bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC).
Authors: Hortobagyi Gabriel N. , Stemmer Salomon M. , Burris Howard A. , Yap Yoon Sim , Sonke Gabe S. , Paluch-Shimon Shani , Campone Mario , Petrakova Katarina , Blackwell Kimberly L. , Winer Eric P. , Janni Wolfgang , Verma Sunil , Conte Pier Franco , Arteaga Carlos L. , Cameron David A. , Xuan Fengjuan , Miller Michelle Kristine , Germa Caroline , Hirawat Samit , O'Shaughnessy Joyce 
Published: September 2018

1038 Background: Endocrine therapy (ET) is the basis of first-line (1L) treatment for HR+ ABC. However, ET resistance are almost universal. At the first interim analysis (IA) of MONALEESA-2 (NCT01958021), ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in patients (pts) with HR+, HER2– ABC.1 Here we report updated efficacy and safety data from MONALEESA-2 with a further ~11 months of follow-up. Methods: Postmenopausal women with no prior therapy for ABC were randomized 1:1 toRIB (600 mg/day, 3-weeks-on/1-week-off) + LET(2.5 mg/day, continuous) vs PBO + LET. The primary endpoint was locally assessed PFS. Secondary endpoints include overall survival (OS; key) and safety. OS significance was defined by a p-value threshold of 3.15 x 10-5. Tumor assessments were performed every 8 weeks for the first 18 months, and every 12 weeks, thereafter. Results: 668 pts were enrolled (334 in each arm). At the second IA for OS (data cut-off Jan 2, 2017), the median duration of follow-up was 26.4 months; 116 deaths and 345 PFS events had occurred. OS data remain immature, with 15.0% vs 19.8% of pt deaths in the RIB + LET vs PBO + LET arm (HR = 0.746; 95% CI: 0.517–1.078; p= 0.059). Updated PFS analyses confirmed continued treatment benefit in the RIB + LET vs PBO + LET arm. The 24-month PFS rates (RIB + LET vs PBO + LET) were 54.7% vs 35.9%. Treatment benefit was consistent across pt subgroups. The most common Grade 3/4 laboratory abnormalities (≥10% of pts; RIB + LET vs PBO + LET) were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%). Conclusion: After 26+ months of follow-up, treatment benefit with 1LRIB + LET persists in postmenopausal women with HR+, HER2– ABC. The study remains immature for OS analysis. The safety profile of RIB + LET remains manageable. 1. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48. Clinical trial information: NCT01958021.
Is androgen receptor useful to predict the efficacy of anti-estrogen therapy in advanced breast cancer?
Authors: Rocca Andrea , Bronte Giuseppe , Ravaioli Sara , Puccetti Maurizio , Tumedei Maria Maddalena , Scarpi Emanuela , Maltoni Roberta , Sarti Samanta , Cecconetto Lorenzo , Bedei Lucia , Fedeli Anna , Andreis Daniele , Pietri Elisabetta , Calistri Daniele , Amadori Dino , Bravaccini Sara 
Published: September 2018

1042 Background: The androgen receptor (AR) is widely expressed in breast cancers but its role in estrogen receptor (ER)-positive tumors is still controversial. However, the AR/ER ratio may impact prognosis and the response to antiestrogen endocrine therapy (ET). Methods: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced breast cancer (ABC). We evaluated patients treated with first-line ET (2002–2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy. ER, progesterone receptor (PgR), Her2, Ki67 and AR expression was determined by immunohistochemistry. A cut-off of < 1% immunostained cells was used to categorize AR expression. AR expression was analyzed in relation to the other conventional biomarkers (ER, PgR, Her2 and Ki67), best response (CR, PR, SD, PD), and time to progression (TTP) (months). TTP was estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios and their 95% confidence intervals (95% CI) were estimated using the Cox regression model. The Chi-square test was used to evaluate correlations between categorical variables and best response. p values < 0.05 were considered statistically significant. Results: Of the 102 evaluable patients (93% were treated with an aromatase inhibitor), biomarkers were assessed in primary tumors in 70 cases, in metastases in 49 and in 17 in both). Median TTP was 17 months (95% CI 14-21.5, median follow-up 75 months). The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR expression. Differences in TTP according to AR status were not statistically significant. AR/PgR ≥ 0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.030). AR status in primary tumors or metastases was not associated with PD as best response. In contrast, Ki67 > 20% and PgR < 10% showed a significant association with PD as best response. Using a cut off of ≤10% for AR expression, results did not change. Conclusions: AR expression does not appear to be useful to predict the efficacy of ET in ABC. Ki67 and PgR exert a greater impact on the efficacy of hormone therapy than AR.
Molecular alterations to predict survival and response to chemotherapy of pediatric low-grade glioma.
Authors: Zapotocky Michal , Ryall Scott , Arnoldo Anthony , Mistry Matthew , Lassaletta Alvaro , Guerreiro Stucklin Ana Sofia , Krishnatry Rahul , Ramaswamy Vijay , Laughlin Suzanne , Dirks Peter , Huang Annie , Bartels Ute Katharina , Bouffet Eric , Tabori Uri , Hawkins Cynthia 
Published: September 2018

