bluuebunny/crossref_metadata_2025_split huggingface dataset:
FGFR gene amplification and response to endocrine therapy in metastatic hormone receptor positive (HR+) breast cancer.
Authors: Drago Joshua Z. , Niemierko Andrzej , Spring Laura , Moy Beverly , Juric Dejan , Isakoff Steven J. , Iafrate A. John , Ellisen Leif W. , Bardia Aditya 
Published: September 2018

1013 Background: Amplification in Fibroblast Growth Factor Receptor (FGFR) genes occurs in 10% of breast cancers, is associated with poor prognosis, and appears to drive resistance to endocrine therapies in vitro. However, the role of FGFR in modulating the clinical response to endocrine therapies is unclear, and could have important implications given that FGFR is a potential therapeutic target. This study aims to evaluate the association between FGFR amplification and clinical response to endocrine therapy in HR+ metastatic breast cancer (MBC). Methods: Primary or metastatic tumor specimens from patients with HR+/HER2 negative MBC underwent dual-color fluorescence in situ hybridization (FISH) of the FGFR1 locus on chromosome 8p. FISH ratios of ≥2 were considered positive for gene amplification (FGFR+). Time to progression (TTP) on first line endocrine therapy was evaluated in FGFR+ versus wild type (WT) patients using actuarial analysis. Results: Between 2012 and 2016, we identified 95 patients with HR+ MBC who underwent FGFR FISH testing. Of these, 24 (25.3%) were FGFR+. FGFR+ and WT patients did not differ in being postmenopausal at initial breast cancer diagnosis (28.6% vs. 31.7%; p = 1.0), having de-novo MBC (16.7% vs. 21.1%; p = 0.773), having received adjuvant chemotherapy (75% vs. 76.8%; p = 1.0) or having received adjuvant endocrine therapy (90% vs. 91.1%; p = 1.0). However, FGFR+ patients tended to be younger than WT patients (54.3 vs. 59.3 years; p = 0.045), and more likely to have PR-negative MBC (50.0% vs. 19.1%; p = 0.011). While there was no difference in TTP on first-line chemotherapy in FGFR+ vs. WT patients (5.0 vs. 6.2 months; p = 0.8), FGFR+ patients had a shorter median TTP on first-line endocrine therapy than WT (8.5 vs. 10.8 months; p = 0.047). These results were similar when stratified by presence of de-novo metastatic disease. Conclusions: In patients with HR+ MBC, FGFR gene amplification is associated with shorter time to progression on first line endocrine therapy. Further studies are needed to confirm these findings, and to investigate potential strategies for endocrine therapy and FGFR-directed combinatorial therapy in FGFR+ breast cancer.
Long-term survival of de novo stage IV human epidermal growth factor receptor 2 (HER2)-positive breast cancers treated with HER2 targeted therapy.
Authors: Wong Yao , Raghavendra Akshara Singareeka , Hatzis Christos , Irizarry Javier Perez , Vega Teresita , Barcenas Carlos Hernando , Chavez-Mac Gregor Mariana , Valero Vicente , Tripathy Debu , Pusztai Lajos , Murthy Rashmi Krishna 
Published: September 2018

1021 Background: An increasing number of metastatic HER2 positive cancers represent de novo stage IV disease as fewer early stage patients relapse. We hypothesize that a subset of these has long progression free survival (PFS) after initial combined modality HER2-targeted therapies. Methods: 483 patients with de novo stage IV HER2 positive breast cancer diagnosed between 1998-2015 were identified through the medical records at Yale and MD Anderson Cancer Centers, respectively. Treatment, clinical variables and survival were extracted and compared between those who achieved “no evidence of disease” (NED) status with initial therapy and those who did not. Results: All patients received trastuzumab and 94 (20%) also received pertuzumab as first line therapy.The median OS was 5.5 years (95% Cl: 4.8-6.2); OS rates at 5 and 10 years were 54% (95% CI: 48%-60.4%) and 18% (95% Cl: 11.4%-28.3%), respectively and PFS were 41% (95% CI: 35%-48%) and 41% (95% CI: 35%-48%). Sixty-three patients (13.0%; 95% CI: 