bluuebunny/crossref_metadata_2025_split huggingface dataset:
AcSé-ESMART: European Proof of Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors in Children and Adolescents–Arm D: Olaparib and irinotecan.
Authors: Gatz Susanne Andrea , Rubino Jonathan , Rossoni Caroline , Andre Nicolas , Aerts Isabelle , Thebaud Estelle , Nebchi Souad , Rondof Windy , Hübschmann Daniel , Mortimer Peter G. , Paoletti Xavier , Vassal Gilles , Geoerger Birgit 
Published: May 2019

10047 Background: AcSé-ESMART is a proof-of-concept, phase I/II, multicenter, prospective basket trial designed to explore targeting agents in a molecularly enriched cancer population; treatment arms with targeted agents as single agent or in combination regimens are explored independently. Arm D explores the PARP inhibitor olaparib (ola) in combination with irinotecan (iri). The design is based on the hypothesis that in pediatric cancer pathogenic BRCA alterations are extremely rare and proliferative capacity is high requiring a chemotherapy sensitisation approach. Preclinical data in pediatric cancer suggest PARP inhibitor activity in other genomic alterations impairing homologous recombination (HR) and demonstrate synergy with iri. We here report the results of the Phase I part of the trial. Methods: Children and adolescents with relapsed/refractory cancer and comprehensive molecular profiling (whole exome and RNA sequencing) at relapse were eligible. Dose-escalation followed a continuous reassessment method design of pre-specified dose combinations of oral ola and iv iri. Plasma for pharmacokinetics (PK) was collected. Results: From Oct 2016 to April 2018, 27 pts (19 sarcomas, 3 brain tumors, 5 other) with a median age of 15 y (range 4;22) were enrolled over 4 dose levels. Dose limiting toxicities occurred in 7 of 24 evaluable pts (gastrointestinal (n = 4), febrile neutropenia (n = 1), thrombocytopenia (n = 2)). The RP2D was defined as ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Twenty-three pts evaluable for response received a median of 2 cycles (range 1-27+). Confirmed PRs were seen in one osteosarcoma, one pinealoblastoma and one neuroblastoma; time to progression was 22.4, 50 and 89+ weeks, respectively. Eight pts experienced disease stabilization (median 14.8 weeks, range 9;42.3). PK and biomarker analysis (ie. HR alterations, DNA and gene expression signatures) is ongoing to identify factors associated with clinical benefit and data will be presented. Conclusions: The RP2D of the combination is ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Preliminary activity led to the ongoing Phase II part of the arm. Clinical trial information: NCT02813135.
Renal function after treatment for childhood cancer: A report from the St. Jude Lifetime Cohort Study.
Authors: Green Daniel M. , Wang Mingjuan , Krasin Matthew J. , Srivastava Deokumar , Howell Carrie R. , Jay Dennis W. , Ness Kirsten K. , Greene William , Lanctot Jennifer Q. , Shelton Kyla C. , Davidoff Andrew M. , Ehrhardt Matthew J. , Mulrooney Daniel A. , Robison Leslie L. , Hudson Melissa M. 
Published: May 2019

10048 Background: We assessed renal function in a large, clinically assessed cohort of childhood cancer survivors. Methods: Creatinine and qualitative urine protein was measured in 2753 survivors (>10 years (years) post-diagnosis, age ≥18 years). Renal function was graded per the Kidney Disease International Global Outcomes 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD). Multivariable logistic regression was used to estimate associations between demographics, treatment exposures, and CKD (grades 1-5 and 3-5). Radiation treatment was expressed as percentage of total kidney volume treated with 5 (V5), 10 (V10), 15 (V15) and 20 (V20) Gray. Results: Among 2753 survivors, 48.7% were female and 82.5% non-Hispanic white. Median age at diagnosis - 7.3 years (interquartile range [IQR]=3.3-13.2), median age at evaluation - 31.4 years (IQR=25.8-37.8), and median time from diagnosis to evaluation - 23.2 years (IQR=17.6-29.7). Prevalence of grades 1-5 and 3-5 CKD was 7.4% and 2.1%, respectively (grade 1=113, grade 2=30, grade 3=44, grade 4=5, and grade 5=8). Individual and cumulative aminoglycoside doses and treatment with high-dose methotrexate were not associated with CKD (data not shown). Cumulative number of doses of ambisome/abelcet and of amphotericin B were significant risk factors for grades 1-5 and grades 3-5 CKD in models for V15 and V20 (data not shown). The multivariable results for V10 are shown in the Table. Conclusions: In addition to nephrotoxic antineoplastic and supportive care therapy, race, ethnicity, and body composition contribute to risk of CKD in long-term survivors. These novel results inform late effects reduction strategies for future treatment protocols and identify survivors at highest risk for CKD. [Table: see text]
Combined effect of radiotherapy and anthracyclines on risk of breast cancer among female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Veiga Lene H. S. , Curtis Rochelle E. , Morton Lindsay M. , Withrow Diana , Howell Rebecca M. , Smith Susan A , Weathers Rita , Oeffinger Kevin C. , Moskowitz Chaya S. , Henderson Tara O. , Arnold Michael A. , Gibson Todd M. , Leisenring Wendy , Neglia Joseph Philip , Turcotte Lucie Marie , Whitton John , Robison Leslie L. , Inskip Peter , Armstrong Gregory T. , Berrington de González Amy 
Published: May 2019

