bluuebunny/crossref_metadata_2025 huggingface dataset:
The first report of pediatric patients with solid tumors treated with venetoclax.
Authors: Goldsmith Kelly C. , Verschuur Arnauld , Morgenstern Daniel A. , van Eijkelenburg Natasha , Federico Sara Michele , Fraser Christopher , Forlenza Christopher J. , Ziegler David Simon , Gerber Nicolas U. , Khaw Seong Lin , Cooper Todd Michael , Flotho Christian , Prine Betty A. , Salem Ahmed H. , Unnebrink Kristina , Tong Bo , Palenski Tammy L. , Place Andrew E.
Published: May 2020

10524

Background: Dependence on the prosurvival protein B-cell lymphoma 2 (BCL-2) occurs in certain pediatric solid tumors, resulting in tumorigenesis and resistance to therapies. Venetoclax (VEN), an orally administered BCL-2-selective inhibitor, has preclinical anticancer activity in human-derived neuroblastoma models. Reported here are preliminary results from pediatric patients (pts) with recurrent or refractory (R/R) solid tumors treated with VEN monotherapy or VEN with cyclophosphamide and topotecan (Cy-Topo). Methods: This phase 1 open-label, 2-part study (NCT03236857) enrolled pts < 25 yr old with R/R malignancies; we report only on pts with solid tumors. Following a dose ramp-up, pts received 800 mg VEN (age/weight-adjusted adult equivalent) once daily for the first 8 wk; Cy-Topo was added optionally after wk 8. Dose-limiting toxicities (DLTs) were assessed during the first 21 days of VEN therapy or cycle 1 of VEN-Cy-Topo. Objectives included safety, toxicity, and preliminary efficacy. Results: As of Dec 17, 2019, 11 solid tumor pts were enrolled: neuroblastoma (n = 6), rhabdomyosarcoma (n = 2), Wilms’ tumor, Carney-Stratakis syndrome, and low-grade fibromyxoid sarcoma (n = 1 each). Median age was 11 yr (range 3–22); median time on study was 6.9 mo (range 1.2–17.8). All pts experienced ≥1 treatment-emergent adverse event (TEAE); vomiting (72%; all grades) was most common. Grade ≥3 TEAEs were reported in 82% of pts; febrile neutropenia (64%), decreased blood cell count, and neutropenia (36% each) were the most common. Seven pts received 800-mg monotherapy for 8 wk; 3 of these pts did not receive Cy-Topo after monotherapy. Of the 7 pts who received VEN-Cy-Topo, 3 pts received 400 mg VEN with Cy-Topo. DLTs of grade 4 neutropenia/thrombocytopenia with delayed count recovery occurred in 2 pts on 800 mg VEN-Cy-Topo, necessitating a dose de-escalation (to 400 mg VEN). Grade 4 neutropenia occurred in 2 pts on 400 mg VEN with Cy-Topo, leading to the addition of myeloid growth factor to the therapy regimen. The best response after 8 wk of VEN monotherapy was stable disease (SD). Six pts were evaluable for tumor response with VEN-Cy-Topo; 1 neuroblastoma pt had a complete response after 5 cycles of 400 mg VEN, 4 pts had SD (3 on 800 mg and 1 on 400 mg VEN) and 1 (800 mg VEN) had progressive disease as best response. Conclusions: Continuous dosing of VEN with Cy-Topo was not tolerated due to cytopenias in 4/7 pts with solid tumors. Discontinuous dosing of VEN with Cy-Topo is being explored. Clinical trial information: NCT03236857.
Obstetrical and perinatal complications in survivors of childhood, adolescent, and young adult cancer: A population-based study.
Authors: Zgardau Alina , Nathan Paul C. , Gupta Sumit , Ray Joel G. , Baxter Nancy N. , Nagamuthu Chenthila , Lau Cindy , Park Alison
Published: May 2020