10.2% -16.4%) achieved NED. The PFS and OS at 5 and 10 years were the same 100% and 98% (95% CI: 94.6%-100%), respectively. For patients with no-NED (n = 420), the median OS was 4.7 years (95% Cl: 4.2-5.3), the PFS and OS rates at 5 and 10 years were 12% (95% CI: 4.5%-30.4%) and 0% and 45% (95% CI: 38.4%-52.0%) and 4% (95% CI: 1.3%-13.2%), respectively. NED patients had significantly longer progression free survival (log-rank test p≤0.001) and overall survival (log-rank test p≤0.001), more frequently had single organ site metastasis (76% vs 57%, p = 0.005), and more frequently had surgery for primary tumor (59% vs. 25%, p ≤0.001) than no-NED patients, but there was no significant difference in age, grade, race, year of diagnosis, ER status, treatment distribution, or radiation between the groups. Conclusions: About 13% of de novo, stage IV, HER-2 positive MBC patients achieved NED with HER-2 targeted therapies, all of these patients were progression free at 5 years and overall survival at 10-years was 98% compared to 4% among those with no-NED in our data sets. These results suggest that aggressive multimodality therapy of newly diagnosed stage IV HER2 positive cancers to render them NED may be warranted.
The effect of pembrolizumab in combination with CD19-targeted chimeric antigen receptor (CAR) T cells in relapsed acute lymphoblastic leukemia (ALL).
Authors: Maude Shannon L. , Hucks George E , Seif Alix Eden , Talekar Mala Kiran , Teachey David T. , Baniewicz Diane , Callahan Colleen , Gonzalez Vanessa , Nazimuddin Farzana , Gupta Minnal , Frey Noelle V. , Porter David L. , Levine Bruce L , Melenhorst Jan J. , Lacey Simon F. , June Carl H. , Grupp Stephan A. 
Published: September 2018

103 Background: CD19-targeted CAR T cells show CR rates of 70-95% in B-ALL. Yet a subset of patients do not respond or relapse due to poor CAR T cell expansion and persistence. We hypothesized that PD-1 checkpoint pathway inhibition may improve CAR T cell expansion, function and persistence. Methods: Four children with relapsed B-ALL treated with murine (CTL019) or humanized (CTL119) anti-CD19 CAR T cells received 1-3 doses of the PD-1 inhibitor pembrolizumab (PEM) for partial/no response or prior history of poor CAR T cell persistence starting 14d-2mo post CAR T cell infusion. Results: PEM increased and/or prolonged detection of circulating CAR T cells in all 4 children, with objective responses in 2/4. It was well tolerated, with fever in 2 pts and no autoimmune toxicity. Pts 1-3 received CTL119 for CD19+ relapse after prior murine CD19 CAR T cells. Pt 1 had 1.2% CD19+ residual disease despite expansion with detectable CTL119 by D28 and received PEM at 2mo for progressive disease with decreasing circulating CTL119. CTL119 became detectable at 0.2% of CD3+ cells by flow cytometry, but disease progressed. Pt 2 had no response after initial CTL119 expansion with a rapid disappearance by D28. After CTL119 reinfusion with PEM added 14d later, circulating CAR T cells remained detectable at 4.4% by D28, but disease progressed with decreased CD19 expression. In Pt 3, prior treatment with both CTL019 and CTL119 produced CR with poor CAR T cell persistence followed by CD19+ relapse. CTL119 reinfusion combined with PEM at D14 resulted in CR with prolonged CTL119 persistence (detectable at D50 compared to loss by D36 after 1st CTL119 infusion). Pt 4 received PEM for widespread extramedullary (EM) involvement at D28 post CTL019 infusion despite marrow remission. Initial CTL019 expansion peaked at 63% at D10 and fell to 20% at D28. Resurgence of CTL019 expansion, with a 2nd peak of 70% 11d after PEM, was associated with dramatic reduction in PET-avid disease by 3mo post CTL019. Conclusions: PEM was safely combined with CAR T cells and increased or prolonged CAR T cell detection, with objective responses seen. Immune checkpoint pathways may impact response to CAR T cell treatments and warrant further investigation. Clinical trial information: NCT02374333, NCT02906371.