10503 Background: RAS/MAPK pathway mutations have been identified as the major drivers of pediatric low-grade glioma (pLGG). The impact of these alterations on outcome and response to therapy is still unknown. Methods: We performed a large population based study of all pLGG diagnosed from 1985-2015. Detailed treatment and very long term outcome data was collected on all patients. Known pLGG-related alterations were detected using NanoString and QX200™Droplet Digital™PCR. Molecular data was correlated with outcome and response to chemotherapy. Results: In our cohort of 614 patients, BRAF was found to be altered in 57% and wild-type (WT) in 43% of patients without neurofibromatosis 1 (NF1). Among BRAF-WT we identified H3.3K27M, FGFR1-TACC1, MYBL1 and other alterations. Molecular alterations stratified pLGG into several risk groups. Ten-year progression free survival (PFS) was 72.3% for NF1, 69.5% for KIAA1549-BRAF, 53.5% for BRAF-WT, 30.3% for BRAF-V600E and 0% for H3.3K27M mutations (p < 0.0001). Similarly, overall survival (OS) at 10 years delineated difference between excellent survival of KIAA1549-BRAF and NF1 compared to BRAF-V600E and BRAF-WT (p = 0.0005). Interestingly, all patients with FGFR1-TACC1 and MYBL1 were alive despite observed progressions. Strikingly, response to chemotherapy determined by changes in tumor size at 6 months of therapy correlated with pLGG alteration. Objective response to first line chemotherapy was observed in 46% of patients with KIAA1549-BRAF and 35% of NF1. In contrast, only 15% BRAF-V600E and 18% BRAF-WT responded and 41% tumors grew after six months of chemotherapy. Moreover, 5-year PFS after chemotherapy was strikingly low for BRAF-V600E and BRAF-WT (25% and 31.9% respectively) compared to KIAA1549-BRAF (50%) and NF1 (76.7%) (p = 0.001). This translated to decreased OS for BRAFV600E and BRAF-WT patients (p = 0.042). Conclusions: Our study provides evidence that molecular alterations dictate the outcome of pLGG. KIAA1549-BRAF harbors excellent prognosis and choice of therapy should be made in favor of less toxic agents to minimize deleterious late effects. In contrast, poor prognosis is associated with lack of response to chemotherapy in BRAF-V600E and BRAF-WT tumors.
Measuring mercaptopurine (6MP) adherence using red cell 6MP metabolite levels in children with acute lymphoblastic leukemia (ALL): A COG AALL03N1 study.
Authors: Hoppmann Anna Lynn , Hill Torrey , Chen Yanjun , Landier Wendy , Hageman Lindsey , Evans William E. , Angiolillo Anne L. , Bostrom Bruce C. , Casillas Jacqueline N. , Lew Glen , Maloney Kelly W. , Mascarenhas Leo , Ritchey A. Kim , Termuhlen Amanda M. , Carroll William L. , Wong Florence Lennie , Relling Mary V. , Bhatia Smita 
Published: September 2018

