bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired RB1 mutations in estrogen receptor-positive (ER+) clinically advanced and metastatic breast cancer (MBC).
Authors: McGregor Kimberly , Sokol Ethan , Danziger Natalie , Pavlick Dean , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Lin Douglas I. , Williams Erik Abraham , Ramkissoon Shakti H. , Severson Eric Allan , Hemmerich Amanda , Duncan Daniel , Huang Richard , Chung Jon , Reddy Venkataprasanth P. , Venstrom Jeffrey , Schrock Alexa Betzig , Alexander Brian Michael , Ross Jeffrey S. 
Published: May 2020

1053 Background: Prior to use of cell cycle inhibitor drugs such as palbociclib, mutations in the retinoblastoma cell cycle inhibitory gene ( RB1) were extremely uncommon. To assess recent descriptions of RB1 mutations in MBC as treatment related, we compared primary untreated ER+ breast cancer samples from patients who developed MBC with ER+ MBC metastasis biopsies in post-primary treatment patients. Methods: Extracted DNA from 15 untreated primary breast tumors (PBx) and 36 treated metastatic MBC tumors (MBx) were sequenced by hybrid capture genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. PD-L1 expression was determined by IHC (Dako 22C3). Results: The age distribution, GA per tumor, CDH1 and ERBB2 GA frequencies were similar in PBx and MBx. GA in ESR1 (P < 0.0008), classically associated with acquired hormonal therapy resistance, and PIK3CA (p < 0.11) were increased in the MBx vs the PBx samples. RB1 GA were more frequent in the MBx samples (11%) than the pre-treatment PBx samples (0%, P < 0.31). GA not associated with targeted therapy programs were similar in both groups. In addition to low frequencies of ERBB2 amplification in the ER+ tumors, the most frequent potentially targetable GA identified in both PBx and MBx included GA in FGFR1 and NF1. BRCA1 GA were identified in the MBx group only. Biomarkers of potential immunotherapy benefit including MSI status, TMB levels and PD-L1 IHC staining were at similarly low levels in both groups. Additional cases are being identified to expand the cohort sizes for final presentation. Conclusions: In addition to the well-known acquisition of hormonal therapy resistance mutations in ESR1 and PIK3CA in ER+ MBC, this study also supports the acquisition of RB1 mutations when post-treatment metastasis biopsies are sequenced rather than pre-treatment primary tumors. This increase in RB1 mutation identification is associated with exposure of the tumors to anti-cell cycle drugs such as palbociclib in the treated but not the untreated cohort. [Table: see text]
LAG-3 overexpression in pediatric Hodgkin lymphoma.
Authors: Moerdler Scott , Ewart Michelle , Peng Mou , Zang Xingxing , Cole Peter D. 
Published: May 2020

10531 Background: The role of the PD-1/PD-L1 axis in Hodgkin Lymphoma (HL) has led to FDA approval for use of inhibitors in chemotherapy-refractory HL. Numerous additional immune checkpoints may be useful targets, but have not yet been evaluated in HL. LAG-3, a related checkpoint, has been demonstrated to be overexpressed on tumor infiltrating lymphocytes (TILs) of a variety of cancers with associated poor outcomes. LAG-3 is known to inhibit T cell proliferation and activation, representing a possible therapeutic pathway for anti-tumor immunity. However, LAG-3 has yet to be evaluated in pediatric cancers. The purpose of this study is to characterize the expression pattern and clinical significance of LAG-3 in pediatric HL using immunohistochemistry. Methods: Patient tumor samples from prior Children’s Oncology Group clinical trials (AHOD0031) with matched patient outcome data containing 200 patient samples were obtained. 