10529

Background: Women who survive cancer diagnosed in childhood, adolescence or young adulthood may develop long-term health issues. Data are lacking on adverse reproductive outcomes such as infertility and obstetrical and perinatal complications. Methods: Using linked Ontario provincial cancer and obstetrical registries, we assembled a cohort of female cancer survivors diagnosed before age 21 years from 1985-2012. We matched survivors by age and geographic region to females without a prior cancer diagnosis. Outcomes included i) any recognized and past 20 weeks’ gestation pregnancy; ii) perinatal complications; and iii) obstetrical complications (including a broad composite of severe maternal morbidity [SMM]). Multivariable Cox proportional hazard and modified Poisson models compared survivors to a non-cancer group and assessed demographic, diagnostic and treatment risk factors in survivors. Results: 3,486 survivors were matched to 17,428 women without prior cancer. Median age at cancer diagnosis was 12 years (IQR 5-16) and median follow-up was 26 years (IQR 21-32). 599 (17.2%) survivors had at least one recognized pregnancy compared to 3,885 (22.3%) women without prior cancer (Hazard Ratio [HR] 0.79, 95% Confidence Interval [CI] 0.7-0.9, p < .0001). Among those who had a recognized pregnancy, 581 (97.0%) survivors carried a pregnancy > 20 weeks’ gestation vs. 3791 (97.6%) in the non-cancer group (Relative Risk [RR] 1.0, CI 0.98-1.04). Factors significantly associated with a decreased likelihood of achieving at least one recognized pregnancy among survivors included brain tumour, cranial radiation, exposure to an alkylating agent or hematopoietic stem cell transplantation (HSCT). Among women who had a livebirth or stillbirth, survivors had a RR of 2.3 (CI 1.5-3.6) for SMM and 3.2 (CI 1.6-6.6) for cardiac morbidity. Factors associated with SMM among survivors included brain tumour and pre-existing kidney disease. Among livebirth pregnancies, cancer survivors were at higher risk of preterm birth (RR 1.6, CI 1.2-2.0), especially those who received an alkylating agent or HSCT. Conclusions: Survivors of childhood, adolescence or young adulthood cancer are less likely to achieve a recognized pregnancy compared to women without prior cancer. Those who carry a pregnancy >20 weeks’ gestation are at higher risk for SMM and preterm birth. Fertility planning and counseling can be informed by cancer diagnosis and treatment, and high-risk obstetrical care is recommended for survivors at elevated risk of an adverse pregnancy outcome.
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.
Phase I/II study of SAR439859, an oral selective estrogen receptor degrader (SERD), in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC).
Authors: Campone Mario , Bardia Aditya , Ulaner Gary A. , Chandarlapaty Sarat , Gosselin Alice , Doroumian Séverine , Pelekanou Vasiliki , Celanovic Marina , Linden Hannah M.
Published: May 2020

