bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictor of trastuzumab-induced cardiotoxicity in breast cancer (BC) patients: HER2/neu 655 polymorphisms, biochemical and clinical features.
Authors: Blancas Isabel , Gómez Celia , Martín-Pérez Francisco Javier , Garrido Jose Manuel , Rodríguez-Serrano Fernando 
Published: May 2020

1033 Background: The introduction of trastuzumab in the treatment scheme of the HER2 BC patients has improved the evolution of the disease. Nevertheless, some of this patients develop cardiotoxicity. We studied some of our population of HER2 positive BC patients treated with trastuzumab trying to find predictors for developing cardiotoxicity, specifically the association of the HER2 Ile655Val A˃G polymorphism with trastuzumab-induced cardiotoxicity and with survival and some biochemical and clinical features. Methods: For the study breast cancer patients were recruited from San Cecilio University Hospital in Granada (Spain) who were treated with trastuzumab. HER2 Ile655Val A˃G polimorphism was performed in 93 patients using Taqman SNP technology. We analyzed the relation of polymorphisms with disease free survival (DFS) and overall survival (OS). We also could asses 66 patients who had biochemical measurement of NTpro BNP during the treatment with trastuzumab and cardiovascular risk factors including diabetes, hypertension, smoking, hypercholesterolemia and body mass index (BMI). Cardiotoxicity was defined as a ≥ 10% decrease of the left ventricular ejection fraction (LVEF) from baseline, a LVEF below 40% or any clinical manifestation of heart insufficiency. NT-proBNP cut-off points were considered to stablish normal or abnormal values adjusted by patient age. Results: Genotype frequencies of HER2/neu 655 met Hardy-Weinberg equilibrium (p = 0.363). Logistic regression analysis adjusted by hormonal status and anthracycline treatment showed higher cardiotoxicity risk for AG vs AA Her2-Ile655 polimorphism (OR = 3.00, CI95% 1.07-8.41, p = 0.037) or for AG vs AA+GG Her2-Ile655 polimorphism (OR = 3.21, CI95% 1.15-8.96, p = 0.026). We did not find association between HER2neu Ile655Val polymorphism and DFS or OS. NT-proBNP baseline higher than the range (OR 5.9, 95% CI 1.2 - 28.5, p = 0.028) and diabetes mellitus (OR 22.0, 95% CI 5.7 - 85.4, p = 0.000) were found to be related with the development of cardiotoxicity. Conclusions: HER2-Ile655 A˃G polymorphism is significantly associated with higher risk of trastuzumab-induced cardiotoxicity but it is not correlated with DFS neither OS. Diabetes or baseline high NT-proBNP levels are predictors for the development of trastuzumab-induced cardiotoxicity. These parameters should be considered for a closer follow up and for preventive actions as accurate glycaemic control for patients who will receive trastuzumab.
Management of adverse events in patients with HER2+ metastatic breast cancer treated with tucatinib, trastuzumab, and capecitabine (HER2CLIMB).