95% confidence intervals were calculated based on a range of observed prevalence of immune checkpoint expression. Using immunohistochemistry, paraffin embedded samples were tested for the expression of LAG-3 and PD-L1. Samples were stained for CD30 to better delineate Reed Sternberg cells from the remainder of the tumor microenvironment. Immune checkpoint staining was compared to positive controls of normal tonsil tissue, and negative controls of 3T3 cells. Expression intensity was scored by a Pediatric Pathologist. Results: 115 unique HL patient cases with evaluable HL tissue and correlating clinical outcome data were analyzed. Samples from 73/115 patients (63%) demonstrated positive LAG-3 staining, defined as over 10% of TILs expressing LAG-3. No demographic data including gender, race/ethnicity, age, or stage were significantly associated with LAG-3 expression. While not statistically significant there was a numerical difference in event free survival (EFS) and patients with LAG-3 expression demonstrated worse EFS. In terms of degree of LAG-3 expression, patients with the lowest positive expression were found to have the worst EFS, and those with highest expression demonstrated the best EFS. 97% of patient cases were found to be PD-L1 positive. 71/73 (97%) of patients who expressed LAG3 were also PDL1+, and 71/106 (67%) of PDL1+ cases were also LAG3+. LAG-3 and PD-L1 were found to be independent (p = 0.09). Conclusions: This project is innovative in its characterization of LAG-3 as an immune checkpoint target in pediatric HL. We hope that the information from this project will be used to support new clinical trials for pediatric patients with Hodgkin lymphoma.
Trends in conditional survival and predictors of late death in neuroblastoma.
Authors: Olsen Hannah , Campbell Kevin M. , Bagatell Rochelle , DuBois Steven G. 
Published: May 2020

10533 Background: Significant advances in the treatment of neuroblastoma have been made in the past several decades. There are scant data examining how these improvements have changed over time and differentially affected conditional survival among high- and non-high-risk patient groups. Methods: We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results Database. We analyzed clinical characteristics and survival outcomes for 4717 neuroblastoma patients. Kaplan-Meier methods were used to estimate overall survival (OS) and conditional overall survival (COS) conditioned on having survived 1, 2, or 5 years from diagnosis, with estimates compared between groups using log-rank tests. Results: Five-year OS was 41.46% (95% CI 38.77-44.13) for the high-risk group and 91.13% (95% CI 89.49-92.53) for the non-high-risk group. Both groups saw significant improvements in OS by decade (p<0.001). Five-year COS among 1-year survivors was 52.69% (95% CI 38.77-44.13) for the high-risk group and 96.75% (95% CI 95.57-97.62) for the non-high-risk group. One-year survivors in the high-risk group showed a statistically significant improvement in COS over time. No difference in COS was observed among 5-year high-risk survivors. There were no statistically significant changes in COS over time for 1- and 5-year survivors in the non-high-risk group. In the high-risk and non-high-risk groups, 82% and 32% of late deaths (>5 years from diagnosis) were attributable to cancer, respectively. Statistically significant adverse prognostic factors for late death were age >1 year at diagnosis, metastatic disease, and non-thoracic primary site (p=0.001). Conclusions: Improvements in COS over time have largely benefited high-risk patients, though they are still at higher risk for late death due to cancer when compared to non-high-risk patients. Age, stage, and primary site, but not treatment decade, influence outcomes among 5-year survivors. [Table: see text]
Neuromuscular dysfunction and associated health/socioeconomic outcomes: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Rodwin Rozalyn L , Chen Yan , Yasui Yutaka , Leisenring Wendy M. , Gibson Todd M. , Nathan Paul C. , Howell Rebecca M. , Krull Kevin R. , Mohrmann Caroline , Hayashi Robert J. , Chow Eric Jessen , Oeffinger Kevin C. , Armstrong Gregory T. , Ness Kirsten K. , Kadan-Lottick Nina S. 