10514 Background: Non-adherence to 6MP (monitored with medication event monitoring system [MEMs]) is associated with an increased risk of relapse in children with ALL.(JAMA Oncol, 2015) Self-report over-estimates true medication intake, particularly in non-adherent patients.(Blood, 2017) However, monitoring adherence using MEMs is logistically difficult. We investigated whether red cell 6MP metabolite levels (thioguanine nucleotide [TGN] and methylated mercaptopurine [MMP]) taken together, could identify non-adherent patients. Methods: The analysis included children with ALL in maintenance. To minimize variability in TGN and MMP levels due to pharmacogenetics, we excluded TPMT heterozygotes and homozygote mutants. We also excluded Asians to remove variability due to NUDT15. TGN and MMP levels were drawn at 6 consecutive monthly time points for each patient and averaged. TGN and MMP levels (pmol/8 x 108red cells) were standardized, adjusted for 6MP dose intensity, and then analyzed using cluster analysis (Spath, H. [1980]). Results: The 373 patients eligible for analysis yielded 5 clusters. Cluster #1 (n = 119; mean MMP: 15,656; mean TGN: 158); Cluster #2 (n = 211; MMP: 6,042; TGN: 135); and 3 very small outlying clusters (total N = 43). Adjusting for age, sex, race/ethnicity, cytogenetics and NCI risk, we found that patients in Cluster #2 were 2.6 times as likely to be non-adherent (MEMs-based adherence < 95%) compared to Cluster #1 (95% CI 1.5-4.4; P= 0.0007). Mean MEMs-based adherence was significantly higher for patients in Cluster #1 (94.3%) when compared to those in Cluster #2 (87.8%, p = 0.0002). Using Fine-Gray proportional subdistribution hazards models for competing risks and adjusting for clinical and sociodemographic factors, we found that patients in Cluster #2 were at a 2.3-fold higher risk of relapse compared with those in Cluster #1 (95%CI, 1.0-6.4, p = 0.058). Conclusions: These findings illustrate the potential for using a combination of red cell TGN and MMP levels in identifying non-adherent patients. We propose to use these and clinical and demographic factors associated with non-adherence in creating an adherence calculator.
Genomic index in pediatric synovial sarcoma (SYNOBIO study): The European Pediatric Soft Tissue Sarcoma Group (EpSSG) experience.
Authors: Orbach Daniel , Mosseri Veronique , Pissaloux Daniel , Brennan Bernadette , Ferrari Andrea , Chibon Frederic , Bisogno Gianni , De Salvo Gian Luca , Chakiba Camille , Corradini Nadege , Minard-Colin Veronique , Kelsey Anna , Ranchère-Vince Dominique 
Published: September 2018

10529 Background: A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has recently been developed, and shown a high prognostic value in adult soft tissue sarcomas. GI correlates with genomic instability, and has emerged as independent prognostic factor associated with the risk of metastases developing in synovial sarcoma (SS). The aim, therefore, was to assess GI in pediatric patients with SS, to assess its value as a prognostic factor and its role in risk stratification. Methods: All pediatric/adolescent/young adults’ (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Tumors had a central pathological review or harbored the specific fusion transcript (SYT-SSX). Definition of GI was A2/C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI1 group corresponds to cases with no or few alterations (flat profile, GI≤1) and GI2 group cases with many alterations (complex CGH profile; GI>1). Results: A total of 48 patient’s samples were available. The median age of the cohort was 13 years (range: 4-24). Patients received surgery only (19%), with adjuvant therapy (17%) or perioperative therapy (64%). GI1 group corresponded to 54.2%, and GI2 to 45.8%. After a median follow up of 58 months (range: 0.1-107), 10 tumor events occurred and 5 patients died. Patients with high GI have more axial (P<0.01), invasive (P=0.04) and higher therapeutic risk groups’ tumors (unresectable/axial tumors; P<0.015). Respectively for GI1 vs. GI2 groups, 5-year event free survival (EFS) rates were 91.8±5.6% vs. 58.9±11.2% (P<0.0084) and 5Y-Metastatic Free Survival 91.8±5.5% vs. 68.6±10.6% (P=0.055). In multivariate analysis, GI adjusted for IRS groups, site and tumor size remains prognostic for EFS (P<0.025). Conclusions: Although tumor events were rare for SS in NRSTS 2005, high GI selected patients with high risk tumor features and predicted a poorer outcome. GI may explain aggressive behavior of some pediatric SS. Founding sources: “Enfant-et-santé/SFCE,” “Info sarcome,” and “La ligue contre le cancer.”
Palbociclib exposure-response analyses in second-line treatment of hormone-receptor positive advanced breast cancer (ABC).
Authors: Sun Wan , Yu Yanke , Hoffman Justin , Turner Nicholas C. , Cristofanilli Massimo , Wang Diane Dan 
Published: September 2018

