bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burden of out-of-pocket spending among high-deductible health plan members with metastatic breast cancer.
Authors: Leopold Christine , Wagner Anita K. , Zhang Fang , Lu Christine , Earle Craig , Nekhlyudov Larissa , Ross-Degnan Dennis , Wharam James Frank 
Published: September 2018

1029 Background: 50% of workers have high-deductible health plans (HDHP) that require major outofpocket (OOP) spending for cancerrelated care. The OOP burden among patients with advanced cancer in HDHPs is unknown. Our objective was to estimate OOP spending for women with metastatic breast cancer (mbc) stratified by health plan type. Methods: Our data source was administrative health insurance claims and enrollment data of members insured though a large national health plan. We included 7142 women age 25-64 with mbc who had at least 6 months enrollment before the diagnosis and at least 12 months followup. We used a time series design and plotted OOP spending stratified by HDHP vs low-deductible plan. Primary outcome measures included: (1) 20042012 calendar trends in total annual OOP spending, (2) monthly total OOP spending in the 6 months before and 24 months after women were diagnosed with mbc, and (3) monthly total OOP spending in the last 6 months of life. Plots were adjusted for age, socioeconomic status, race/ethnicity, and US region of residence, and we then conducted linear regression to assess for statistical significance of trends. Results: In 2004, average annual OOP spending for women with mbc cancer in low-deductible health plans was $1196.2 and increased to $2570 in 2012, a yearly increase of $159.2 (113.2205.2). For women in HDHP average OOP spending in 2004 amounted to $2648 and increased to $3736.4 in 2012, representing an annual increase of $160.4 per year (105.4215.4) Average OOP spending per person month peaked in the month of diagnosis to $1633.8 for women in HDHPs and to $643 among low-deductible plan members. Average OOP spending in the last 6 months of life were $285.7 per person month among low-plan ($1714.2 per 6 months) and $607.3 among HDHP ($3644 per 6 months). Conclusions: To our knowledge, this is the first analysis to estimate OOP spending for women with mbc accounting for enrollment in HDHPs versus low-deductible plans. We found that OOP spending is increasing over time and is high in the last 6 months of life. HDHP members with mbc faced much higher OOP spending than women in traditional plans across all analyses. Findings raise concerns that HDHPs could worsen access to mbc treatments.
Safety of trastuzumab emtansine (T-DM1) in HER2-positive advanced breast cancer (BC) patients (pts): Primary results from KAMILLA study cohort 1.
Authors: Barrios Carlos H. , Wuerstlein Rachel , Anton Antonio , Delaloge Suzette , Montemurro Filippo , Bonneterre Jacques , Quenel-Tueux Nathalie , Linn Sabine C. , Button Peter , Lindegger Nicolas , Ellis Paul Anthony 
Published: September 2018