Published: May 2020

10546 Background: Childhood cancer survivors are at risk for neuromuscular dysfunction. We estimated the prevalence and cumulative incidence of neuromuscular dysfunction in a cohort of childhood cancer survivors and examined associations with treatment exposures and health/socioeconomic outcomes. Methods: CCSS participants ≥5 years from cancer diagnosed between 1970-1999 (n = 25,583, 46.5% female, median [range] age 54.4 [15.1-57.6] years) and siblings (n = 5,044, 52.3% female, median [range] age 54.1 [32.5-57.0] years) were included. Neuromuscular dysfunction was identified by self-report of 1) motor dysfunction: impaired balance, tremor, or extremity weakness; 2) sensory dysfunction: impaired touch sensation. Multivariable analyses examined predictors of dysfunction by diagnosis. Results: Cumulative incidence of neuromuscular dysfunction was elevated at 20 years from diagnosis in survivors (24.3%, 95% CI 23.8-24.8; motor 18.2%, sensory 13.5%) versus siblings (8.9%, 95% CI 8.1-9.7). In survivors five years from diagnosis, motor dysfunction was associated with exposure to cytarabine (OR = 1.39, 95% CI 1.10-1.77) and spinal radiation (OR = 2.11, 95% CI 1.31-3.41) in acute lymphoblastic leukemia/non-hodgkin lymphoma (ALL/NHL), vinca alkaloids (OR 1.29, 95% CI 1.03-1.60) and brain radiation (OR = 1.58, 95% CI 1.35-1.85) in central nervous system tumors, and cytarabine (OR = 3.73, 95% CI 1.62-8.57) and non-brain/spine radiation (OR = 1.84, 95% CI 1.42-2.40) in bone/soft tissue tumors. Sensory dysfunction was associated with exposure to vinca alkaloids (OR = 3.45, 95% CI 1.06-11.22) in ALL/NHL, and platinum agents (OR = 1.31, 95% CI 1.03-1.67) and spinal radiation (OR = 3.71, 95% CI 1.24-11.11) in bone/soft tissue tumors. Survivors with neuromuscular dysfunction were at increased risk for adverse health/socioeconomic outcomes (Table). Conclusions: Neuromuscular dysfunction is a prevalent morbidity in childhood cancer survivors, associated with specific therapies within a particular diagnosis. Interventions are needed to identify and improve neuromuscular dysfunction given its association with adverse health/socioeconomic outcomes. [Table: see text]
Updated results from the phase IIIb complement-1 study of ribociclib (RIB) plus letrozole (LET) in the treatment of HR+, HER2-advanced breast cancer (ABC).
Authors: De Laurentiis Michelino , Borstnar Simona , Campone Mario , Warner Ellen , Salvador Bofill Javier , Jacot William , Dent Susan Faye , Martin Miguel , Ring Alistair E. , Cottu Paul H. , Lu Janice M. , Ciruelos Eva , Azim Hamdy A. , Chatterjee Sanjoy , Zhou Katie , Wu Jiwen , Ankrah Nii , Zamagni Claudio 
Published: May 2020

1055 Background: Real-world evidence is important as it complements data from randomized controlled trialse report updated results from CompLEEment-1, a Phase IIIb trial evaluating RIB+LET in an expanded population, the largest CDK4/6i trial in ABC to date. Methods: Patients (pts) with HR+, HER2– ABC, ≤ 1 line of prior CT and no prior ET for ABC received RIB+LET. Study design has been reported previously (De Laurentiis, et al. ASCO 2019). Primary endpoints were safety and tolerability. Results: 3,246 pts received ≥ 1 dose of study treatment. Median duration of follow-up was 25.4 months (mos) (15 additional mos since interim analysis [De Laurentiis, et al. ABC5 2019]). Median treatment exposure was 17.8 mos. Baseline characteristics indicated a diverse population, including men (1.2%), premenopausal women (22.2%), and pts aged ≥ 70 years (19.5%); 112 (3.5%) pts had an ECOG PS of 2, 194 (6.0%) pts received prior CT for ABC, and 51 (1.6%) pts had stable CNS lesions. The most common adverse events (AEs) were neutropenia (61.1%), nausea (35.9%), and fatigue (23.4%). Grade 3/4 hematologic abnormalities ( > 5.0 %) were decreased neutrophils (54.8%), leukocytes (25.9%), and lymphocytes (12.6%). Grade 3/4 