bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor genomics and response to CDK 4/6 inhibitors for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Spring Laura , Niemierko Andrzej , Juric Dejan , Zangardi Mark , Abraham Elizabeth , Dias-Santagata Dora , Ellisen Leif W. , Isakoff Steven J. , Iafrate A. John , Moy Beverly , Bardia Aditya 
Published: September 2018

1046 Background: The combination of endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor, such as palbociclib, has changed the treatment paradigm of HR+ MBC, particularly as 1stline therapy. However, there are no predictive biomarkers at present, and little is known about the impact of tumor genomics on outcomes. For example, mutations in TP53 could impact the ability of p53 to negatively regulate p21, thereby promoting cell cycle progression despite CDK 4/6 inhibition. The aim of this study was to evaluate the association between tumor genomics, particularly PIK3CA and TP53 mutations, and response to CDK 4/6 inhibitors in HR+ MBC. Methods: All HR+/HER2- MBC patients at our institution receiving a CDK 4/6 inhibitor in the second line or beyond were identified. Tumor genomics were analyzed utilizing the institutional tumor genotyping next generation sequencing (NGS) assay known as “Snapshot-NGS assay” on DNA isolated from the tumor, covering key oncogenic driver mutations and tumor suppressor genes. The log-rank test was used for statistical analysis. Results: A total of 83 patients with HR+/HER2- MBC were identified, of which 61 had available tumor genotyping results available (52 metastatic specimens). The median line of therapy was three. Median progression-free survival (PFS) on CDK 4/6 inhibitor-based therapy, as second line or beyond, was 9.2 months (mo) overall. No significant difference in PFS was seen among patients with PIK3CA (n = 31) mutations (7.1 vs. 9.7 mo; p = 0.28) or with any alteration in the PI3K/Akt/mTOR (n = 36) pathway (8.2 vs. 9.3 mo; p = 0.40). The presence of a p53 mutation (n = 9) or complex tumor genomics (n = 14) demonstrated a trend towards shorter PFS (5.5 vs. 9.2 mo; 5.5 vs. 9.5 mo, respectively), although statistical significance was not reached due to small numbers (p = 0.76; p = 0.31). In a multivariable analysis adjusting for age and prior lines of therapy, similar results were observed. Conclusions: This study suggests patients with HR+ MBC harboring p53 mutations or complex tumor genomics may experience shorter PFS on CDK 4/6 inhibitor-based therapy in the second line and beyond, and these novel findings require validation in additional studies.
Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma.
Authors: Hegde Meenakshi , DeRenzo Christopher C. , Zhang Huimin , Mata Melinda , Gerken Claudia , Shree Ankita , Yi Zhongzhen , Brawley Vita , Dakhova Olga , Wu Meng-Fen , Liu Hao , Hicks John , Grilley Bambi , Gee Adrian P. , Rooney Cliona M. , Brenner Malcolm K. , Heslop Helen E. , Wels Winfried , Gottschalk Stephen , Ahmed Nabil M. 
Published: September 2018

10508 Background: Outcome for patients with advanced sarcoma is extremely poor and treatment options are limited. Encouragingly, in our phase 1 dose-escalation trial (Ahmed et al, JCO 2015), systemic administration of up to 1x108/m2 autologous HER2-CAR T cells in patient with HER2+ sarcoma was safe. While T cells did not expand, 4/19 evaluable patients are alive 37-61 months post infusion without evidence of disease. The goal of this study was to evaluate if lympohodepleting chemotherapy can safely induce the expansion of HER2-CAR T cells. Methods: In a phase 1 clinical study, NCT00902044, we administered 1x108/m2 autologous HER2-CAR (with a CD28.zeta signaling domain) T cells to patients with refractory/metastatic HER2+ sarcoma after lymphodepletion. Results: Six patients with refractory/metastatic HER2+ sarcoma (4 osteosarcoma, 1 rhabdomyosarcoma, 1 synovial sarcoma) with a median age of 16 (range: 4 to 55) received up to 3 infusions of 1x108 cells/m2 CAR T cells after lymphodepletion with either fludarabine (Flu; n = 3) or Flu and cyclophosphamide (Flu/Cy; n = 3). Flu and Flu/Cy induced lymphopenia with an absolute lymphocyte count (ALC) of < 100/ml at the day of the T-cell infusion. Only Flu/Cy induced neutropenia (absolute neutrophil count [ANC] < 500/ml) for up to 14 days. 4/6 patients developed grade 1-2 cytokine release syndrome (CRS) within 24 hours of CAR T-cell infusion that resolved completely with supportive care within 3 days of onset. T cells expanded in 5/6 patients (median 89-fold (range: 41 to 2,893) with a median peak expansion on day 7 (range: 5 to 28). CAR T cells could be detected by qPCR in 6/6 patients at 6 weeks post infusion. One patient with rhabdomyosarcoma metastatic to the bone marrow had a complete responses (CR), 2 had stable disease (SD), and 3 had progressive disease (PD). Two patients are alive with a median overall survival of 14.2 months. Conclusions: Infusion of autologous HER2-CAR T cells after lymphodepletion is safe, and can be associated with objective clinical benefit in patients with advanced HER2+ sarcoma. These findings warrant further evaluation in a phase 2b study as a single agent or in combination with other approaches. Clinical trial information: NCT00902044.
Type, intensity, and duration of chemotherapy (CHT) and their correlation with prognosis of localized soft tissue Ewing tumors (STET): Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).
Authors: Koscielniak Ewa , Scheer Monika , Sparber-Sauer Monika , Hallmen Erika , Leuschner Ivo , Kazanowska Bernarda , Ljungman Gustaf , Niggli Felix , Ladenstein Ruth , Bielack Stefan S. , Muenter Marc W. , von Kalle Thekla , Feuchtgruber Simone , Klingebiel Thomas 
Published: September 2018