Authors: Okines Alicia Frances Clare , Paplomata Elisavet , Wahl Tanya A. , Wright Gail Lynn Shaw , Sutherland Stephanie , Jakobsen Erik , Valdes Frances , Chan Arlene , Clark Amy Sanders , Conlin Alison Katherine , Lustberg Maryam B. , Specht Jennifer M. , Pluard Timothy J. , Zhu Xiaofu , Krop Ian E. , Gelmon Karen A. , Slamon Dennis J. , Ramos Jorge , An Grace , Hamilton Erika Paige 
Published: May 2020

1043 Background: Tucatinib (TUC) is an investigational TKI, highly selective for HER2 without significant inhibition of EGFR. HER2CLIMB is a randomized trial of TUC vs placebo in combination with trastuzumab and capecitabine in patients (pts) with HER2+ breast cancer (NCT02614794, Murthy NEJM 2019). The most common G ≥3 adverse events (AEs) with higher incidence on the TUC arm (diarrhea, palmar-plantar erythrodysesthesia syndrome [PPE], and elevated liver enzymes) are described herein. Methods: Given that pts on the TUC arm had a longer duration of tx than those on the control arm, time-at-risk exposure-adjusted incidence rates of diarrhea, AST, ALT, and PPE were calculated as the number of pts with an event divided by the total exposure time-at-risk of an initial occurrence of the event among pts in the tx group. Time-to-event analyses were conducted for AST/ALT/bilirubin (in aggregate), diarrhea, and PPE. Results: Diarrhea and elevated AST/ALT/bilirubin on both the TUC and control arms were primarily G1/2 and manageable with dose modifications, and in some cases of diarrhea, with antidiarrheal tx. Median time to diarrhea onset was shorter on the TUC arm compared to control. For AST/ALT/bilirubin and PPE, median time to first onset was Cycles 1 and 2. On the TUC arm, antidiarrheals were used in 49.7% of cycles in which diarrhea was reported (39.8% on the control arm), and when used, the median duration of use on each arm was 3 days per cycle. Prophylactic antidiarrheals were not required per protocol. When adjusted for exposure (time-at-risk exposure-adjusted incidence rate per 100 person-years), the difference in G ≥3 events between tx arms becomes similar for diarrhea and PPE (21 vs 17 and 21 vs 19). The difference in G ≥3 events between arms is reduced for AST and ALT (7 vs 1 and 8 vs 1). Conclusions: TUC with trastuzumab and capecitabine was well-tolerated. Rates of G ≥3 diarrhea and PPE were similar between tx arms. Elevated liver enzymes were higher on the TUC arm, but were transient and reversible. Discontinuation of TUC due to AEs was rare. Clinical trial information: NCT02614794 . [Table: see text]
Peripheral endothelial function changes during HER2-directed therapy differ based on whether or not a patient receives anthracycline.
Authors: Hazim Antonious Ziad , Nhola Lara F. , Villarraga Hector R. , Patel Shruti R , Sandhu Nicole , Lerman Amir , Loprinzi Charles L. , Ruddy Kathryn Jean , Herrmann Joerg 
Published: May 2020

1044 Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.
Patient-matched tissue and liquid biopsies identify shared and acquired genomic alterations in breast cancer.
Authors: Sokol Ethan , Sivakumar Smruthy , Jin Dexter , Danziger Natalie , McGregor Kimberly , Pavlick Dean , Dennis Lucas , Ross Jeffrey S. , Frampton Garrett M. , Venstrom Jeffrey , Hegde Priti , Molinero Luciana , Oesterreich Steffi , Chung Jon 
Published: May 2020

1050 Background: Liquid biopsy-based comprehensive genomic profiling (CGP) is a minimally invasive approach to potentially identify truncal driver alterations and mechanisms of acquired resistance. However, there are limited data comparing solid tissue and plasma biopsies from the same patient in breast cancer. Methods: CGP was performed on matched tumor tissue and plasma samples from 444 patients with breast cancer (Foundation Medicine, Inc.) to identify short variant mutations and rearrangements in at least 62 genes. ER/PR/HER2 status was abstracted for a subset of patients (n = 273). Patients were primarily ER+/HER2- (58%) with fewer HER2+ (16%) and TNBC (25%). Results: Samples were temporally heterogeneous with a median time between matched tissue-plasma collection of 276 days (interquartile range 45 - 650). Positive percent agreement (PPA) to tissue biopsy was 81.5% with higher PPA for collection interval ≤1y v > 1y (82.5% v 76.5%). PPA was highest in known truncal driver genes ( AKT1, PTEN, BRCA2, BRCA1, TP53, PIK3CA: 85-89% PPA). PPA of tissue to liquid biopsy was 50.5% with strong time dependence (62.4% ≤1y, 37.9% > 1y), presumably due to intervening therapies. Acquired alterations in liquid biopsy were primarily known resistance mechanisms ( ESR1, NF1, ERBB2, PIK3CA, PTEN, TP53, BRCA1, and BRCA2), were often polyclonal, associated with longer collection intervals, and exhibited higher prevalence in the ER+/HER2- subtype (62% ER+/HER2-, 33% HER2+, 42% TNBC). Acquired alterations significantly enriched in ER+ cases included ESR1, NF1, ERBB2 and TP53. For PIK3CA, a PPA of 84.6% was observed with solid as baseline and 79.1% with liquid as baseline; prevalence was similar (36.5% solid, 35.6% liquid). Alpelisib companion diagnostic alterations (CDx) had a similar PPA (84.0% solid, 83.3% liquid). Overall percent agreement (OPA) for PIK3CA CDx in paired samples was 91.4% (406/444). When acquired PIK3CA alterations are observed they tend to be subclonal, co-occur with shared PIK3CA alterations, and consist of rare alterations (E726K, E453K, M1043I). Conclusions: While high PPA to tissue was observed for alterations in truncal driver genes, acquired alterations observed in plasma were frequently polyclonal, often identify potential mechanisms of therapeutic resistance and are, in part, a function of time and intervening treatments relative to tissue CGP. These results demonstrate high PPA to tissue suggesting that liquid biopsy has clinical validity in identifying truncal alterations and can also identify acquired alterations in breast cancer.