A phase II, randomized, open-label 3-arm clinical trial of fulvestrant (F) plus goserelin (G) versus anastrozole (A) plus goserelin (G) versus goserelin (G) alone for hormone receptor (HR) positive, tamoxifen (T) pretreated premenopausal women with recurrent or metastatic breast cance r(MBC) (KCSG BR10-04).
Authors: Kim Ji-Yeon , Im Seock-Ah , Jung Kyung Hae , Ro Jungsil , Sohn Joohyuk , Kim Jee Hyun , Park Yeon Hee , Kim Tae Yong , Kim Sung-Bae , Lee Keun-Seok , Kim Gun Min , Kim Se Hyun , Ahn Jin Seok , Lee Kyung-Hun , Ahn Jin-Hee , Park In Hae , Im Young-Hyuck 
Published: September 2018

1041 Background: Endocrine therapy(ET) is the preferred treatment for HR(+) MBC. For premenopausal patients who were pretreated with T, ovarian function suppression with G ± aromatase inhibitor(A.I.) is a reasonable option. Fulvestrant yields favorable outcomes in postmenopausal women with MBC. We investigated the efficacy and safety of F+G and A+G in comparison with G alone in premenopausal women with HR(+), T-pretreated MBC. Methods: In this multicenter, open-label, randomized phase 2 study, women > 18 years with HR(+), T-pretreated MBC were stratified by presence of visceral metastasis and recurrence within or after 1 year of completion of adjuvant T. Premenopausal women with T-pretreated MBC eligible for ET were randomly assigned (1:1:1) to F+G (F 500 mg IM + G 3.6 mg SC Q 4 wks), or A +G (A 1 mg P.O. qd + G 3.6 mg SC Q 4 wks) or G (G 3.6 mg SC Q 4 wks). The primary endpoint was time to progression(TTP), analyzed by intention to treat with log-rank test. Secondary endpoints included overall survival, overall response rate, clinical benefit rate and toxicities according to NCI CTCAE v3.0 (ClinicalTrials.gov, No. NCT01266213). Results: Of 138 eligible pts, 44 were randomly assigned to F+G, 47 to A+G, 47 to G. The median duration of follow-up was 28.8 months(mo) and median age was 43 (range; 23.0-55.0). The median TTP was 16.3 mo(95% C.I. 7.5-25.1) for F+G, 14.5 mo(95% C.I. 11.0-18.0) for A+G, and 13.5 mo(95% C.I. 10.3-16.8) for G alone, respectively. For the comparison of each experimental arm to control arm, 24-mo TTP were analyzed: F+G vs G(%±SE): 40.5±7.5 vs. 25.3±7.0, one-sided P = 0.048, A+G vs G(%±SE): 23.9±7.2 vs. 25.3±7.0, one-sided P = 0.304. Grade 3/4 toxicities were rarely observed. Most common adverse events were grade 1 joint stiffness and arthralgia which were more frequently observed in F+G compared to A+G and G (P = 0.018 and 0.015, respectively). Conclusions: The combination of F+G as well as G ±A.I. might be a valid option for HR(+) premenopausal women with T-pretreated MBC and further investigation is warranted. Clinical trial information: NCT01266213.
First-line ribociclib plus letrozole for postmenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC): MONALEESA-2 safety results.