1033 Background: KAMILLA is a single-arm, open-label, phase 3b safety study of T-DM1 in pts with HER2-positive advanced BC from 278 sites in 40 countries. We report the primary analysis of the first study cohort (N = 2003). Methods: Pts with HER2-positive, locally advanced or metastatic BC (locally confirmed) with progression after prior treatment with chemotherapy and a HER2-directed agent for metastatic BC or within 6 mo of completing adjuvant therapy were enrolled. Pts received T-DM1 3.6 mg/kg every 3 wks until unacceptable toxicity, withdrawal, or disease progression. The primary outcome was safety. Results: A total of 2002 pts were treated (median age 55 yrs, range, 26–88). Most pts had a baseline ECOG score of 0 (n = 1110, 55.4%) or 1 (n = 775, 38.7%), and 1232 (61.5%) had ER and/or PR positive tumors. Median time since initial BC diagnosis was 5 yrs (range, 0–53). Most pts had received ≥2 prior lines of therapy (0–1 prior lines: 29.7%; ≥2: 66.0%); 1855 (92.8%) received prior targeted therapy in the locally advanced/metastatic setting. Median T-DM1 exposure was 5.6 mo (range, 0–46). Adverse events (AEs) were reported in 93.0% (n = 1862). Serious AEs occurred in 21.3% (n = 427), most commonly vomiting (17, 0.8%), pneumonia (16, 0.8%), anemia (13, 0.6%), and pyrexia (13, 0.6%). Grade ≥3 AEs occurred in 40.8% (n = 816), most commonly anemia (60, 3.0%), thrombocytopenia (55, 2.7%), and fatigue (50, 2.5%). Additional AEs of grade ≥3 (multiple individual items grouped) were thrombocytopenia/platelet count decrease (74, 3.7%), hepatic disorders (139, 6.9%), and hemorrhage (46, 2.3%). Grade 5 AEs occurred in 2.2% (n = 45). Treatment discontinuation was most often due to disease progression (1495, 78.1%). Median progression-free survival was 8.3 (95% CI: 8.0–9.7), 6.5 (5.6–8.0), 5.9 (5.6–8.1), 5.6 (5.0–5.9), and 5.6 (5.4–6.6) mo in pts with 0–1, 2, 3, 4, and 5+ prior lines of therapy. Median overall survival was 27.2 mo (95% CI: 25.5–28.7). Conclusions: KAMILLA isthe largest (to date) cohort of T-DM1 treated pts and these data are consistent with safety and efficacy seen in prior randomized studies, thereby supporting T-DM1 as therapy for previously treated HER2-positive advanced BC pts. Clinical trial information: NCT01702571.
A phase II study of eribulin mesylate in combination with trastuzumab and pertuzumab in patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC).
Authors: Luis Ines Maria Vaz Duarte , Guo Hao , Barry William Thomas , Krop Ian E. , Wagle Nikhil , Lowe Alarice , Gore Danielle , Andrews Chelsea , Osmani Wafa , Isakoff Steven J. , Tung Nadine M. , Winer Eric P. , Lin Nancy U. , Freedman Rachel A. 
Published: September 2018

1034 Background: As a single agent, eribulin is an active agent among MBC pts. In the first-line setting, pertuzumab improves progression free and overall survival when added to trastuzumab and chemotherapy (CT); however there are limited data in the second line or beyond. The primary aim of this study was to evaluate the activity of eribulin in combination with trastuzumab and pertuzumab in pts with HER2+ MBC whose cancers are refractory to trastuzumab containing regimens. Safety and toxicity were examined and correlative studies are also planned. Methods: Single center, single-arm, phase II, 2 cohorts study planned to enroll up to 81 pts. The studied combination would be of clinical interest if the true overall response rate (ORR) was 40% among those without prior pertuzumab exposure (Cohort A) and 30% among those with prior pertuzumab exposure (Cohort B). The trial was stopped prematurely due to low accrual. Prior to the start of the phase II study, a run-in established dose of eribulin with standard dose of trastuzumab and pertuzumab (1.4mg/m2 days 1, 8 /21 days). Results: Of 32 pts enrolled, 6 were in the run-in, 19 in Cohort A and 7 in Cohort B. Most pts were heavily pre-treated (median [range] lines of CT for metastatic disease, run-in: 4[2-11], cohort A: 2.5 [0-7], cohort B: 3[1-8]). In cohort A, 5 pts had partial responses (ORR = 26% [95% CI 9-51%]), 1 (5%) experienced stable disease (SD) lasting ≥ 6 months and 11 (58%) had a SD lasting < 6 months. In cohort B, the ORR was 0% [95% CI 0-41%]), 1(14%) experienced SD lasting ≥ 6 months and 5 (75%) had a SD lasting < 6 months. The combination was well tolerated, most adverse events (AE) were mild to moderate. Hematologic toxicity was the most frequent grade 3-4 AE. Analyses looking at tissue genomic markers and cell free DNA will be presented. Conclusions: We observed modest activity of the treatment combination in those without prior pertuzumab exposure but limited activity in unselected pts with HER2+ MBC. The study was limited by small sample size. Correlative studies may help us to understand resistance and response to eribulin with anti-HER2 therapy and the interplay between CT and targeted therapy. Clinical trial information: NCT01912963.
Predictors of prolonged benefit from palbociclib (PAL) plus fulvestrant (F) in women with endocrine-resistant hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) advanced breast cancer (ABC) in PALOMA-3.
Authors: Cristofanilli Massimo , DeMichele Angela , Giorgetti Carla , Slamon Dennis J. , Im Seock-Ah , Masuda Norikazu , Verma Shailendra , Loi Sherene , Colleoni Marco , Theall Kathy Puyana , Huang Xin , Bartlett Cynthia Huang , Turner Nicholas C. 
Published: September 2018