Phase I study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors.
Authors: Casanova Michela , Bautista Francisco , Campbell Hewson Quentin , Makin Guy , Marshall Lynley V. , Verschuur Arnauld , Canete Adela , Corradini Nadège , Ploeger Bart , Mueller Udo , Zebger-Gong Hong , Chung John Woojune , Geoerger Birgit 
Published: May 2020

10507 Background: In pediatric patients with solid tumors, regorafenib demonstrated acceptable tolerability and preliminary anti-tumor activity. This phase 1 study evaluated regorafenib in combination with vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intravenous vincristine (1.5 mg/m2, Days 1 and 8) and irinotecan (50 mg/m2/day, Days 1–5) plus once-daily oral regorafenib (patients 6– < 24 months: 60 mg/m2 escalating to 65 mg/m2; patients 2– < 18 years: 72 mg/m2 escalating to 82 mg/m2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. As per protocol, at least 50% of patients were required to have RMS. Results: At the time of the cut-off, of 21 treated patients (RMS, n = 12; Ewing sarcoma, n = 5; neuroblastoma, n = 3; Wilms tumor, n = 1), two had concomitant (72 mg/m2) and 19 had sequential (72 mg/m2, n = 6; 82 mg/m2, n = 13) dosing. Median age was 10 years (1.5–17.0). Patients received a median of 3 cycles (1–17); dose reductions of irinotecan occurred in 62% of patients. Grade 3 dose-limiting toxicities were reported in both patients receiving concomitant dosing (peripheral neuropathy and liver injury; pain, vomiting, febrile aplasia) and one patient each in the sequential groups (rash and elevated AST; thrombocytopenia). Concomitant dosing was discontinued. The maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in the sequential combination was 82 mg/m2. The most common grade ≥3 treatment-emergent adverse events were neutropenia (71%), thrombocytopenia (33%), leukopenia (29%), anemia (24%), and ALT increased (24%). The response rate was 38%, including 1 complete (RMS) and 7 partial responders (5 RMS, 2 Ewing sarcoma); 3 of whom had prior irinotecan. Six (4 with alveolar subtype) of 12 patients with RMS had a response. Nine patients (43%) had stable disease (maximum duration 17 cycles). After the cut-off, partial response was reported for two additional patients (1 RMS, 1 Ewing sarcoma). Conclusions: Regorafenib can be combined at its single agent RP2D of 82 mg/m2 with standard-dose vincristine/irinotecan (with appropriate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Clinical activity was observed in patients with sarcoma. Clinical trial information: NCT02085148.
Maintenance therapy with oral cyclophosphamide plus celecoxib in patients with metastatic Ewing sarcoma: Results of the Italian Sarcoma Group/AIEOP EW-2 study.