Authors: Janni Wolfgang , Burris Howard A. , Blackwell Kimberly L. , Hart Lowell L. , Chan Arlene , Nusch Arnd , Burdaeva Olga Nikolaevna , Alba Emilio , Yardley Denise A. , Bachelot Thomas Denis , Gil Gil Miguel J. , Richards Donald A. , Sparano Joseph A. , Kattan Joseph Gergi , Bourgeois Hugues Pierre , El Karak Fadi Rafic , Ramaswamy Bhuvaneswari , Sutradhar Santosh C. , Miller Michelle Kristine , Conte Pier Franco 
Published: September 2018

1047 Background: In the randomized, phase III MONALEESA-2 study (NCT01958021), first-line therapy with ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor; 600 mg/day; 3-weeks-on/1-week-off) + letrozole (LET; 2.5 mg/day) in postmenopausal women with HR+, HER2– ABC significantly prolonged progression-free survival vs placebo (PBO) + LET (hazard ratio: 0.556; p = 0.00000329; Hortobagyi GN et al. N Engl J Med 2016;375:1738–48). Here we present further safety analyses from MONALEESA-2. Methods: Adverse events (AEs) were characterized per CTCAE v4.03. Analyses of key AEs included time to first event, duration (time to AE resolution), and the rate of associated dose interruptions or reductions. Results: Safety analysis included 664 patients (pts; RIB + LET: 334; PBO + LET: 330). Neutropenia was the most common all-grade (G) and G3/4 AE in the RIB + LET arm (Table); febrile neutropenia rates were low (RIB + LET arm: 1.5%) with no associated deaths. Median time to first event for G ≥2 neutropenia in the RIB + LET arm (based on neutrophil counts) was 16 days. Other common G3/4 AEs (increased by ≥5% in the RIB + LET vs PBO + LET arm) were leukopenia (21% vs 1%), elevated alanine aminotransferase (ALT; 9% vs 1%), lymphopenia (7% vs 1%), and elevated aspartate aminotransferase (AST; 6% vs 1%). Neutropenia was the most common AE leading to dose interruptions/reductions; G3/4 neutropenia led to dose interruptions in 48% vs < 1% and reductions in 30% vs 0% of pts in the RIB + LET vs PBO + LET arm. 7.5% vs 2.1% of pts (RIB + LET vs PBO + LET) discontinued due to AEs; common AEs leading to discontinuation ( > 1% pts) were elevated ALT (5% vs < 1%), elevated AST (3% vs 1%), and vomiting (2% vs 0%). Conclusions: First-line RIB + LET had a manageable safety profile in postmenopausal women with HR+, HER2– ABC. Neutropenia was the most common AE in the RIB arm, and was transient and reversible with dose modifications. Additional AE analyses will be presented. Clinical trial information: NCT01958021. [Table: see text]
A phase I trial of pomalidomide for children with recurrent, progressive/refractory central nervous system (CNS) tumors: A Pediatric Brain Tumor Consortium (PBTC) study.
Authors: Fangusaro Jason R. , Mitchell Duane Anthony , Kocak Mehmet , Onar-Thomas Arzu , Sadighi Zsila Sousan , Baxter Patricia Ann , Hwang Eugene I. , Huang Jianping , Dunkel Ira J. , Fouladi Maryam , Warren Katherine E. 
Published: September 2018

10543 Background: CNS malignancies are the most common solid tumors among children. Novel therapies are needed to help improve the survival outcomes in children with recurrent disease. Pomalidomide is an immunomodulatory agent thought to also function through a combination of anti-angiogenic, anti-inflammatory and cytotoixic activity making it a good candidate to explore in pediatric CNS tumors. Methods: A Phase I trial of pomalidomide was conducted among children ≥ 3 to < 21 years old with recurrent, progressive/refractory CNS tumors using the “rolling 6” dose escalation design. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day course. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. Results: 29 children were enrolled and 25 were evaluable for dose limiting toxicity (DLT) evaluation. The MTD was 2.6 mg/m2 (Dose level 2). DLTs observed at dose level 3 (3.4 mg/m2) included diarrhea (n = 1), thrombocytopenia (n = 1) and lung infection (n = 1), all grade 3. The most common toxicities were grade 1 lymphopenia (55%), leukopenia (62%) and thrombocytopenia (38%). There were no obvious differences in tolerability based on age or steroid use. Pharmacokinetics were similar to those observed in adults and increased in a dose-dependent manner. At the RP2D of 2.6 mg/m2, the Cmax was 97.4 ng/mL and the t½ was 4.1 hours. The median number of treatment cycles was 1.6 (0.2-12.3). Two patients, one with an oligodendroglioma and one with anaplastic pleomorphic xanthoastrocytoma, had long term stable disease for 9 and 18+ cycles. No objective responses were observed. Twelve month progression-free and overall-survivals were 5.2+/-3.6% and 12.8+/-8.5%, respectively. Immunologic correlate analyses are ongoing. Conclusions: The RP2D of pomalidomide is 2.6 mg/m2 in children with recurrent brain tumors. Further prospective evaluation of this agent alone or in combination will be necessary to better understand its efficacy in specific pediatric CNS tumor populations. Clinical trial information: NCT02415153.