1070

Background: SERDs competitively antagonize and degrade the ER and can block signaling in ER-dependent tumors resistant to standard endocrine therapy (ET). This study (NCT03284957) investigates SAR439859, a potent oral SERD, in ER+/HER2- mBC. We present pooled dose escalation/expansion (Part A/B) data for SAR439859. Methods: Postmenopausal patients (pts) with ER+/HER2- mBC treated for ≥ 6 mos with prior ET received SAR439859 ≥ 150 mg QD (Part A) or 400 mg QD (Part B). Chemotherapy and targeted therapy in the advanced setting were allowed. Objective response rate (ORR; RECIST v1.1), clinical benefit rate (CBR; complete or partial response [PR] or stable disease [SD] ≥ 24 weeks), safety, and pharmacokinetics (PK) were assessed. Results: Pts (n = 62; Part A, 13; Part B, 49) had a median age of 63 yrs (range 37–88) and ECOG PS 0 (59.7%) or 1 (40.3%); 93.5% had visceral disease. All had prior ET, 74.2% had prior targeted therapy and 48.4% had ≥ 3 prior lines in the advanced setting. 61.3% of pts had treatment-related adverse events (TRAEs), all grade 1–2. Most frequent: hot flush (16.1%), constipation, arthralgia (both 9.7%), decreased appetite, vomiting, diarrhea, nausea (all 8.1%), fatigue (6.5%). No pts discontinued due to AEs. CBR was 35.6% overall, with antitumor activity irrespective of ESR1 mutation status (Table). In pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14), ORR was 21.4% and CBR 64.3%. PK data for Part B and ESR1 mutation data will be provided. Conclusions: SAR439859 had a favorable safety profile with limited TRAEs. In these heavily pre-treated pts (prior targeted therapy in 74.2%), ORR and CBR were similar to historical fulvestrant performance in pts with no prior targeted therapy. Encouraging ORR and CBR in pts with no prior SERD, CDK4/6 or mTOR inhibitors (n = 14; ORR 21.4%; CBR 64.3%) supports SAR439859 development in earlier lines of therapy. Clinical trial information: NCT03284957 . [Table: see text]
Evaluation of DNA repair biology signatures to predict specific carboplatin (C) versus docetaxel (D) benefit in advanced triple-negative breast cancer (aTNBC).
Authors: Tovey Holly , Parker Joel S. , Hoadley Katherine A. , Kennedy Richard D. , Sipos Orsolya , Kilburn Lucy , Kernaghan Sarah , Gazinska Patrycja , Haider Syed , Pinder Sarah E , Bliss Judith , Perou Charles M. , Grigoriadis Anita , Tutt Andrew , Cheang Maggie Chon U ,   on behalf of the TNT trial management group
Published: May 2020

1074

Background: In the Triple Negative Trial we observed no improved response rate (RR) to C over D in aTNBC [Tutt et al, Nat Med 2018], but we did in BRCA1/2 mutated (mut) patients (pts). We hypothesise tumors with other aberrant DNA damage response (DDR) characteristics having higher RR to DNA damage inducing C than D. Methods: We tested the predictive value of DDR process related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 & DDR Deficiency (DDRD)) on 192 treatment naïve primary tumours (PT) by total RNA-sequencing. Odds ratio (OR) for RR are reported. Paired PT & recurrent (REC) signature scores were compared. Results: Unexpectedly, high DDRD and PARPi7 were associated with higher RR to D than C ( p =0.01 & 0.06). No effect was observed for CIN70 or TP53 signature. To assess whether the unexpected results were due to biological changes 12 PT-REC pairs were available from pts who received chemotherapy (CT) between PT & REC. CIN70 increased from PT to REC, DDRD (non-significantly) & PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. The BRCA1/2 & DDRD-treatment interactions only held in pts who received CT before trial entry (table). The PARPi7-treatment interaction only held in CT naïve pts. In CT naïve pts, high CIN70 tumors suggested higher C RR as hypothesized. Restricted to the 149 PAM50 basal-like pts, results were non-significant but similar trends seen. Conclusions: In this trial of aTNBC, DDRD high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDRD score. The hypothesised CIN70 treatment interaction was observed in CT naïve pts. Our results suggest care is required in application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT. [Table: see text]
The landscape of genomic alterations detected in serial circulating tumor DNA (ctDNA) in clinical progressive metastatic breast cancer.
Authors: Jacob Saya , Davis Andrew A. , Gerratana Lorenzo , Shah Ami N. , Katam Neelima , Zhang Qiang , Wehbe Firas , Flaum Lisa E. , Siziopikou Kalliopi P. , Platanias Leonidas C. , Gradishar William John , Behdad Amir , Cristofanilli Massimo
Published: May 2020