1053 Background: Palbociclib (PAL) is an oral inhibitor of cyclin-dependent kinases 4 and 6 approved for ABC. Exposure-response analyses for efficacy and safety endpoints were performed to evaluate the current PAL clinical dosing regimen (125 mg daily, 3 weeks on and 1 week off) and dose modification strategy in 2nd-line ABC. Methods: The present analyses used data from PALOMA3, a phase 3 study comparing the safety and efficacy of fulvestrant plus either PAL or placebo in 2nd-line ABC patients (PTs). A Bayesian pharmacokinetic (PK) analysis was conducted to estimate PAL PK parameters for individual PTs. Average concentration of PAL over the entire treatment (Cavg) was derived from average daily dose intensity divided by post hoc estimates of clearance for each PT. Time varying Cavg (Cavgt) was also derived to account for dose modifications up to each observation point. Kaplan-Meier method and the Cox proportional hazards model were employed to explore relationship between progression-free survival (PFS) and Cavg, Cavgt, as well as other prognostic factors. A semi-mechanistic PK-pharmacodynamic (PD) model was built to quantify the relationship between PAL concentration and absolute neutrophil count (ANC). Results: The median PFS for low and high PAL exposure groups divided according to Cavg were similar (9.47 and 10.9 months, respectively) and significantly higher than that of the control arm (4.57 months). While Cavgtwas found to be a significant predictor for PFS in univariate analysis (P-value < 0.05), this relationship was not significant in the multivariate analysis where other significant prognostic factors were also included. The PK-PD analysis for safety endpoint indicated higher PAL concentrations were associated with lower ANC, which is consistent with the fact that ANC profiles were well managed by dose modification strategies, i.e., dose interruption, delay and reduction. Conclusions: The analysis results suggested PTs were benefited similarly from fulvestrant plus PAL treatment with manageable safety profile, supporting a favorable benefit-risk profile of PAL under the current dosing regimen and dose modification strategy in 2nd-line ABC. Funding: Pfizer Inc. Clinical trial information: NCT01942135.
Intensified induction therapy with reduced total anthracycline exposure in pediatric low-risk acute myeloid leukemia.
Authors: Minson Katherine Ashley , Herring Caitlin , Metts Jonathan , Sabnis Himalee , Cooper Todd Michael , Woods William G. , Keller Frank G. 
Published: September 2018

10533 Background: Despite advances in risk stratification and therapy, the post-induction disease free survival (DFS) and overall survival (OS) for children with low-risk acute myeloid leukemia (LR-AML) remain low with DFS and OS of 50% and 68%, respectively, on the standard arm of the recent Children’s Oncology Group (COG) trial, AAML1031. Additionally, current therapy for pediatric LR-AML contains anthracycline doses exceeding thresholds known to increase the risk of adverse cardiac effects. In an effort to decrease exposure to cardiotoxic therapy, the Aflac Cancer and Blood Disorders Center adopted an institutional practice to treat LR-AML patients with a regimen of intensified induction therapy with decreased anthracycline exposure (Aflac-AML consisting of ADE10, Mitox/HiDAC, HiDAC/VP, Capizzi II). The aim of this study is to describe the associated toxicities and outcomes of this regimen in pediatric LR-AML. Methods: We retrospectively reviewed medical records of patients diagnosed with de novo LR-AML and treated per the Aflac-AML regimen from 2011-2014. Charts were reviewed for cardiac outcomes, ICU admissions, and the rate of infectious toxicities. DFS and OS were determined using Kaplan-Meier survival analysis. Results: We identified 11 LR-AML patients treated with Aflac-AML therapy. Patients received a planned 317 mg/m2 cumulative anthracycline dose vs 442 mg/m2for those treated on AAML1031. There was no decrease in LVEF with a mean change of +2.17% for Aflac-AML patients from the time of diagnosis to therapy completion (p = 0.23). The primary infectious toxicities observed were febrile neutropenia and bacterial infections with a median of 36.4±6% documented bacterial infections per cycle. Fungal and viral infections were rare as were ICU admissions – median 4.5±4% per cycle – and there were no toxic mortalities. The 3-year DFS and OS from end of induction I for Aflac-AML patients were 72.7% and 90.9%, respectively. Conclusions: The Aflac-AML regimen resulted in short-term toxicities and outcomes comparable to current chemotherapy regimens for pediatric LR-AML but with reduced anthracycline exposure. These data support use of this regimen for pediatric LR-AML patients.
Targeting the cell cycle for cancer therapy in rhabdomyosarcoma.
Authors: Stewart Elizabeth , Honnell Victoria , Ocarz Monica , Blankenship Kaley , Dapper Jason , Freeman Burgess , Shelat Anang , Pappo Alberto S. , Dyer Michael A. 
Published: September 2018