Phase I study of pexidartinib (PLX3397) in children with refractory leukemias and solid tumors including neurofibromatosis type I (NF1) related plexiform neurofibromas (PN).
Authors: Hittson Lauren , Glod John , Amaya Melissa , Derdak Joanne , Widemann Brigitte C. , Kaplan Rosandra N. 
Published: September 2018

10546 Background: Refractory tumors remain a significant treatment challenge, and novel approaches targeting the tumor microenvironment may hold promise. Pexidartinib, an oral inhibitor of tyrosine kinases including CSF1R, KIT and FLT3, has activity in adults with tenosynovial giant cell tumor. Methods: We are conducting a phase 1 trial (NCT02390752) to determine the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK) of pexidartinib in patients (pts) 3-21 years old with refractory leukemias and solid tumors including NF1 PN. The MTD is based on cycle (C) 1 toxicities. Pexidartinib is given once daily continuously (1C = 28 days) at DL 1: 400 mg/m2/dose, 2: 600mg/m2/dose, or 3: 800 mg/ m2/dose. Response is assessed after C1 and then every other C, and for NF1 PN with volumetric MRI analysis after every 4 C. Results: Fourteen pts (8 M:6 F, median age 16 years, (range 4-21) with CNS tumors (n = 2), sarcomas (n = 7), peritoneal mesothelioma (n = 1), leukemia (n = 1), NF1 PN (n = 3) have enrolled at DL1 (n = 4), DL2 (n = 4) and DL3 (n = 6). No dose-limiting toxicities have been observed and 11 pts are evaluable for MTD determination (received ≥ 85% of pexidartinib doses in C1). Common non-DLT toxicities are fatigue, decrease in WBC, increase in creatinine kinase and serum amylase, headache, anorexia, vomiting, diarrhea, and hair hypopigmentation. Mean (SD) pexidartinib C1 day 1 PK parameters at [DL1 (n = 4), DL2 (n = 4), and DL3 (n = 4)] were: Cmax DL1 2,813 ng/mL (1,483), DL2 6,065 ng/mL (1,308), DL3 10,323 ng/mL (2,129); AUC0-24h DL1 44,492 ng·h/mL (12,904), DL2 76,569 ng·h/mL (25,790), DL3 132,903ng·h/mL (40,482). The mean (SD) accumulation ratio (C1 D15 AUC0-24h : C1 D1 AUC0-24h ) was 3.9 (0.7) for DL1, 2.4 (0.3) for DL2, and 1.4 (0.6) for DL3. Pts received a median of 1 C (range (1-21+). Pts with NF1 PN received 1, 4, and 6 C of pexidartinib and had stable disease. One pt with peritoneal mesothelioma is receiving C 21. Conclusions: In children, pexidartinib was tolerated at all dose levels, and the recommended phase II dose (RP2D) is 800 mg/m2/dose once daily. This dose exceeds the adult RP2D of 1000 mg/day. Enrollment on the expansion cohort is ongoing. Clinical trial information: NCT02390752.
Long-term outcomes after irradiation (RT) for pediatric low-grade glioma.
Authors: Tsang Derek S. , Murphy Erin Sennett , Merchant Thomas E. 