1084

Background: Metastatic breast cancer (MBC) is associated with genomic evolution, representing a challenge at clinical progression. While tissue and blood next-generation sequencing (NGS) allows for the baseline detection of alterations, non-invasive longitudinal assessment of ctDNA can provide a tool for monitoring tumor evolution. We characterized genomic changes using serial ctDNA testing in patients with clinical progression. Methods: Patient data was obtained under an IRB-approved protocol and ctDNA was collected at Northwestern University between 2015-2019. All ctDNA samples were analyzed using the Guardant360 NGS assay. Of 255 patients with MBC, 86 had at least two serial ctDNA collections with the second collection drawn at first progression (P1) by imaging and clinical assessment. Participants were followed until second clinical progression (P2). We analyzed type of alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs variations in MAF and NOA at P1 and P2 were tested through Wilcoxon test. Results: We identified 44 HR+, 20 HER2+ and 22 TNBC cases. Median lines of therapy were 3 (interquartile range (IQR): 1-6) for HR+, 3 (IQR: 1-5) for HER2+, and 2 (IQR: 1-4) for TNBC. The most likely alterations between baseline to P1 were TP53 (p < 0.0075), PIK3CA (p < 0.0126), AR (p < 0.0126), FGFR1 (p < 0.0455) and ESR1 (p < 0.0143). In the HR+ subset , ESR1 was statistically more likely at P1. ESR1 at P1 was also associated with development of new liver lesions (p < 0.0320). ERBB2 mutation at P1 was associated with new lung (p < 0.0050) or bone lesions (p < 0.0030). Increase in NOA was observed between baseline and P1 (p < 0.0001), P1 and P2 (p < 0.0001), and baseline to P2 (p < 0.0004). MAF was increased between baseline and P2 (p < 0.0480). Conclusions: Serial ctDNA testing identified resistance alterations ( TP53, PIK3CA, AR, ESR1, FGFR1), with some mutations indicating new sites of disease ( ESR1, ERBB2). Heterogeneity of ctDNA was significantly associated with progressive disease. Prospective evaluation of the impact of serial ctDNA testing on treatment decisions is needed to expand the role of precision medicine in MBC. [Table: see text]
Outcomes for black versus white women with stage IV breast cancer enrolled on investigator-initiated clinical trials at Emory.
Authors: Ekpo Princess , Torres Mylin Ann , Rupji Manali , Switchenko Jeffrey M. , Subhedar Preeti , Gogineni Keerthi , Bhave Manali A.
Published: May 2020

1086

Background: Black women are 40% more likely to die from their breast cancer compared to White women. Inadequate representation of Blacks in clinical trials may contribute to health care inequity. Emory’s Winship Cancer Institute (WCI) in Atlanta serves a significant Black population and has a unique opportunity to engage these underrepresented patients in clinical trials. We aimed to assess clinical outcomes in Black versus White women with metastatic breast cancer (MBC) enrolled on investigator-initiated clinical trials (IITs) at Emory. Methods: Black and White women with MBC enrolled on IITs conducted at WCI between 1/2009 and 1/2019 were retrospectively evaluated. Descriptive statistics were generated for all patient characteristics. Univariate analyses and a multiple logistic regression model were used to assess the effect of age and race on clinical response, length of time on trial, number of therapy lines prior to trial enrollment, and toxicity on trial. Overall survival was assessed using Kaplan Meier analysis. Results: Sixty-two women with MBC were included [White, n = 41 (66%), and Black, n = 21 (34%), p = 0.55]. Over 90% of women were enrolled on phase II clinical trials and received targeted therapy. Mean age at clinical trial consent was 53.2 and 55.9 years in Black and White women, respectively (p = 0.36). While the majority of women had hormone-receptor positive disease, a higher percentage of Blacks had triple negative breast cancer (29% vs. 17% in Whites, p = 0.39). Black women had fewer lines of systemic therapy prior to trial enrollment (2.86 vs. 4.3, respectively, p = 0.017) and were enrolled on trial for less time than White women (5.67 mo vs. 7.83 mo, respectively, p = 0.22). There were no differences in toxicity rates among patients enrolled on IITs based on race. Black women were more likely to have progressive disease (PD) on trial (45% in Blacks vs. 20% in Whites, p = 0.05). While there was no significant difference in overall survival (p = 0.482), there was a trend towards shorter survival in Black women (51.3 mos vs. 64 mos, respectively). Conclusions: Black women with MBC who enrolled on IIT trials at Emory had worse treatment response and a trend towards poorer survival compared to White women. More research is needed to determine whether this is due to adverse biology. These results reinforce the need for exploration of biomarkers of response by race and ethnicity and improved representation of Blacks in clinical trials to inform real world efficacy.
Surgery at primary and metastatic sites for stage IV breast cancer (BC): A National Cancer Database (NCDB) analysis.
Authors: Bilani Nadeem , Elson Leah , Elimimian Elizabeth Blessing , Liang Hong , Nahleh Zeina A.
Published: May 2020