biochemical abnormalities ( > 5.0 %) were increased ALT (9.1%) and AST (6.7%). An increase of > 60 ms in QTcF interval from baseline occurred in 189 (5.9%) pts, while post-baseline QTcF of > 480 to ≤ 500 ms and > 500 ms occurred in 59 (1.8%) and 42 (1.3%) pts, respectively. Treatment-related AEs led to treatment discontinuation in 418 (12.9%) pts. Of 74 (2.3%) on treatment deaths, 38 (1.2%) were due to breast cancer. Median time to progression was 27.1 mos (95% CI, 25.7-NE), overall response rate was 43.6% (95% CI, 41.5-45.8%), and clinical benefit rate was 69.1% (95% CI, 67.1-71.1%) for pts with measurable disease at baseline. Conclusions: This analysis confirms the safety and efficacy of RIB+LET in a large, diverse cohort of pts with HR+, HER2– ABC (with no previous ET for ABC), closely resembling real-world clinical practice. Safety and efficacy data were consistent with those observed in the MONALEESA trials, supporting the use of RIB+LET in the first-line setting. NCT02941926. Clinical trial information: NCT02941926 .
Expression of the senescence biomarker p16INK4a among childhood, adolescent, and young adult cancer survivors.
Authors: Smitherman Andrew Brian , Ayer Miller Vanessa L , Mitin Natalia , Deal Allison Mary , Muss Hyman B. 
Published: May 2020

10556 Background: The mechanism of accelerated aging among survivors of childhood, adolescent, and young adult cancer is not clearly understood. Cellular senescence may contribute to this process. We measured peripheral blood T lymphocyte p16INK4a expression, a biomarker of cellular senescence and aging, among pediatric and young adult cancer survivors hypothesizing that p16INK4a expression is higher due to chemotherapy exposure and among frail survivors. Methods: Two cohorts were enrolled from January 2018 to December 2019 at an academic medical center. One, a cross-sectional cohort of young adult cancer survivors and age-matched, cancer-free controls in whom we assessed p16INK4a expression and clinical frailty. Frailty was measured with the modified Fried Frailty Index that evaluates skeletal muscle index, weakness, slowness, leisure energy expenditure, and exhaustion. A second cohort underwent prospective measurement of p16INK4a expression before and after cancer chemotherapy. Eligibility among survivors and newly diagnosed patients required treatment with an alkylating agent, an anthracycline / anthracenedione, or both. Multivariable linear regression was used to model expression of p16INK4a by patient age at assessment, treatment intensity, and frailty status. Results: The cross-sectional cohort enrolled 60 young adult survivors and 29 age-matched, cancer-free controls with median age 21 years and range 17-29 years for both groups. Survivors were a median of 5.5 years from end of treatment. The prospective cohort enrolled nine newly diagnosed patients (range 1-18 years). Expression of p16INK4a was higher among young adult cancer survivors as compared to age-matched controls (9.6 v. 8.9 log2 p16 units, p < 0.01) representing a 25-year age acceleration in the survivors. Expression of p16INK4a increased among newly diagnosed patients from matched pre- to post-treatment samples (7.3 to 8.9 log2 p16 units, p = 0.002). Nine survivors (16%) met criteria for being frail and had higher p16INK4a expression as compared to robust survivors (10.5 [frail] v. 9.5 [robust] log2 p16 units, p = 0.055). Conclusions: Chemotherapy is associated with increased cellular senescence in pediatric and young adult cancer survivors as reflected in expression of p16INK4a indicating an increase in molecular age following chemotherapy exposure. The large proportion of frail survivors in this study also exhibited higher levels of p16INK4a suggesting that cellular senescence may be associated with early aging observed among these survivors.
Hospice use at end of life in children with cancer: The effect of insurance.
