CDK 4/6 inhibitors for the treatment of HR+/HER2- MBC. [Table: see text]