10527 Background: The optimal type and intensity of CHT in the treatment of STET is still a matter of debate. The CWS group has treated STET similar to rhabdomyosarcoma. We have analyzed the prognosis of STET in relation to the CHT regimens used in three consecutive CWS studies CWS-91, -96 and CWS- 2002P. Methods: 243 pts with localized STET were included. Their median age was 12 (range 0.1-29) yrs. In the CWS-91 pts with primary tumor resection (IRSG I and II) were treated with VACA (vincristine (VCR), actinomycin D (Act D), cyclophosphamide (CYC), doxorubicin (DOX), for 10 or 20 weeks. All other CWS-91 pts (high risk group, HRG) received EVAIA (ifosfamide (IFO) instead of CYC plus VP16) for 37 weeks. In the CWS-96 and CWS-2002P all STET pts were allocated to the HRG. In CWS-96 therapy was randomized: VAIA (IFO, DOX, Act D, VCR) vs. CEVAIE (Epi-DOX instead of DOX, plus carboplatin and VP16), for 25 weeks. In CWS-2002P VAIA (25 weeks) plus maintenance CHT with CYC and vinblastine (VBL) for 26 weeks were used. The cumulative doses varied: IFO 24-72 g/m², CYC 4.8-7.35 g/m², DOX 120-360 mg/m², Act D 3-9 mg/m², VP16 1.8-5.4 g/m². Irradiation was stratified depending on results of the primary or secondary resection and response. Results: 5 yr event free (EFS) and overall survival (OS) were 64% and 73%. The median observation time of survivors was 9 yrs. 5yr EFS and OS by study were: CWS-91 64 % and 72 %, CWS-96 57% and 70 %, CWS-2002P 78 % and 86 % respectively (n.s.). 5 yr EFS and OS for VACA arm were 79% and 90%. 5 yr EFS and OS by CHT for HRG were: EVAIA 57% and 65%, VAIA 64% and 80%, CEVAIE 45% and 54%, VAIA with CYC/VBL 84% and 87%, respectively (p = 0 .003). 5yr EFS and OS for irradiated (n = 181) vs. not irradiated (n = 48) patients were 63 % and 72% vs. 63% and 79%, respectively. Conclusions: The outcomes between CHT arms differed significantly: CEVAIA correlated with the worst outcome while VAIA with CYC/VBL showed the best results. A small group of low risk patients have an excellent prognosis with substantially reduced CHT. Ewing tumors are biologically heterogeneous and more diversification in therapy stratification is warranted to avoid overtreatment.
Mortality in young adults with Ewing sarcoma treated at specialized cancer centers in California.
Authors: Alvarez Elysia Marie , Malogolowkin Marcio H. , Pollock Brad , Li Qian , Marina Neyssa , Wun Theodore , Keegan Theresa 
Published: September 2018