Authors: Puma Nadia , Sebastian Asaftei Dorin , Paioli Anna , Bisogno Gianni , Rabusin Marco , Coccoli Luca , Tamburini Angela , Milano Giuseppe Maria , Mascarin Maurizio , Bertulli Rossella , Grignani Giovanni , Manzitti Carla , De Leonardis Francesco , Podda Marta Giorgia , Prete Arcangelo , Picci Piero , Mura Rosamaria , Fagioli Franca , Longhi Alessandra , Luksch Roberto 
Published: May 2020

10517 Background: The prognosis of patients with metastatic Ewing sarcoma remains poor. The primary aim of the ISG/AIEOP EW2 Study (EUDRACT# 2009-011197-15) was to evaluate the feasibility and efficacy of maintenance therapy with oral cyclophosphamide plus celecoxib. Methods: From June 1st 2009 to Nov 22nd 2019, 112 patients with metastatic Ewing sarcoma at onset entered the ISG/AIEOP EW2 study, consisting of induction chemotherapy, radiotherapy and/or surgery at the site of the primary tumor, a consolidation phase with high-dose busulphan/melphalan + autologous stem cell rescue, whole-lung irradiation (12-15Gy), and a maintenance phase of 180 days with cyclophosphamide 50 mg daily (35 mg/mq daily if age < 14 years) plus celecoxib 400 mg twice daily (250 mg/mq twice daily if age < 14 years). Exclusion criteria from the maintenance phase were disease progression, cardiac or gastro-intestinal comorbidity. For CTCAE v4.0 grade 3-4 toxicities a temporary interruption was planned. Results: Seventy-one patients were eligible and entered the maintenance phase. Median age was 16 years (range 13-41); sites of metastases were lung or single bone (n = 56) and multicentric metastatic spread (n = 15). Sixty-one patients terminated the maintenance phase, 4 patients are still on treatment, 1 patient interrupted the treatment due to auto-immune thrombocytopenia at 4 months, 5 patients were withdrawn throughout maintenance due to disease progression/relapse. The duration of maintenance therapy was 89% of the scheduled days, with a median suspension length of 12 days (range 1-44 days). Causes of temporary suspension were hematological toxicity (19 episodes), infections (12 episodes), gastrointestinal disorders (9 episodes), fluid retention/distal oedema (3 episodes), renal disorders (3 episodes). Median follow-up was 42 months. The 3-year EFS of patients who entered the maintenance phase was 0.79 ± 0.09 for lung or single bone, and 0.19 ± 0.11 for those with multicentric metastatic spread. Conclusions: This schedule of maintenance phase is feasible, despite previous intensive treatment. A longer follow-up is needed to monitor side effects and to evaluate clinical outcome of patients with lung or single bone metastases, while the outcome remains dismal for multicentric metastatic Ewing sarcoma. Clinical trial information: NCT02727387.
The first report of pediatric patients with solid tumors treated with venetoclax.
Authors: Goldsmith Kelly C. , Verschuur Arnauld , Morgenstern Daniel A. , van Eijkelenburg Natasha , Federico Sara Michele , Fraser Christopher , Forlenza Christopher J. , Ziegler David Simon , Gerber Nicolas U. , Khaw Seong Lin , Cooper Todd Michael , Flotho Christian , Prine Betty A. , Salem Ahmed H. , Unnebrink Kristina , Tong Bo , Palenski Tammy L. , Place Andrew E. 
Published: May 2020

10524 Background: Dependence on the prosurvival protein B-cell lymphoma 2 (BCL-2) occurs in certain pediatric solid tumors, resulting in tumorigenesis and resistance to therapies. Venetoclax (VEN), an orally administered BCL-2-selective inhibitor, has preclinical anticancer activity in human-derived neuroblastoma models. Reported here are preliminary results from pediatric patients (pts) with recurrent or refractory (R/R) solid tumors treated with VEN monotherapy or VEN with cyclophosphamide and topotecan (Cy-Topo). Methods: This phase 1 open-label, 2-part study (NCT03236857) enrolled pts < 25 yr old with R/R malignancies; we report only on pts with solid tumors. Following a dose ramp-up, pts received 800 mg VEN (age/weight-adjusted adult equivalent) once daily for the first 8 wk; Cy-Topo was added optionally after wk 8. Dose-limiting toxicities (DLTs) were assessed during the first 21 days of VEN therapy or cycle 1 of VEN-Cy-Topo. Objectives included safety, toxicity, and preliminary efficacy. Results: As of Dec 17, 2019, 11 solid tumor pts were enrolled: neuroblastoma (n = 