10053 Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m2). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p < 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend < 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- < 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.
Long-term health status of high-risk neuroblastoma survivors treated with high-dose chemotherapy and hematopoietic stem cell transplantation.
Authors: Haghiri Sandrine , Fayech Chiraz , Dufour Christelle , Pasqualini Claudia , Bolle Stephanie , Boumaraf Amel , Belhout Amel , Journy Neige , Souchard Vincent , Vu-Bezin Giao , Veres Cristina , Haddy Nadia , De Vathaire Florent , Valteau-Couanet Dominique , Fresneau Brice 
Published: May 2019

10054 Background: Current treatment strategies including high-dose chemotherapy with stem cell transplantation rescue (HDC-SCT) have improved 5-year event-free survival for high-risk neuroblastoma (HRNB) patients, but with an increased risk of late treatment-related toxicities. Methods: Between 1980 and 2012, 439 children were treated for HRNB with HDC-SCT in Gustave Roussy (GR), among which 145 were alive and disease-free at 5-year post-SCT. Long-term health data have been collected for those 145 patients, prospectively within the long-term follow-up clinic in GR or retrospectively from pediatric consultations. Results: With a median follow-up post-SCT of 15 years (range 5-34), we observed 6 late relapses, 11 second cancers (including 3 papillary thyroid carcinomas; median delay = 20 years post-SCT [18-22]) and 9 deaths. Event-free and overall survival at 20-year post-SCT were 82% (95%CI = 70–90) and 89% (95%CI = 78–95), respectively. A second health event was observed in 135 patients (median = 3/patient), including 103 patients with at least 1 severe event (median = 1/patient). Cumulative incidence at 15-year post-SCT for second cancers is 4%, cardiac diseases 8%, thyroid 11%, renal 7%, hepatic focal nodular hyperplasia 14%, dental mal-development 70%, and severe hearing loss 20%. Height-for-age z-score was ≤-2 for 30 patients (21%) and ≤-3 for 12 patients (8%). After Busulfan-Melphalan conditioning regimen, 40/43 females and 33/35 males had a gonadal insufficiency. Conclusions: Long-term consequences of HRNB treatment including HDC are frequent and disabling, mainly due to hearing loss and gonadal insufficiency.
Cardiac events in survivors of childhood cancer treated in more recent eras: A report from the Childhood Cancer Survivor Study.
Authors: Mulrooney Daniel A. , Hyun Geehong , Ness Kirsten K. , Ehrhardt Matthew J. , Yasui Yutaka , Duprez Daniel , Howell Rebecca M. , Leisenring Wendy , Constine Louis S. , Oeffinger Kevin C. , Gibson Todd M. , Tonorezos Emily S. , Robison Leslie L. , Hudson Melissa M. , Armstrong Gregory T. 
Published: May 2019

