bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of specialized pediatric palliative care involvement and impact on patterns of end-of-life care in children with cancer: A population-based study.
Authors: Gupta Sumit , Sutradhar Rinku , Rapoport Adam , Nelson Katherine , Liu Ying , Vadeboncouer Christina , Zelcer Shayna M. , Kassam Alisha , Pole Jason D , Earle Craig , Wolfe Joanne , Widger Kimberley 
Published: September 2018

10573 Background: Children with cancer are at risk of receiving high-intensity (HI) care at the end-of-life (EOL) and associated high symptom burden. The impact of palliative care (PC) delivered by generalists or of specialized pediatric palliative care (SPPC) on patterns of EOL care is unknown, with previous studies limited by small sample sizes or low response rates. Methods: Using a provincial registry, we assembled a retrospective cohort of Ontario children with cancer who died between 2000-2012 and who received care through a pediatric institution with a SPPC team and a clinical PC database. Patients were linked to population-based healthcare data capturing inpatient, outpatient, and emergency visits. Clinical PC databases were used to identify patients receiving SPPC. Remaining patients were categorized as having received either general PC (GPC) or no PC depending on the presence of PC associated physician billing or inpatient codes. We determined predictors of SPPC involvement, and whether either SPPC or GPC was associated with HI-EOL outcomes: ICU admission < 30 days from death, mechanical ventilation < 14 days from death, or in hospital death. Sensitivity analyses excluded treatment-related mortality (TRM) cases. Results: 572 patients met inclusion criteria. Children less likely to receive SPPC services included those with hematologic cancers [odds ratio (OR) 0.33, 95th confidence interval (CI) 0.30-0.37; p < 0.001)], in the lowest income quintile (OR 0.44, 95CI 0.23-0.81; p = 0.009), and living at increased distance from the treatment center (OR 0.46, 95CI 0.40-0.52; p < 0.0001). In multivariate analysis, SPPC was associated with a 3-fold decrease in the odds of an EOL ICU admission (OR 0.32, 95CI 0.18-0.57), while GPC had no impact. Similar associations were seen with all other HI-EOL indicators. Excluding TRM had little impact. Conclusions: SPPC, but not GPC, is associated with lower intensity care at EOL. Access to such care however remains uneven. In the absence of randomized trials, these results provide the strongest evidence to date supporting the creation of SPPC teams. These results can be used to support PC advocacy and policy efforts.
A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer.
Authors: Petrylak Daniel Peter , Perez Raymond P. , Zhang Jingsong , Smith David C. , Ruether Joseph D. , Sridhar Srikala S. , Sangha Randeep S. , Lang Joshua Michael , Heath Elisabeth I. , Merchan Jaime R. , Gartner Elaina M. , Chu Rong , Anand Banmeet , Doñate Fernando , Jackson Lynnae , Adams Jeffrey , Melhem-Bertrandt Amal , Rosenberg Jonathan E. 
Published: September 2018