Authors: Johnston Emily E. , Davis Elizabeth , Bhatia Smita , Kenzik Kelly 
Published: May 2020

10558 Background: The National Quality Forum has endorsed hospice care as a metric of high quality end-of-life (EOL) care for adults with cancer. Specific hospice-related quality metrics include hospice enrollment, hospice enrollment for ≥3d, and death outside of the acute care setting. These metrics have been examined extensively in adults and disparities related to a number of clinical and sociodemographic factors, including insurance, have been identified. However, for children with cancer, hospice utilization data is lacking. We addressed this gap by examining location of death and hospice utilization at EOL for children with cancer and determining whether these metrics varied with insurance status. Methods: We used national insurance claims data (Truven) to conduct a population-based analysis of patients with cancer who died between 2011 and 2017 at age 0-21y. The dataset was queried for hospice claims, inpatient claims, and location of death. The association between insurance (private vs. Medicaid) and 1) location of death, 2) hospice enrollment, and 3) days between first hospice claim and death was examined using multivariable regression analysis, adjusting for age at death, gender, and cancer diagnosis (hematologic malignancies vs. solid tumor). Results: A total of 1,492 children died at a mean age of 11y (SD: 6y); 56% were privately-insured, 56% were male, and 30% had hematologic malignancies. Overall, 58% died in the hospital (privately-insured: 54% vs. Medicaid: 63%). Forty-five percent enrolled in hospice (privately-insured: 46% vs. Medicaid: 43%) with 2% returning to the hospital to die after enrolling in hospice. The average time between first hospice claim and death was 3d (privately-insured: 10d vs. Medicaid: 2d, p = < 0.001). When compared to privately-insured children, children on Medicaid had similar likelihood of hospice enrollment (RR = 1.0, 95%Cl = 0.6-1.8). However, children on Medicaid were more likely to die in the hospital (RR = 1.3, 95%CI = 1.1-1.4) and have fewer days between hospice enrollment and death if enrolled in hospice (IRR: 0.5, 95%CI = 0.3-0.8). Conclusions: In this first study to examine national hospice utilization in children with cancer, care varies significantly with insurance status. Children on Medicaid are more likely to die in the hospital and have shorter hospice enrollment duration than children with private insurance. Whether this variation represents EOL care preferences, provider biases, differences in quality and availability of hospice or home care to different insurers, or other barriers needs to be examined.
The effect of neutropenia on patient-reported functioning and quality of life (QOL) among palbociclib participants of the MADELINE study.
Authors: Richardson David , Zhan Lin , Reynolds Maria , Odom Dawn , Hollis Kelly , Mitra Debanjali , McRoy Lynn , Jones Cheryl Fletcher , Mahtani Reshma L. , Hargis Jeffrey B. 
Published: May 2020

1064 Background: MADELINE is an observational, multicenter study of women with HR+/HER2- advanced or metastatic breast cancer who were followed for 6 months to evaluate patient reported QOL after initiating palbociclib combination therapy or other approved treatment in the US. A novel mobile application was developed to capture PROs for QOL at daily, weekly, monthly/cycle-based intervals for up to 6 months. QOL measures were evaluated to determine if palbociclib-treated patients experiencing episodes of neutropenia had associated decreases in QOL compared to patients without episodes of neutropenia. Methods: Patients completed the SF-12 and CES-D-10 at baseline and each cycle. Change from baseline was assessed using mean scores and mixed-effects models. Daily pain and fatigue severity were measured on an 11-point scale (0-10, 10 being worst possible pain/fatigue) and averaged to create weekly scores. Patients indicated weekly how breast cancer or its treatment interfered with family/social life, productivity, physical activity and energy on a 5-point scales (from not at all to a great deal). Demographic and clinical data including adverse events were recorded in an eCRF. Results: 25 sites contributed 139 patients (median [range] age 60 [34, 82]; white: 83%; ECOG 0-1: 87%). During the 6-month follow up period, 45% of patients experienced ≥1 neutropenia event (grade 1-4: 17%, 27%, 24%, 2%) and 11% had an event resulting in a dose change. Least-square (LS) mean change from baseline to end of study for the SF-12 Physical/Mental Component summaries (PCS/MCS) and the CES-D-10 showed no association between neutropenia and decreased QOL. Daily pain/fatigue was relatively stable for those with neutropenia (cycle 1, week 1: 2.8 [1.95] and 1.8 [0.95]; cycle 6, week 1: 2.4 [1.95] and 2.3 [1.59]) and those without (cycle 1, week 1: 2.2 [2.46] and 2.8 [2.39]; cycle 6, week 1: 1.6 [2.29] and 2.4 [2.22]). There was no significant change for impact of breast cancer or treatment across cycles. Conclusions: Patients with neutropenia did not experience decreased QOL compared to patients without neutropenia nor did patients as a whole experience numerically or clinically meaningful decrease in QOL throughout the follow up period. Daily PROs collected suggest a low level of pain/fatigue that did not change substantially over time. [Table: see text]
Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors.