10535 Background: Rhabdomyosarcoma (RMS) is an aggressive malignancy of childhood with a poor prognosis in patients with metastatic or recurrent disease. Inhibitors of Wee1 kinase and heat shock protein 90 (HSP90) have in vitro activity in RMS and have emerged as potential novel treatment strategies. We performed a comprehensive preclinical phase III study to compare the Wee1 inhibitor AZD1775 and HSP90 inhibitor ganetespib (GANET) in combination with irinotecan (IRN) and vincristine (VCR). Methods: Orthotopic xenografts (O-PDXs) were created by injecting luciferase labeled RMS cells into the hind-leg muscle of CD-1 nude mice. Pharmacokinetic studies on RMS O-PDXs were performed to determine matched human AUC-guided dosing. A total of 540 O-PDXs derived from 4 high risk RMS patients, 2 alveolar and 2 embryonal, were randomly enrolled into 14 treatment groups. Six courses of blinded placebo-controlled therapy were given on a clinically relevant schedule. Mice were classified as having progressive disease if tumor approached 20% body weight at any time in the study. For mice completing all 6 courses, bioluminescence was used to determine complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Results: The addition of AZD1775 to IRN and VCR demonstrated the most significant response for all 4 O-PDX lines tested; 70% of mice achieved a CR or PR. GANET combined with IRN and VCR had a 54% response (CR + PR) which was not significantly better than IRN plus VCR for most O-PDXs tested. Overall response data for select treatment groups is shown in the table below. Conclusions: Comprehensive preclinical testing using multiple O-PDX models of RMS that represent the clinical spectrum of disease is feasible. Comparison of novel treatment regimens to standard of care at clinically relevant doses is warranted as justification for future clinical trials. Observation to assess durable response following completion of therapy is ongoing to determine if AZD1775 remains a promising treatment strategy. [Table: see text]
Effect of PD1/PD-L1 checkpoint blockade on efficacy of anti-GD2 antibody ch14.18/CHO in neuroblastoma.
Authors: Lode Holger N. , Zumpe Maxi , Juettner Madlen , Troschke-Meurer Sascha , Loibner Hans , Siebert Nikolai 
Published: September 2018

10548 Background: Immunotherapy (IT) with anti-GD2 antibody (Ab) ch14.18/CHO is effective for treatment of high-risk neuroblastoma (NB) patients mainly due to induction of GD2-specific Ab-dependent cellular cytotoxicity (ADCC). Methods to further enhance the effect are important and currently explored in prospective clinical trials randomizing ch14.18/CHO ± scIL-2. Programmed death-1 (PD-1) is an inhibitory receptor expressed by activated T- and NK-cells, and cancer cells express PD-1 ligand. Here, we report for the first time effect and mechanism of PD-1/PD-L1 blockade in the context of ch14.18/CHO-based IT in preclinical models. Methods: Expression of PD-L1 and PD-1 on NB cells and leukocytes was analyzed by RT-PCR and flow cytometry in the presence of ch14.18/CHO or IL-2. Mechanism of PD-L1 induction was analyzed with anti-CD11b Ab. The effect of PD-1/PD-L1 blockade on ch14.18/CHO-mediated anti-NB immune response was evaluated using anti-PD-1 Ab both in vitro (Nivolumab) and in the syngeneic GD2+ NB NXS2 mouse model (anti-mouse PD-1). Mice (n = 10) were treated with ch14.18/CHO (5x300 µg, i.p.) in combination with anti-PD-1 (8x250 µg, i.p.), and compared to controls. Results: Culture of LA-N-1 (low PD-L1 baseline expression) in the presence of leukocytes and subtherapeutic ch14.18/CHO concentrations for 24h induced strong upregulation of PD-L1 resulting in complete inhibition of ADCC mediated by ch14.18/CHO. Co-incubation with anti-CD11b Ab abrogated this PD-L1 upregulation. Importantly, blockade with Nivolumab reversed the PD-L1-dependent inhibition of ADCC. Mice treated with ch14.18/CHO in combination with PD-1 blockade showed a strong reduction of tumor growth and prolonged survival as well as the highest level of NB cell lysis mediated by serum and leukocytes compared to controls. Conclusions: Ch14.18/CHO-mediated effects upregulate the inhibitory checkpoint PD-1/PD-L1 and combination of ch14.18/CHO with PD-1/PD-L1 blockade results in synergistic treatment effects in mice. This concept will be evaluated in a clinical trial.