106 Background: Enfortumab vedotin, an antibody–drug conjugate, delivers monomethyl auristatin E to tumors expressing Nectin-4, which is overexpressed in metastatic urothelial cancer (mUC). Methods: This Phase I study (NCT02091999) enrolled patients (pts) with solid tumors, including pts with mUC, treated with ≥1 prior chemotherapy regimen. All pts received different dose levels of IV enfortumab vedotin (0.5, 0.75, 1, 1.25 mg/kg) once weekly for 3 out of 4 wks. Nectin-4 expression was determined by IHC on archival tumor specimens and quantified by histochemical scoring (H-score). Primary endpoint was tolerability; secondary endpoint was antitumor activity assessed every 8 wks per RECIST v1.1. Results: As of 3 Jan 2017, 68 pts with mUC (46 M/22 F; median age, 67 yr [range: 41–84]) had been treated. Of these, 62% received ≥2 prior therapies in the metastatic setting and 40% had prior immune checkpoint inhibitor (CPI) therapy. In these pts, Nectin-4 expression was high and prevalent (median H-score, 280 [range: 32–300]). Treatment-related adverse events (TRAEs) were reported in 58 pts (85%); diarrhea, fatigue, nausea, and pruritus were TRAEs reported in ≥25% of pts. Most TRAEs were grade ≤2 in severity; 19 pts (28%) experienced a TRAE of grade ≥3. The most common grade ≥3 AEs (occurring in ≥5 pts), regardless of attribution to treatment, were urinary tract infection (10%) and hypophosphatemia (9%). No treatment-related deaths have occurred. Sixty pts had ≥1 post-baseline assessment. Antitumor activity was observed across the dose range; overall response rate (ORR) was 40% (95% CI: 27.6–53.5) for all evaluable pts (n = 60), 46% (95% CI: 25.6–67.2) in pts with prior CPI exposure (n = 24), and 44% (95% CI: 19.8–70.1) in pts with metastasis to the liver (n = 16). Complete responses were noted in 3 pts at doses ≥1 mg/kg. Median treatment duration was 26 wks (range: 5.1–64.6), median duration of response was 18 wks (95% CI: 8.4–40.1), and median progression-free survival was 17 wks (95% CI: 15.1–23.3). Study enrollment is ongoing. Conclusions: Enfortumab vedotin demonstrated a favorable tolerability profile with encouraging antitumor activity in heavily pretreated mUC, including pts for whom CPIs have failed. Clinical trial information: NCT02091999.
Combination of paclitaxel and LAG3-Ig (IMP321), a novel MHC class II agonist, as a first-line chemoimmunotherapy in patients with metastatic breast carcinoma (MBC): Interim results from the run-in phase of a placebo controlled randomized phase II.
Authors: Duhoux Francois P. , Jager Agnes , Dirix Luc , Huizing Manon Thirza , Jerusalem Guy Heinrich Maria , Vuylsteke Peter , De Cuypere Eveline , Breiner Doris , Mueller Christian , Brignone Chrystelle , Triebel Frederic 
Published: September 2018

1062 Background: IMP321 is a recombinant soluble LAG3-Ig fusion protein that binds to MHC class II molecules and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. The activation of the dendritic cell network with IMP321 the day after a low dose injection of a single agent chemotherapy may lead to stronger anti-tumor CD8 T-cell responses. We report initial results of the safety run-in of a randomized, placebo-controlled phase IIb trial in patients (pts) with hormone receptor positive (HR+) MBC receiving first-line weekly paclitaxel. Methods: In the safety run-in phase 15 pts with MBC received weekly paclitaxel (80 mg/m2; D1, D8, D15) in a four week cycle in conjunction with either 6 mg (n = 6; cohort 1) or 30 mg (n = 9, cohort 2) IMP321 injections s.c. (D2 and D16) for 6 cycles. Patients without progressive disease could continue with a maintenance phase of 12 additional injections of IMP321 every 4 weeks. Blood samples for pharmacokinetics and immuno-monitoring were taken in cycle 1 and 4 just before and after IMP321 injection. Results: In total 15 pts (median age 53 years) were enrolled between Jan 2016 and Oct 2016. No dose limiting toxicities have been reported. Cytokine release syndrome grade 1 was the only serious adverse event (SAE) related to IMP321 and occurred twice in the same patient. Grade 1 and 2 injection site reactions were the most common related AEs and occurred in 14 pts (93 %). A dose-dependent increase in serum IMP321 concentration was observed among the two dose levels with a Cmaxbetween 4 and 24 hours. Increased number of circulating monocytes, dendritic cells and increased activation were observed at both dose levels of IMP321, supporting the working hypothesis. Conclusions: The 30 mg s.c. IMP321 given every two weeks in combination with weekly paclitaxel is the recommended phase 2 dose which is used in the ongoing randomized placebo controlled phase II part of the study. Clinical trial information: NCT02614833.
Overall survival (OS) of men and women with breast cancer according to tumor subtype: A population-based study.
Authors: Leone Julieta , Zwenger Ariel Osvaldo , Leone Bernardo Amadeo , Vallejo Carlos Teodoro , Leone Jose Pablo 
Published: September 2018