6), rhabdomyosarcoma (n = 2), Wilms’ tumor, Carney-Stratakis syndrome, and low-grade fibromyxoid sarcoma (n = 1 each). Median age was 11 yr (range 3–22); median time on study was 6.9 mo (range 1.2–17.8). All pts experienced ≥1 treatment-emergent adverse event (TEAE); vomiting (72%; all grades) was most common. Grade ≥3 TEAEs were reported in 82% of pts; febrile neutropenia (64%), decreased blood cell count, and neutropenia (36% each) were the most common. Seven pts received 800-mg monotherapy for 8 wk; 3 of these pts did not receive Cy-Topo after monotherapy. Of the 7 pts who received VEN-Cy-Topo, 3 pts received 400 mg VEN with Cy-Topo. DLTs of grade 4 neutropenia/thrombocytopenia with delayed count recovery occurred in 2 pts on 800 mg VEN-Cy-Topo, necessitating a dose de-escalation (to 400 mg VEN). Grade 4 neutropenia occurred in 2 pts on 400 mg VEN with Cy-Topo, leading to the addition of myeloid growth factor to the therapy regimen. The best response after 8 wk of VEN monotherapy was stable disease (SD). Six pts were evaluable for tumor response with VEN-Cy-Topo; 1 neuroblastoma pt had a complete response after 5 cycles of 400 mg VEN, 4 pts had SD (3 on 800 mg and 1 on 400 mg VEN) and 1 (800 mg VEN) had progressive disease as best response. Conclusions: Continuous dosing of VEN with Cy-Topo was not tolerated due to cytopenias in 4/7 pts with solid tumors. Discontinuous dosing of VEN with Cy-Topo is being explored. Clinical trial information: NCT03236857.
Obstetrical and perinatal complications in survivors of childhood, adolescent, and young adult cancer: A population-based study.
Authors: Zgardau Alina , Nathan Paul C. , Gupta Sumit , Ray Joel G. , Baxter Nancy N. , Nagamuthu Chenthila , Lau Cindy , Park Alison 
Published: May 2020

10529 Background: Women who survive cancer diagnosed in childhood, adolescence or young adulthood may develop long-term health issues. Data are lacking on adverse reproductive outcomes such as infertility and obstetrical and perinatal complications. Methods: Using linked Ontario provincial cancer and obstetrical registries, we assembled a cohort of female cancer survivors diagnosed before age 21 years from 1985-2012. We matched survivors by age and geographic region to females without a prior cancer diagnosis. Outcomes included i) any recognized and past 20 weeks’ gestation pregnancy; ii) perinatal complications; and iii) obstetrical complications (including a broad composite of severe maternal morbidity [SMM]). Multivariable Cox proportional hazard and modified Poisson models compared survivors to a non-cancer group and assessed demographic, diagnostic and treatment risk factors in survivors. Results: 3,486 survivors were matched to 17,428 women without prior cancer. Median age at cancer diagnosis was 12 years (IQR 5-16) and median follow-up was 26 years (IQR 21-32). 599 (17.2%) survivors had at least one recognized pregnancy compared to 3,885 (22.3%) women without prior cancer (Hazard Ratio [HR] 0.79, 95% Confidence Interval [CI] 0.7-0.9, p < .0001). Among those who had a recognized pregnancy, 581 (97.0%) survivors carried a pregnancy > 20 weeks’ gestation vs. 3791 (97.6%) in the non-cancer group (Relative Risk [RR] 1.0, CI 0.98-1.04). Factors significantly associated with a decreased likelihood of achieving at least one recognized pregnancy among survivors included brain tumour, cranial radiation, exposure to an alkylating agent or hematopoietic stem cell transplantation (HSCT). Among women who had a livebirth or stillbirth, survivors had a RR of 2.3 (CI 1.5-3.6) for SMM and 3.2 (CI 1.6-6.6) for cardiac morbidity. Factors associated with SMM among survivors included brain tumour and pre-existing kidney disease. Among livebirth pregnancies, cancer survivors were at higher risk of preterm birth (RR 1.6, CI 1.2-2.0), especially those who received an alkylating agent or HSCT. Conclusions: Survivors of childhood, adolescence or young adulthood cancer are less likely to achieve a recognized pregnancy compared to women without prior cancer. Those who carry a pregnancy >20 weeks’ gestation are at higher risk for SMM and preterm birth. Fertility planning and counseling can be informed by cancer diagnosis and treatment, and high-risk obstetrical care is recommended for survivors at elevated risk of an adverse pregnancy outcome.