1099

Background: There is no clear evidence of a survival benefit of primary tumor resection in patients with stage IV breast cancer (BC). This large study evaluated factors associated with undergoing primary tumor resection, and whether resection at the primary site, or distant site resection (metastasectomy), was associated with better overall survival (OS). Methods: This retrospective analysis of stage IV BC cases used the 2004-2016 National Cancer Database (NCDB) population. To evaluate variables associated with primary tumor resection, we used univariate analyses (chi-squared and Wilcoxon rank-sum test), followed by multivariate logistic regression. Consequently, we conducted multivariate Cox regression survival analyses on the following groups: 1) all stage IV BC patients; 2) a subset of those with only 1 site of metastasis; and 3) another subset with metastasis to > 1 distant site. Results: A total of 54,871 stage IV BC patients were included in this analysis. From this, we analyzed a subset with only 1 distant site involved (n = 30,480) and another subset with multiple secondary sites (n = 17,344). In total, 15,661 patients underwent surgery at the primary site: 11,451 (73.1%) were non-Hispanic white; 2479 (15.8%) were non-Hispanic black; 981 (6.3%) were Hispanic and 484 (3.1%) were Asian. Variables associated with undergoing resection of the primary tumor were: age, race, Charlson/Deyo score, insurance and facility type, involved breast quadrant, receptor status, N-staging, extent of metastasis and year of diagnosis. Survival analysis of all stage IV patients showed that both lumpectomy (HR 0.59, 95% CI: 0.57-0.62, p < 0.0001) and mastectomy (HR 0.62, 95% CI: 0.60-0.64, p < 0.0001) were associated with better OS when compared to no surgery. The statistical effect was larger in the subgroup with metastasis to 1 site, but still significant in the subgroup with multiple metastatic sites. Distant site resection also yielded a survival benefit compared to no metastasectomy across all 3 groups. In the subgroup with metastasis to only 1 site, metastasectomy was associated with better OS when the metastatic site was liver (HR 0.60, 95% CI: 0.43-0.82, p = 0.0018), lung (HR 0.47, 95% CI: 0.37-0.61, p < 0.0001), and brain (HR 0.70, 95% CI: 0.55-0.88, p = 0.0022). Conclusions: Across all 3 patient subgroups, primary tumor resection (lumpectomy or mastectomy) and metastasectomy were associated with improved OS. Additional stratified analysis in the subgroup with only 1 metastatic site showed benefit of metastasectomy when that site was the lung, liver or brain.
Stress related to electronic health record (EHR) use among oncology trainees: A quality improvement study to optimize information gathering.
Authors: Ganta Teja
Published: May 2020