1069 Background: The outcomes of male breast cancer (MBC) and female breast cancer (FBC) according to tumor subtype are poorly known. Our group previously reported the prognostic significance of tumor subtypes in MBC. The aim of this study was to analyze differences in OS between MBC and FBC according to tumor subtype compared with other factors. Methods: We evaluated men and women with microscopically confirmed invasive breast cancer between 2010 and 2013 with known estrogen receptor (ER) and progesterone receptor (PR) (together hormone receptor [HR]) status and human epidermal growth factor receptor 2 (HER2) status reported to the SEER program. Patients (pts) with other primary either before or after breast cancer were excluded. Pt characteristics were compared between MBC and FBC. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Results: We included 1,187 MBC and 166,054 FBC pts. Median age for MBC was 65 years (range 26-97) and for FBC was 60 years (range 18-108). Median follow-up was 21 months (range 1-48) for both groups. OS at 3 years for MBC and FBC was 85.6% and 90.4%, respectively (p = 0.0002). MBC pts were more frequently ductal, had higher grade, presented with more advanced stage and were more often HR+/HER2- (all p < 0.0001). MBC had worse OS than FBC in HR+/HER2- (Hazard ratio [HaR] 1.5; p = 0.0005), HR+/HER2+ (HaR 2.8; p < 0.0001) and triple negative (TN) (HaR 4.3; p < 0.0001) (p for interaction < 0.02). MBC had significantly worse OS than FBC in stage I and II, but similar OS in stage III and IV (p for interaction < 0.01). In multivariate analysis adjusted for age, race, grade, stage, surgery, radiation and marital status; HR+/HER2+ was the only subtype with significant differences in OS between MBC and FBC (HaR 2.0; p = 0.002). Conclusions: In this cohort, we observed significant differences in the distribution of tumor subtypes between MBC and FBC. OS was significantly different in both groups. Men had worse OS in stage I and II while similar OS in stage III and IV. There were significant differences in OS according to tumor subtype; compared with women, men with HR+/HER2+ tumors had twice the risk of death.
Trop2 gene expression (Trop2e) in primary breast cancer (BC): Correlations with clinical and tumor characteristics.
Authors: Vidula Neelima , Yau Christina , Rugo Hope S. 
Published: September 2018

1075 Background: Trophoblast antigen 2 (Trop2) is a glycoprotein expressed by many cancers. A phase I study of the trop2 antibody drug conjugate (ADC) IMMU-132 has shown promising activity in triple negative (TN) BC. We studied associations of primary BC trop2e with clinical characteristics, outcomes, and selected genes in publically available databases. Methods: Trop2e was evaluated with microarray data from the neoadjuvant I-SPY 1 (n=149), METABRIC (n=1992) & TCGA (n=817) databases. Associations with clinical features were assessed with the Kruskal-Wallis test (all). Correlations with chemotherapy response were evaluated with the Wilcoxon rank sum test (I-SPY 1) & with recurrence free survival (RFS) by the Cox proportional hazard model (I-SPY 1 & METABRIC). Pearson correlations were used to study associations between trop2e & selected genes (all). Results: In all 3 datasets, trop2 was detectable and had a wide range of expression in all BC subtypes. In I-SPY 1, trop2e did not vary by hormone receptor (HR) & HER2 or intrinsic subtype; in METABRIC & TCGA trop2e was lower in HER2+ than HR+/HER2- & TNBC (METABRIC p=0.03, TCGA p=0.007) & in HER2+ enriched and luminal B BC (p < 0.001, METABRIC & TCGA). Trop2e was higher in grade I vs. II/III BC in METABRIC (p < 0.001). No association with chemotherapy response was seen (I-SPY 1) or with RFS (I-SPY 1 & METABRIC). The table below shows significant (p<0.05) gene correlations with trop2e in ≥2 datasets. Conclusions: Trop2e is seen in all BC subtypes, particularly luminal A and TNBC. Trop2e correlates with the expression of genes involved in cell epithelial transformation, adhesion, and proliferation and inversely with immune genes, which may contribute to tumor growth. These findings support the use of trop 2 directed ADC in all BC subtypes. [Table: see text]
The Metastatic Breast Cancer (MBC) project: Accelerating translational research through direct patient engagement.
Authors: Wagle Nikhil , Painter Corrie , Anastasio Elana , Dunphy Michael , McGillicuddy Mary , Kim Dewey , Jain Esha , Buendia-Buendia Jorge , Cohen Ofir , Knelson Erik , Holloway Jamie , Johnson Shawn , Larkin Katie , Adalsteinsson Viktor , Ha Gavin , Freeman Samuel , Gydush Greg , Reed Sarah , Lander Eric , Golub Todd 
Published: September 2018