10058 Background: Contemporary cancer protocols have incorporated modifications to minimize cardiotoxic exposures and preserve long-term health. We investigated the impact of these changes on late cardiac outcomes in a large cohort of adult survivors of childhood cancer. Methods: Congestive heart failure (CHF), myocardial infarction (MI), valvular disease, pericardial disease, and arrhythmias were graded by the National Cancer Institute’s Common Terminology Criteria for Adverse Events among 23,462 five-year cancer survivors [6,193 (26%) treated in the 1970s, 9,363 (40%) in the 1980s, and 7,906 (34%) in the 1990s] and 5,057 siblings. Cumulative incidence and 95% confidence intervals (95% CI) were estimated by treatment decade. Adjusted multivariable subdistribution hazard models were used to estimate hazard ratios (HR) and 95% CI for cardiac outcomes by decade. Mediation analysis examined risks with and without cardiotoxic exposures. Results: For survivors [median age 6 years (range: 0-21) at diagnosis, 28 years (8.2-58) at follow-up], cardiac radiation (RT) exposure declined from 77% of those treated in the 1970s to 55% and 40% in the 1980s and 1990s. Anthracycline exposure increased from 28% to 50% to 64%. The 20-year cumulative incidence of CHF (0.69% for those treated in 1970s, 0.74% in the 1980s, 0.54% in the 1990s) and MI (0.38%, 0.24%, 0.19%) declined in more recent treatment eras (p < 0.01). This change was not seen for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%) or arrhythmias (0.08%, 0.09%, 0.13%). Compared to survivors diagnosed in the 1970s, the risk of CHF, MI, and valvular disease decreased in the 1980s and 1990s, but only significantly for MI (HR 0.64 95% CI 0.47-0.89 and 0.52 95% CI 0.32-0.83). The overall MI risk was attenuated by adjustment for cardiac RT exposure (HR 0.94 95% CI 0.80-1.11), mostly among Hodgkin lymphoma (HL) survivors (HR 0.82 95% CI 0.69-0.98 [unadjusted for RT]; 1.03 95% CI 0.83-1.28 [adjusted for RT]). Conclusions: Reductions in exposure to cardiotoxic cancer therapies have resulted in declines in adverse cardiac outcomes, particularly for the RT-associated risk of myocardial infarction among HL survivors.
Genomic correlates of response to adjuvant trastuzumab (H) and pertuzumab (P) in HER2+ breast cancer (BC): Biomarker analysis of the APHINITY trial.
Authors: Krop Ian E. , Paulson Joseph , Campbell Christine , Kiermaier Astrid Christina , Andre Fabrice , Fumagalli Debora , de Haas Sanne , Salgado Roberto , Denkert Carsten , Loibl Sibylle , Bailey Andrew , Lewis Phillips Gail , Frank Elizabeth , Piccart Martine , Viale Giuseppe , Loi Sherene 
Published: May 2019

1012 Background: We conducted a comprehensive genomic and immune-marker based analysis to identify prognostic and predictive biomarkers beyond clinical parameters (eg nodal status) in the setting of HP-based therapy. Methods: APHINITY, a phase III study, randomized 4805 pt with HER2+ BC to adjuvant chemo/H, plus P or placebo. Tumor Infiltrating Lymphocytes (TILs) were analysed using published methods. A nested case-control design with 1023 pt samples (3 controls matched to 1 distant relapse) underwent DNA (targeted) and RNA sequencing. Inverse probability weighting with Kaplan-Meier estimator weights, and models adjusted for treatment, hormone receptor, nodal status, age and chemotherapy type were used. Results are reported descriptively with 95% CIs. Interaction p-values are unadjusted for multiplicity. Results: DNA-seq, RNA-seq and TIL analyses were successful in 940/1023 (92%), 974/1023 (95%), and 4313/4804 (90%) samples, respectively. Prognosis (arms pooled): PI3K/PTEN/AKT alterations (HR 1.35; CI 1.01-1.79), MYC (HR 1.61; CI 1.16-2.23) or ZNF703 amplification (HR 1.62; CI 1.07-2.47) suggest poorer prognosis while TOP2A amplification (HR 0.49; CI, 0.32-0.74) suggests better prognosis independent of anthracycline use. Higher mRNA expression of an immune signature (IFNG, PD-L1, CXCL9 (HR 0.68; CI 0.52-0.89)) and TILs (HR 0.91; CI 0.86-0.96) also suggest better outcomes. Predictive effects: Table shows the HR for H+P benefit versus H for selected markers. PAM50 subtype did not predict benefit. Conclusions: In this comprehensive biomarker analysis, higher levels of immune markers and HER2 appeared to be associated with better prognosis and greater H+P benefit. Clinical trial information: NCT01358877. [Table: see text]
End-of-study analysis from the phase III, randomized, double-blind, placebo (Pla)-controlled CLEOPATRA study of first-line (1L) pertuzumab (P), trastuzumab (H), and docetaxel (D) in patients (pts) with HER2-positive metastatic breast cancer (MBC).
Authors: Swain Sandra M. , Miles David , Kim Sung-Bae , Im Young-Hyuck , Im Seock-Ah , Semiglazov Vladimir , Ciruelos Eva , Schneeweiss Andreas , Monturus Estefania , Clark Emma , Knott Adam , Restuccia Eleonora , Benyunes Mark , Cortes Javier 
Published: May 2019