Authors: Desai Ami Vijay , Robinson Giles W. , Basu Ellen M. , Foster Jennifer , Gauvain Karen , Sabnis Amit , Shusterman Suzanne , Macy Margaret E , Maese Luke , Yoon Janet , Cash Thomas , Abdelbaki Mohamed , Nazemi Kellie , Weiss Brian D. , Chohan Saibah , Cardenas Alison , Hutchinson Katherine , Bergthold Guillaume , Gajjar Amar J. , Fox Elizabeth 
Published: May 2020

107 Background: The phase 1/2 STARTRK-NG trial (NCT02650401) is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children and adolescents < 21 years old with recurrent/refractory solid tumors, including primary CNS tumors. Methods: After determining the recommended dose as 550mg/m2/day in all-comers, expansion cohorts with gene-fusion-positive CNS/solid tumors ( NTRK1/2/3 and ROS1) are being enrolled. Results: As of 1 July 2019 (data cut-off), 34 patients (4.9 months to 20 years old; median age 7 years) have been evaluated for response to treatment with entrectinib. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using RANO for CNS tumors, RECISTv1.1 for solid tumors, or Curie score for neuroblastomas. Responses in fusion-positive patients were assessed by blinded independent central review (BICR), and occurred at doses ≥400mg/m2. Best responses in patients with fusion-positive CNS tumors (n = 8) were four CR ( ETV6-NTRK3, EML1-NTRK2, GOPC-ROS1, and TPR-NTRK1), two PR ( KANK1-NTRK2 and EEF1G-ROS1), and two PD ( EML4-ALK and PARP6-NTRK3). In patients with fusion-positive solid tumors (n = 6) best responses were three CR ( DCTN1-ALK, ETV6-NTRK3, and ETV6-NTRK3), and three PR ( TFG-ROS1, EML4-NTRK3, and KIF5B-ALK). Responses (Investigator-assessed) in patients with non-fusion tumors (n = 20) were one CR ( ALK F1174L mutation), four SD, ten PD, and five patients were unevaluable or had no data. The objective response rate (defined as the total number of CR and PR) in fusion-positive patients was 86% (12/14) versus 5% (1/20) in non-fusion patients. Similarly, PFS was 17.5 months (95% CI 7.4–NE) in fusion-positive patients versus 1.9 months (1.8–5.7; p = 0.0002) in non-fusion patients. Most commonly reported treatment-related adverse events included weight gain (n = 14 [5 Grade 3/4]), elevated creatinine (n = 13), anemia (n = 13), nausea (n = 11), increased ALT (n = 10 [1 Grade 3/4]), increased AST (n = 10 [1 Grade 3/4]), decreased neutrophils (n = 9 [6 Grade 3/4]), and bone fractures (n = 7, of which 4 were treatment related). Conclusions: In children and adolescents < 21 years old, entrectinib has produced striking, rapid, and durable responses in solid tumors with target gene fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.