1076 Background: The Metastatic Breast Cancer Project is a nationwide research study, launched in Oct 2015 in collaboration with patients (pts) and advocacy groups, that directly engages pts through social media and seeks to empower them to share their experiences, clinical information, and samples to accelerate research. Methods: MBC pts enroll by providing their information at mbcproject.org. Pts are sent a saliva kit and asked to mail back a sample which is used to extract germline DNA. We contact pts medical providers and obtain medical records (MRs) and stored tumor samples. Pts may also submit a blood sample, used to extract cell free DNA (cfDNA). Whole exome sequencing (WES) is performed on tumor, germline, and cfDNA; transcriptome sequencing is performed on tumor. Clinical and genomic data are used to generate genomic landscapes in pt subgroups and to identify mechanisms of response and resistance to therapies. Data are shared widely through public databases. Pts receive regular study updates. Results: In 12 months, 2908 MBC pts from 50 states enrolled. 95% completed the 16-question survey about their cancer, treatments, and demographics. 1730 (60%) completed the online consent form. 100-200 pts continue to enroll monthly. To date, 1539 saliva kits were mailed and 1120 samples were received (73%). 992 unique treating institutions were reported by pts, including 733 institutions reported by only 1 pt each and 5 institutions reported by more than 40 pts each. We have obtained MRs from 253 patients (67% yield) and tumor samples from 85 pts (67% yield). WES was successfully completed for 79 tumors of 88 attempted (90%). WES has been performed on initial cfDNA samples. Conclusions: A direct-to-patient approach enabled rapid identification of thousands of MBC pts willing to share MRs, saliva, and tumor samples, including many with rare phenotypes. Remote acquisition of MRs, saliva, tumor, and blood for pts located throughout the US is feasible. We estimate that for ~33% of consenting patients, we can obtain medical records, saliva, and tumor tissue. Genomic analysis of tumor and cfDNA from subgroups including young pts, pts with extraordinary responses, and pts with de novo MBC will be presented.
The role of high-dose chemotherapy (CT) and stem-cell support in high-risk stage II, locally advanced, and responding stage IV breast cancer (BC): The Israeli experience with 20 years median follow-up.
Authors: Peretz Idit , Rizel Shulamith , Hardan Izhar , Stemmer Salomon M. 
Published: September 2018

1077 Background: Lately, updated data led the medical community to reconsider the use of intensive CT with stem-cell support for selected groups of BC patients (pts). Herein, we provide an update on a study investigating the efficacy, feasibility, and toxicity of high-dose CT with stem-cell support in pts with high-risk stage II, chemosensitive stage III and IV BC. Methods: The protocol offered adjuvant/neoadjuvant/induction doxorubicin-based CT, 75-90 mg/m2 X 4 courses followed by high-dose CT (cyclophosphamide 6000 mg/m2, carboplatin 800 mg/m2, and thiotepa 500 mg/m2) and autologous stem cell support with growth factors. Post-transplant local radiotherapy was delivered. Pts who were hormone receptor (HR) positive received Tamoxifen. Results: From 2/1994 to 11/1998, 292 BC pts were referred to the study from all Israeli oncology centers. Median follow-up from transplant was 20 (range, 18-22) years; 119 had stage 2 disease (42 with 4-9 positive nodes, 77 with ≥10 positive nodes); 87 had stage 3 disease, of whom 50 had locally advanced/inflammatory BC treated with neoadjuvant CT; and 86 had chemosensitive stage IV BC. Two acute transplant-related deaths and one death due to late transplant-related toxicity were reported. Median age at transplant was 45 (range, 24-63) years. Overall survival (OS) by HR status is presented in the table. In total, 167 of the 292 pts died (based on death status data retrieved from the Registry of the Ministry of the Interior), representing OS of 42%. The OS rates for stage II, III, and IV were 55%, 45%, and 23%, respectively. Conclusions: Long-term accurate follow-up of pts receiving well-defined treatments remains an important tool in cancer research. High-dose CT with stem-cell support could represent a therapeutic/curative option in select BC patients in all disease stages. Reintroduction of this approach should be re-examined. [Table: see text]
Single agent activity of DS-8201a, a HER2-targeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors.
Authors: Doi Toshihiko , Iwata Hiroji , Tsurutani Junji , Takahashi Shunji , Park Haeseong , Redfern Charles H. , Shitara Kohei , Shimizu Chikako , Taniguchi Hiroya , Iwasa Tsutomu , Taira Shinichiro , Lockhart Albert C. , Fisher Jennifer M. , Jikoh Takahiro , Fujisaki Yoshihiko , Lee Caleb C. , Yver Antoine , Tamura Kenji 
Published: September 2018