1020 Background: Progression-free and overall survival (PFS and OS) were significantly improved with 1L P + H + D v Pla + H + D in 808 pts with HER2-positive MBC in CLEOPATRA (NCT00567190). OS was increased by an unprecedented 15.7 mo (median 56.5 mo with P + H + D v 40.8 mo with Pla + H + D; HR 0.68; 95% CI 0.56, 0.84; p < .001) with a median follow-up of 50 mo [Swain et al. NEJM 2015]). Here we report the end-of-study analysis with a median follow-up of 99 mo (max 120 mo). Methods: In this descriptive analysis, OS was compared between arms using the log-rank test, stratified by prior treatment status and geographic region. The Kaplan–Meier approach was used to estimate median OS, and a stratified Cox proportional hazards model was used to estimate the HR and 95% CIs. Subgroup analyses of OS were performed for stratification factors and other baseline characteristics. Results: Clinical cutoff was Nov 23, 2018. Since Jul 2012, 50 pts crossed from the Pla to the P arm. These pts are counted in the Pla arm for efficacy analyses and up to the first dose of P for safety analyses. The OS HR was 0.69 (95% CI 0.58, 0.82), favoring P + H + D. Median OS was 57.1 mo in the P arm (402 pts) and 40.8 mo in the Pla arm (406 pts; Δ 16.3 mo). The 8-year landmark OS rates were 37% and 23%, respectively. The OS benefit in predefined subgroups, including in pts previously treated with H in the (neo)adjuvant setting (88 pts, HR 0.86; 95% CI 0.51, 1.43), remained consistent with the overall result and previous reports. The overall safety profile of P + H + D was consistent with the known P safety profile. There was only one new serious adverse event suggestive of congestive heart failure (onset ~77 mo on treatment in the P arm, resolution in 34 days, pt continued on study medication) and one new symptomatic left ventricular systolic dysfunction (onset ~46 mo after crossing to the P arm, resolution in 34 days) since the previous analysis. Conclusions: The OS improvement with 1L P + H + D v Pla + H + D for pts with HER2-positive MBC was maintained after an additional 4 years of long-term follow-up, as were the safety and cardiac safety profiles. Clinical trial information: NCT00567190.
Tucatinib, palbociclib, and letrozole in HR+/HER2+ metastatic breast cancer: Report of phase IB safety cohort.
Authors: Shagisultanova Elena , Chalasani Pavani , Brown-Glaberman Ursa Abigail , Gradishar William John , Brenner Andrew Jacob , Stopeck Alison , Gao Dexiang , McSpadden Tessa , Kabos Peter , Borges Virginia F. ,   on behalf of Academic Breast Cancer Research Consortium
Published: May 2019