1050 Background: PAL+F improved progression-free survival (PFS) over F + placebo (P) in patients (pts) with endocrine-resistant HR+/HER2– ABC. We examined factors predictive of long-term benefit on PAL+F. Methods: Pre/postmenopausal pts with HR+/HER2– ABC that progressed on prior endocrine therapy (ET) were randomized 2:1 to PAL (125 mg/d oral [3 wk on, 1 wk off]) + F (500 mg) or P+F. Characteristics of pts with prolonged benefit (treatment [tx] duration ≥18 mo for PAL+F; ≥12 mo for P+F based on median PFS and tx duration) were compared with the intent-to-treat (ITT) population. Results: PAL+F improved PFS vs P+F (11.2 vs 4.6 mo; hazard ratio, 0.50). By Aug 2016, 138 pts had long-term benefit: 100/347 (29%) pts on PAL+F received tx for ≥18 mo, including 70 (20%) who received > 2 y (26–39 cycles). In contrast, 38/174 (22%) pts on P+F received ≥12 mo of tx; only 16 (9%) received > 2 y (27–38 cycles). No apparent differences in baseline characteristics of pts with long-term benefit were observed between groups except that a greater proportion of those on P+F had a single site of disease involvement (40% PAL+F vs 63% P+F). Pts with long-term benefit on PAL+F had lower rates of visceral disease (42% vs 60%), liver metastases (18% vs 40%), and ≥3 disease sites (27% vs 39%) at baseline vs the ITT population; no difference in sensitivity to prior ET was observed (84% vs 79%). Objective response rate (ORR) was higher among pts with prolonged benefit on PAL+F vs ITT (36% vs 26%). Conclusions: PAL+F is associated with prolonged benefit in about a third of pts treated with the combination in PALOMA-3. These pts achieve higher ORR compared to other study pts and the benefit is independent of baseline site and number of metastatic recurrences and prior endocrine sensitivity. Benefit from F alone is less prolonged and appears limited to those with 1 site of disease involvement. The analysis confirms the efficacy of PAL+F in HR+ ABC with visceral recurrence. Biomarker analyses are ongoing in pts with long-term benefit to understand molecular features predictive of tx sensitivity. Funding: Pfizer. Clinical trial information: NCT01942135.
A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.
Authors: Fangusaro Jason R. , Onar-Thomas Arzu , Young-Poussaint Tina , Wu Shengjie , Ligon Azra H , Lindeman Neal Ian , Banerjee Anuradha , Packer Roger , Kilburn Lindsay B. , Pollack Ian , Jakacki Regina , Qaddoumi Ibrahim A. , Fisher Paul Graham , Dhall Girish , Baxter Patricia Ann , Kreissman Susan G. , Doyle L. Austin , Smith Malcolm A. , Dunkel Ira J. , Fouladi Maryam ,   Pediatric Brain Tumor Consortium
Published: September 2018

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.
ACNS1221: A phase II study for the treatment of non metastatic desmoplastic medulloblastoma in children less than 4 years of age—A report from the Children Oncology Group.
Authors: Lafay-Cousin Lucie , Bouffet Eric , Onar-Thomas Arzu , Billups Catherine A , Hawkins Cynthia , Eberhart Charles , Horbinski Craig , Robinson Giles W. , Strother Douglas R. , Heier Linda , Souweidane Mark M. , Fouladi Maryam , Gajjar Amar J. ,   Children Oncology Group
Published: September 2018