11015

Background: Poor EHR usability is associated with physician burnout [1]. Oncology providers are tasked with coordinating data from multiple sources/tabs within an EHR (biomarkers, genetic data, imaging, etc.) to make treatment plan decisions. It is hypothesized that oncology trainees will have decreased stress using an EHR tool to optimize data gathering. Methods: This single-institution quality improvement study aims to decrease the time and stress associated with navigating the EHR to review/document laboratory data among first-year clinical oncology fellows rotating on consult services at The Mount Sinai Hospital as measured by self-reported survey data. An EHR tool was built that pulls into the note a drop-down list of user-selectable laboratory panels grouped according to hematologic/oncologic disease presentations. A survey was sent to all fellows in the program to assess attitudes toward the EHR. All 1st-year fellows were given access to the EHR tool as they are the ones who primarily rotate on consult services. After 3 months, a follow-up survey was sent to 1st-year clinical fellows to assess satisfaction with the EHR intervention. Results: For the baseline survey, there are a total of 17 respondents (response rate 77%). 70.6% of fellows believe using the EHR increases their level of stress. The most prevalent reasons cited for frustrations with the EHR are “Hard to read other providers’ notes” (82.4%), “Gathering information from multiple different pages” (76.5%), “Increased documentation requirements” (76.5%), “Inability to quickly navigate the system” (64.7%). For the follow-up survey targeting 1st-year fellows, there are a total of 6 respondents (response rate 100%). 5 fellows tried the EHR tool at least once. Of those 5 fellows, 100% use it daily in clinical practice while on consult services, believe it makes notes more legible, believe it saves time spent in chart review, and believe it decreases their stress associated with navigating the EHR. Conclusions: A majority of clinical oncology fellows believe that the EHR contributes to their stress. The reasons cited suggest that interventions that optimize note-writing and chart-reviewing may decrease stress. The majority of fellows who used this EHR tool believe the tool improved their efficiency and stress levels. This suggests more widespread use of this tool among oncology clinicians may contribute to wellness although further studies to increase utilization must be taken.
A single-arm multicenter phase II trial of doxorubicin (Doxo) in combination with trabectedin (Trab) given as first-line treatment to patients with metastatic/advanced uterine (U-LMS) and soft tissue leiomyosarcoma (ST-LMS): Final results of the LMS-02 study.
Authors: Pautier Patricia , Floquet Anne , Chevreau Christine , Penel Nicolas , Guillemet Cecile , Delcambre Corinne , Cupissol Didier , Selle Frederic , Isambert Nicolas , Piperno-Neumann Sophie , Saada-Bouzid Esma , Bertucci Francois , Bompas Emmanuelle , Boudou-Rouquette Pascaline , Collard Olivier , Le Brun Ly Valérie , Toulmonde Maud , Le Cesne Axel , Lacas Benjamin , Duffaud Florence
Published: May 2020

11506

Background: U-LMS and ST-LMS are rare tumors with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. Overall response rates (ORR) given in the 1st-line setting do not exceed 50% for U-LMS and 35% for ST-LMS with a mean response duration of 3- 6 months without impact on overall survival (OS). In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with ORR of 59.6% in U-LMS, and 39.3% in ST-LMS with manageable toxicity (Pautier; Lancet oncol 2015). Herein, we report the updated results of progression-free survival (PFS) and final results of overall survival (OS). Methods: Patients (pts) received 60 mg/m² intravenous Doxo followed by trabectedin 1.1 mg/m2 as a 3-hour infusion on Day 1 and pegfilgrastim on Day 2, repeated every 3 weeks for up to 6 cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results: Overall, 108 patients with LMS with a median age of 59 years and mostly metastatic disease (85%) were enrolled. Of those, 77 patients (71.3%) have received all 6 cycles of treatment, and 20 patients (18.5%) had metastasis resection. With a median follow-up of 7.2 years (95% CI: 6.9 - 8.2), the overall median PFS was 10.1 months (95% CI: 8.5 - 12.6), being 8.3 months (95 CI: 7.4 - 10.3) and 12.9 months (95% CI: 9.2 - 14.1) in U and ST group, respectively. Median OS was 34.4 months (95% CI: 26.9 - 42.7), being 27.5 months (95% CI: 17.9 - 38.2) in U-LMS and 38.7 months (95% CI: 31.0 - 52.9) in ST-LMS group. The median OS among the 20 pts with surgery was not reached vs 31.6 months in the population without surgery (95% IC: 23.9 - 35.4). Conclusions: The Doxo +Trab combination is an effective 1st-line therapy for pts with LMS, with promising PFS and OS results and an acceptable safety profile. Merely for comparison, the most recent results of Doxo alone in metastatic LMS, given in 1st-line setting in a phase III ANNOUNCE trial conducted during the same period, reported median PFS of 6.9 months, and median OS of 21.9 months (ASCO 2019 LBA3). Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing this combination vs Doxo alone in 1st-line therapy in metastatic LMS are pending. Clinical trial information: NCT02131480 .