1029 Background: Based on preclinical synergy, we are conducting a phase IB/II clinical trial of tucatinib (HER2 small molecule inhibitor, T), palbociclib (CDK4/6 inhibitor, P) and letrozole (aromatase inhibitor, L) in HR+/HER2+ metastatic breast cancer (MBC). Methods: Post-menopausal, or pre-menopausal women on ovarian suppression, with prior ≥2 HER2 inhibitors at any time of disease; ≥1 HER2 inhibitor for MBC or front line bone/soft tissue only disease are eligible provided ≤2 endocrine agents for MBC. Prior CDK4/6 or HER2 small molecule inhibitors are not allowed. Treatment entails T 300 mg BID, P 125 mg/day 21 days on, 7 days off, and L 2.5 mg/day. Safety was assessed using CTCAE v.4.03 with standard definitions for dose limiting toxicity (DLT). Dose reductions of T and / or P for DLTs, and discontinuation of either P or L for toxicity were allowed at any time during the study. Safety thresholds were set as DLTs in ≤7/20 pts for T, ≤15/20 pts for P, or ≤14/20 pts attributable to both T and P. Results: Phase Ib enrolled 20 pts from 11/16/17 to 12/5/18. The median age is 53y (22-70y), median number of prior lines of MBC therapy is 2 (0-5). 70% of pts have visceral disease and 45% CNS disease. Prior treatment includes 100% of pts with trastuzumab and pertuzumab, and 45% of pts with prior TDM-1. One pt required dose reduction of T; 9 (45%) had dose reduction and 2 (10%) discontinued P for DLTs. One pt discontinued L. Safety boundaries were not crossed. The most common grade (G) ≥3 toxicities were neutropenia (G3 55%, G4 15%), diarrhea (G3 20%), infections (G3 20%), thrombocytopenia (G3 10%) and mucositis (G3 10%). The frequency and type of toxicities were consistent with those previously reported for each single agent. PK analysis showed no interaction between P and T. As of 1/4/19, 14 pts (70%) remain on study (5 pts for ≥6 months) and 6 pts removed for progression. No withdrawals for toxicity and no deaths on study. The longest time on study (ongoing) is 10 months for pts without CNS disease, and 6 months for pts with CNS disease. Conclusions: T, P, L combination showed an acceptable safety profile and encouraging antitumor activity. RP2D of T is 300mg PO BID in combination with full doses of P and L. Enrollment in phase II cohort is ongoing. Clinical trial information: NCT03054363.
High frequency of HER2-specific immunity observed in patients (pts) with HER2+ cancers treated with margetuximab (M), an Fc-enhanced anti-HER2 monoclonal antibody (mAb).
Authors: Nordstrom Jeffrey L. , Muth John , Erskine Courtney L. , Sanders Catherine , Yusko Erik C. , Emerson Ryan O , Lee Min-Jung , Lee Sunmin , Trepel Jane B , Im Seock-Ah , Bang Yung-Jue , Giaccone Giuseppe , Bauer Todd Michael , Burris Howard A. , Baughman Jan E. , Rock Edwin P. , Moore Paul A. , Bonvini Ezio , Knutson Keith L 
Published: May 2019

1030 Background: Previous studies have shown that 44-71% of trastuzumab (T)-treated pts develop HER2-specific immunity (Clin Cancer Res 2007, 13:5133; Cancer Res 2016, 76:3702; Breast Cancer Res 2018, 20:52). M is an Fc-engineered mAb that shares similar HER2 binding and antiproliferative activity as T. The Fc region of M has been engineered for increased affinity to the activating FcγRIIIA (CD16A) and lower binding to the inhibitory FcγRIIB (CD32B), attributes that may enhance the mAb’s immune function, such as antigen presentation. Methods: HER2+ cancer pts who progressed on prior therapy received M (0.1-6 mg/kg QW for 3 of every 4 weeks [N = 34]; or 10-18 mg/kg Q3W [N = 32]) in phase 1 trial NCT01148849. PBMC and plasma were collected pre-dose and 50 days post-dose for 46 pts and > 4 years for 3 pts on long-term treatment. Response to HER2 or control antigens (Ag) was assessed by IFNγ ELISpot and antibody (Ab) ELISA. In 14 pts, T-cell antigen receptor (TCR) repertoire was assessed by immunosequencing. Results: Following M treatment, mean frequencies of IFNγ-producing T cells specific for intra- or extracellular fragments of HER2 increased by 2.5 to 6-fold (p < 0.0027, paired t test). Most (95%) of subjects responded to ≥2 of 6 (median = 5) HER2 Ag. Mean HER2-specific Ab concentration increased by 19-54% (p < 0.0001), with all subjects responding to ≥2 (median = 5) of the 6 Ag. A small 1.6-fold increase in IFNγ response to control CMV/EBV/Flu (but not tetanus or cyclin D1) peptides was observed; no increase in Ab response to control Ag was noted. Subsets of HER2-specific T-cell and Ab responses persisted during long-term treatment. Median TCR clonality increased by 54% (p = 0.003), with an average of 125 unique clones expanding, while overall TCR diversity remained unchanged (p = 0.19). Conclusions: Treatment of HER2+ cancer with M was associated with enhanced HER2-specific T-cell and Ab responses together with increased TCR clonality, indicative of a more focused T-cell repertoire. The high frequency of HER2-specific immunity in M-treated patients ( > 95%) is consistent with its enhanced Fc region contributing to linkage of innate and adaptive immune responses.