10505 Background: Nodular desmoplastic medulloblastoma and medulloblastoma with extensive nodularity (ND/MBEN) have been associated with a more favorable outcome in younger children. However, treatment-related neurotoxicity remains a significant concern in this vulnerable group of patients. Methods: We prospectively conducted a single-arm multicenter trial of conventional chemotherapy for non-metastatic ND/MBEN, based on a modified HIT SKK2000 regimen excluding the use of intraventricular methotrexate (MTX) injection, with the aim to achieve a similar outcome with reduced treatment related neurotoxicity. The design required 37 patients and targeted a 2-year PFS of ≥ 90%. Secondary objectives included evaluation of feasibility of timely central pathology review, prospective evaluation of the cohort’s molecular profile and neurocognitive outcomes. Results: Between 12/2013 and 07/2016, 26 patients were enrolled, including 16 males and 10 females, diagnosed at a median age of 19.7 months (7.1-42.9 months). Four patients had residual disease at baseline. There were 19 ND and 7 MBEN medulloblastoma, confirmed by central pathology review. All cases were reviewed within 10 days by at least 2 of the 3 neuropathologists. The study was closed early following interim analysis due to a higher than expected relapse rate. At last follow-up, 7 patients had relapsed (3 local, 2 distant and 2 combined) at a median time of 9.7 months from diagnosis (range, 9.5-13.7 months). One patient subsequently died of disease. The current median follow-up for the 25 survivors is 1 year (range, 0.2-1.9 years) and the 1 year PFS rate is 66.2% (SE 12.2%). Based on the currently available information, older age (p = 0.07) and ND histology (p = 0.009) appear to be associated with worse PFS. To date none of the patients with MBEN histology have relapsed. Conclusions: The proposed modified regimen of chemotherapy without intraventricular MTX failed to achieve the desirable 2 y PFS of 90%, leading to premature closure of the study. Ongoing molecular characterization of the cohort may help uncover patients who may still benefit from this regimen. Clinical trial information: NCT02017964.
Biomarkers of brain injury and neurologic outcomes in children treated with chemotherapy for acute lymphoblastic leukemia (ALL).
Authors: Cheung Yin Ting , Khan Raja B. , Liu Wei , Brinkman Tara M. , Edelmann Michelle N. , Reddick Wilburn E. , Pei Deqing , Panoskaltsis-Mortari Angela , Srivastava Deokumar , Cheng Cheng , Robison Leslie L. , Hudson Melissa M. , Pui Ching-Hon , Krull Kevin R. 
Published: September 2018

10521 Background: Little is known about neurotoxic mechanisms associated with chemotherapy in children with ALL. Cerebrospinal fluid (CSF) biomarkers of brain injury may provide insight into this process. Methods: 235 patients (51% male; mean [SD] age diagnosed 6.8 [4.7] years) treated on a chemotherapy only protocol provided CSF samples following diagnosis and through consolidation. CSF was assayed for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF], total-Tau [T-Tau]) and astrogliosis (glial fibrillary acidic protein [GFAP]). Leukoencephalopathy was evaluated by brain MRI’s during therapy. At ≥5 years post-diagnosis, 138 (70%) of the 198 still eligible survivors (without relapse and unrelated neurologic injury) completed neurocognitive testing and brain diffusion tensor imaging of white matter integrity at age 13.6 [4.6] years. Log-binomial and general linear models were used to examine whether biomarker changes from baseline through consolidation were related to serum methotrexate exposure, acute leukoencephalopathy, and long-term brain outcomes. Results: NGF and T-Tau increased from baseline to consolidation ( P's < 0.001), while MBP and GFAP were elevated at baseline and remained so through consolidation. The number of intrathecal injections (methotrexate, hydrocortisone, cytarabine) was positively correlated with NGF increase at consolidation ( P= 0.005). Increases in GFAP (RR 1.2; 95% CI [1.0 – 1.4]), MBP (RR 1.1 [1.0 – 1.1]) and T-Tau (RR 1.8 [1.1 – 2.8]) were related to higher risk for acute leukoencephalopathy, and higher diffusivity in frontal lobe white matter at ≥5 years post-diagnosis ( P’s < 0.05). Increase in T-Tau at consolidation was associated with worse long-term sustained attention ( P= 0.03), and visual- ( P= 0.04) and visual-motor ( P= 0.02) processing speed. Conclusions: Glial injury, which is evident at diagnosis, may be related to leukemia and methotrexate exposure. Neuronal injury is associated with intrathecal chemotherapy and long-term neurocognitive and brain imaging outcomes. Monitoring CSF biomarkers may be useful in identifying individuals at risk for poor neurological outcomes.
Cardiac effects of chimeric antigen receptor (CAR) T-cell therapy in children.
Authors: Burstein Danielle S. , Maude Shannon L. , Grupp Stephan A. , Griffis Heather , Rossano Joseph W. , Lin Kimberly Y. 
Published: September 2018