108 Background: Human epidermal growth factor 2 (HER2) is a potential strong tumor driver for breast (BC) and gastric cancer (GC) as well as other HER2 expressing tumors. Antibody-drug conjugates (ADC) provide wider therapeutic window by more efficient and specific drug delivery. DS-8201a is a HER2 targeting ADC of high drug to antibody ratio (7 to 8) with a novel topoisomerase I inhibitor. In preclinical studies, DS-8201a showed a broader antitumor spectrum than T-DM1, including efficacy against low HER2 expressing tumors. Current trial includes dose escalation (Part 1) and expansion (Part 2) focusing on HER2 expressing solid tumors (NCT02564900). Methods: Part 1 used a modified continuous reassessment method to identify the expansion dose in patients (pts) with BC or GC. Part 2 was designed to evaluate the safety and efficacy in 4 expansion cohorts: T-DM1 treated HER2+ BC, trastuzumab treated HER2+ GC, BC with low HER2 expressing and other HER2 expressing solid tumors. Adverse events (AEs), objective response rate (ORR) and durability of responses were assessed. Results: 89 pts were administered in total: 24 pts in Part 1 and 65 pts (BC, GC, colorectal, salivary and non-small cell lung cancer) in Part 2 with median prior therapies of 4. DS-8201a was administered up to 8.0 mg/kg in Part 1, and dose levels of 6.4 and 5.4 mg/kg IV every 3 weeks were chosen for Part 2. There was no dose limiting toxicity, and maximum tolerated dose was not reached in Part 1. The most common AEs in Part 1 and Part 2 were nausea (62%), anorexia (56%) and platelet count decreased (28%). 29% pts experienced ≥ Gr3 AEs (Gr3: 25% Gr4: 4%). The ORR and disease control rate (DCR: CR + PR + SD) are shown in the table. ORR and DCR were 40% and 90%, respectively in evaluable 73 pts including 14 low HER2 expression. One T-DM1 treated BC pt achieved CR. 4 PRs were achieved in pts with low HER2 expression. 63 pts in total are currently being treated. Median duration of treatment was ≥27 weeks in Part 1 and not reached in Part 2. Conclusions: DS-8201a was well tolerated and is remarkably active in heavily pretreated HER2 expressing cancers. Clinical trial information: NCT02564900. [Table: see text]
Whole exome sequencing of metaplastic breast cancer (MpBC): Effect of mutation status on survival.
Authors: Baez Vallecillo Luis , Chang Jeffrey T , Chen Ken , Moss Tyler J. , Shaw Kenna Rael , Meric-Bernstam Funda , Eterovic Agda Karina , Mills Gordon B. , Mani Sendurai , Li Xiaoxian (Bill) , Gilcrease Michael , Moulder Stacy L. 
Published: September 2018

1090 Background: Metaplastic Breast Cancer (MpBC) is considered a chemo-refractory, aggressive subtype that is characterized by squamous and/or mesenchymal differentiation and associated with a high rate of molecular aberrations that activate the PI3K pathway. The goal of this study was to correlate outcomes data with underlying genomic aberrations in MpBC. Methods: A cohort of 52 archived samples of MpBC collected from 1986 and 2016 that had clinical outcomes data available for central review underwent hybrid capture sequencing of 202 cancer-related genes (n = 52) and, when sufficient material was available, whole exome sequencing (n = 21). Relapse free (RFS) and overall (OS) survival analyses at 5 years were compared between patients having mutation vs. wild-type (WT) in the whole genome using Kaplan-Meier statistics. Results: The variant allele frequency (VAF) was relatively low with most mutations having a VAF of < 50%. TP53 mutation was found in 33 tumors (63%) and was associated with improved RFS (HR = 2.4; p = 0.03) and OS (HR = 3.7; p = 0.006) compared to WT. Aberrations in the PI3K/AKT/mTOR pathway were present in 29% of tumors and associated with diminished OS (HR = 0.27; p = 0.02) but not RFS (HR = 0.67; p = 0.32). Though uncommon, the presence of an AKT1 (6%) mutation was associated with worse RFS (HR = 0.006; p = 0.006) and OS (HR = 0.0005; p < 0.0001). Conclusions: Surprisingly, TP53 mutation was associated with better prognosis in MpBC with increased RFS and OS. Mutations in AKT1 were uncommon but associated with a significantly worse RFS and OS. Notably, all patients harboring an AKT1 mutation died within a year of diagnosis. Mutations activating the PI3K/AKT/mTOR pathway were associated with worse OS.