Published: September 2018

10549 Background: Treatment for pediatric low-grade glioma (LGG) is variable, depending on age and tumor location. Systemic therapy (ST) is often used to delay RT, but ST does not result in durable local control. The goal of this study was to evaluate event-free survival (EFS) and toxicities for pediatric LGG treated with RT over a 30-year period. Methods: All patients age ≤21 with intracranial pediatric LGG (WHO grade I-II) treated with RT at a single institution since May 1986 were included in this retrospective review. Patients with metastatic disease (M+) received craniospinal irradiation (CSI); otherwise, RT was conformal. EFS and overall survival (OS) were measured from the first day of RT. Events included death, progression, or secondary high-grade glioma. Results: 221 patients were eligible. Median follow-up was 11.3 yrs (range, 0.1-30.5). Median RT dose was 54 Gy. 10-yr EFS and OS were 67.9% (95% CI 60.4-74.3) and 91.1% (95% CI 85.8-94.5) for non-metastatic patients, respectively. For 12 M+ patients treated with CSI, 10-yr EFS and OS were 58.9% (95% CI 23.4-82.5) and 70.0% (32.9-89.2), respectively. 28.6% developed pseudoprogression (PP) with median time to onset and resolution of 6.1 months (IQR 3.6-14.6) and 6.4 months (IQR 3.5-11.7), respectively. Patients with PP had improved 10-yr EFS (83.4% vs. 61.0%, HR 0.40, p = .006). Patients with grade II tumors and who received pre-RT ST had lower EFS (Table). Sex, NF-1, tumor location, extent of surgery and CSI were not independently associated with EFS. 10-yr cumulative incidence of grade ≥2 vasculopathy was 7.5% (95% CI 4.9-11.4). There were 12 cases of secondary high-grade glioma, with a 20-yr cumulative incidence of 5.5% (95% CI 2.6-11.4). Conclusions: Irradiation provides long-term control of pediatric LGG in a majority of patients. Receipt of pre-RT systemic therapy was associated with reduced EFS; this association requires further investigation. [Table: see text]
Genome-wide discovery of novel susceptibility loci for treatment-associated hypothyroidism among survivors of pediatric medulloblastoma.
Authors: Brown Austin L , Biclamowicz Kevin J. , Sonabend Rona , Scheurer Michael E. , Lupo Philip , Paulino Arnold , Dreyer ZoAnn Eckert , Mahajan Anita , Chintagumpala Murali M. , Okcu M. Fatih 
Published: September 2018

10571 Background: Pediatric medulloblastoma patients exposed to craniospinal radiation (CSI) are at high risk of developing endocrinopathies, including hypothyroidism. We sought to evaluate the role of genetic variation on hypothyroidism susceptibility among survivors of pediatric medullobastoma. Methods: Records from 61 medulloblastoma survivors treated at Texas Children’s Hospital between 1997 and 2013 were reviewed. All patients completed baseline and yearly follow-up thyroid assessments. Genome-wide genotyping was performed on Illumina HumanOmni1 and HumanOmni2.5 BeadChip single nucleotide polymorphism (SNP) arrays. Following standard quality control measures and exclusion of rare variants (minor allele frequency [MAF] < 5%), 572,562 autosomal SNPs were included in our analyses. The association between each SNP and hypothyroidism was tested using Fisher’s exact test and logistic regression, assuming additive allelic effects. Results: A total of 25 patients (41%) developed hypothyroidism with median follow-up of 8.3 years from diagnosis (range: 1.8-17.2 years). Primary hypothyroidism was identified in 9 (36%) cases, while the remaining 16 (64%) developed central hypothyroidism. Hypothyroidism was detected in 13 of 40 (33%) individuals exposed to < 30 Gy CSI and 12 of 21 (57%) individuals exposed to ≥30 Gy CSI (p = 0.06). Genome-wide association analysis identified several risk loci, including 3 variants associated with hypothyroidism (p-value < 1x10-5) at chromosome 2q11.2 ( NPAS2 gene). The top overall SNP (MAF = 27.5%, p-value = 6.5x10-7) remained strongly associated with hypothyroidism after accounting for possible confounders, including CSI dose, CSI type (proton/photon), age, sex, and genetic ancestry. Conclusions: Our findings suggest susceptibility to treatment-related hypothyroidism is strongly influenced by common genetic variation in NPAS2. The NPAS2 gene, a central component of the circadian rhythm network, is a transcriptional activator and regulator of DNA damage response and DNA repair genes.