10531 Background: Treatment with CAR T-cells targeting CD19 for pediatric leukemia has demonstrated significant efficacy with the principal toxicity being cytokine release syndrome (CRS). However, the cardiac effects related to CAR T-cell therapy have not been systematically evaluated. Methods: A retrospective chart review was performed on a large cohort who received CAR T-cell therapy from April 2012 through September 2016. Baseline oncologic and cardiac characteristics were recorded. Cardiomyopathy was defined as an ejection fraction < 55%, shortening fraction < 28%, or diastolic dysfunction. Primary outcome was cardiac event, defined as need for inotropic support or echocardiographic decline in function. Descriptive and univariate analyses were performed. Results: 93 patients were included [55% male, mean age 11.8 yrs (range 1.7-27.1)]; 98% had B cell ALL. Prior to treatment, 15% had cardiomyopathy and 1 patient had single ventricle Fontan palliation. Cardiac events occurred in 34 (36%) with mean onset 4.8 days (range 1-9) after CAR T-cell infusion, of whom 12 (35%) had abnormal systolic or diastolic function on echocardiogram and 6 (18%) required milrinone for cardiac support. 21 (22%) patients had CRS requiring tocilizumab and vasoactive infusions; there were no cardiac-related deaths. Factors associated with cardiac events included higher pre-treatment blast % on bone marrow biopsy [OR 10.45 (95% CI 3.87-28.22) for blast > 10%; p < 0.001] but not cardiomyopathy (p = 0.356), total body irradiation (p = 0.717) or anthracycline dose (p = 0.711). At discharge, 7 (7.5%) patients had worse cardiac function than at baseline, but only 2 (2%) had persistent cardiac dysfunction by 6 months post-infusion. Pre-treatment factors were not associated with persistent dysfunction. Conclusions: This is the first study to describe the cardiac effects of CAR T-cell therapy in children. CAR T-cell therapy appears to be safe, even in patients with cardiomyopathy. Although one-third experienced a cardiac event, persistent cardiac dysfunction is rare. Children with a pre-treatment blast > 10% were most at risk for cardiac events, a finding that may help identify patients who warrant close observation and early intervention with pressor support.
Clinical outcomes of adolescents and young adults (AYA) with advanced solid tumors participating in phase I trials.
Authors: Sundar Raghav , McVeigh Terri Patricia , Petruckevitch Ann , Diamantis Nikolaos , Ang Joo Ern , Chenard-Poirier Maxime , Collins Dearbhaile Catherine , Lim Joline Si Jing , Ameratunga Malaka , Khan Khurum Hayat , Kaye Stanley B. , Banerji Udai , Lopez Juanita Suzanne , De Bono Johann S. , Van Der Graaf Winette T.A. 
Published: September 2018

10536 Background: AYA cancer patients are relatively under-represented in clinical trials, with no published data regarding their outcomes in phase I studies. Trials utilizing novel therapeutic agents are often considered in these patients, due to their tendency to have good organ reserve, and ability to tolerate additional lines of therapy. This study describes the experience of AYA patients with advanced solid tumors treated in a specialized drug development unit. Methods: Patient characteristics and clinical outcomes of AYA patients (defined as age 15 to 39 years at time of initial cancer diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, United Kingdom, between 2002 and 2016, were captured and analyzed from case and trial records. Results: From a database of 2631 patients treated on phase I trials, 219 AYA patients (8%) were identified. Major tumor types included gynaecological cancer (24%), sarcoma (18%), gastrointestinal (16%) and breast cancer (11%). Patients had a median of 3 previous lines of systemic chemotherapy (range 0 – 6), and 19% participated in 2 or more phase I studies. Twenty (9%) had a known hereditary cancer syndrome (most commonly BRCA), 27% had a family history (FH) of cancer, 15% no FH and 49% no FH documented. Molecular characterization of tumors (n = 45) identified mutations most commonly in p53 (33%) , PI3KCA (18%) and KRAS (9%) . Major trial categories included DNA damage repair (16%), PI3K (16%) and anti-angiogenesis (15%) agents. Grade 3/4 toxicities were experienced in 25% of patients (10% hematological). Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median progression free survival was 2.3 months (95% CI: 1.9 to 2.8), median OS was 7.6 months (95% CI: 6.3 to 9.5), and 2-year OS was 11%. Of patients with responses, 35% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusions: A sub-group of AYA patients with advanced solid tumors derive considerable benefit from participating in trials involving novel therapeutics. Future research must focus on predictive biomarkers and molecular profiling to identify those that would benefit from novel therapies.