10538 Background: Ewing sarcoma is a rare malignancy of the soft tissue or bone that is most frequently seen in children and adolescents. One study suggested that care at specialized cancer centers (SCC) may mitigate survival disparities associated with public insurance in patients with sarcoma, but no large population-based studies have considered how location of care affects survival outcomes. Methods: We performed a retrospective, population-based cohort analysis of patients hospitalized within one year of diagnosis with primary Ewing sarcoma between 2000–2013 using the California Cancer Registry linked with state hospitalization data. Patients were divided into two groups based on whether they received inpatient treatment at a SCC [Children’s Oncology Group (if age ≤25) and/or National Cancer Institute-designated center] or not. We excluded 12 patients whose location of cancer treatment could not be determined. Multivariable Cox proportional hazards regression identified factors associated with mortality. Results are presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI). Results: Of the 470 patients with newly diagnosed Ewing sarcoma, 40% were female, 52% were non-Hispanic white, and 53% had private health insurance. Sixty-one percent received their inpatient care at a SCC. Multivariable analysis across all ages demonstrated that higher mortality was associated with increasing age, metastatic disease, and large tumors, but mortality was not impacted by treatment at an SCC (HR 0.77, CI: 0.55-1.08; p = 0.134). However, when analyses were stratified by age, treatment at a SCC was associated with lower mortality among patients ages 19–39 years, but not among younger or older patients, and this association was only apparent within 2 years of diagnosis (HR = 0.43, CI: 0.23-0.79; p = 0.007). Conclusions: Our results suggest that treatment for Ewing sarcoma at a SCC significantly improves survival in young adults adjusted for other factors known to be associated with poor prognosis (metastatic disease, larger tumor size and older age). The lower mortality in this age group may be due to access to clinical trials and other specialized services specific to young adults available at SCCs.
Pilot study of a comprehensive precision medicine platform for children with high-risk cancer.
Authors: Lau Loretta , Byrne Jennifer , Ekert Paul G , Failes Tim , Fellowes Andrew , Fletcher Jamie , Gifford Andrew , Haber Michelle , Kumar Amit , Lock Richard , Marshall Glenn , McCowage Geoffrey Brian , Mould Emily , Norris Murray , Trahair Toby , Tsoli Maria , Tyrrell Vanessa , Wadham Carol , Xie Jinhan , Ziegler David Simon ,   Zero Childhood Cancer National Program
Published: September 2018

10539 Background: Genomic analyses can identify actionable mutations in a subset of childhood cancers. However it has been challenging to translate actionable mutations into substantial benefits for adult cancers despite high mutation frequency. Methods: To test whether we could enhance identification of personalised therapies for high risk (HR) childhood cancers we conducted a pilot study (TARGET) evaluating a novel, comprehensive precision medicine platform incorporating molecular profiling, in vitro and in vivo drug testing. Results: We evaluated the first 29 patients with HR cancer (expected survival < 30%) enrolled prospectively over 15 months. Samples were collected from 15 CNS tumors, 10 solid tumors and 4 leukemias. All samples underwent targeted DNA sequencing. Pathogenic or likely pathogenic mutations were found in 59% (17/29) of tumors. 41% (12/29) had potentially actionable mutations. RNA-sequencing was performed on 27 samples. Previously described fusions were identified in 19% (5/27; 1 targetable, 1 clinical relevant and 3 diagnostic fusions). 37% (10/27) of samples also had actionable aberrations related to copy number changes or RNA expression. In vitro culture and establishment of patient-derived xenograft (PDX) were attempted in 19 and 21 fresh samples, respectively. The success rate of establishing a primary culture was 42% (8/19) and PDX engraftment rate was 67% (14/21). At least 1 drug hit was identified in 5 (56%) of the 9 samples screened using a high throughput drug screen of up to 165 compounds. Drug testing has been completed in 4 PDXs and was informative in all 4 cases allowing prioritisation of treatment recommendations. Genomic analysis in combination with RNA-seq, in vitro drug screening and PDX drug testing enriched the analysis and increased the ability to make personalised treatment recommendations from 41% (targeted panel alone) to 66%. Conclusions: This pilot study demonstrates that this novel, comprehensive platform is feasible and has the potential to improve outcome for HR childhood cancers. A multicentre study testing the implementation of the platform on a national level (PRISM trial) will open for Australian children with HR cancer under the Zero Childhood Cancer Program in 2017.
The role of taxanes in HR+ve/HER2-ve metastatic breast cancer (MBC) patients (pts) from adjuvant to metastatic setting in the clinical practice: Results from GIM13-AMBRA study.
Authors: Mustacchi Giorgio , Cazzaniga Marina Elena , Romagnoli Emanuela , Montemurro Filippo , De Laurentiis Michele , Riccardi Ferdinando , Turletti Anna , Beano Alessandra , De Angelis Claudia , Graziano Vincenzo , Livi Lorenzo , Del Mastro Lucia , Biganzoli Laura , Garrone Ornella , De Placido Sabino , Marchetti Paolo , Pronzato Paolo ,   On Behalf of AMBRA-GIM 13
Published: September 2018

1055 Background: The molecular subtypes of BC have individual patterns of behavior, prognosis and sensitivity to treatment, with subsequent implications for the choice of, or indeed role, for adjuvant (Adj) and metastatic chemotherapy (CHT). Taxanes (T) play a central role in chemotherapy for BC. However, previous studies have reported that T are relatively ineffective in patients with Luminal (HR+ve) BC compared with other subtypes. Aim of the present analysis is to describe the use of T in the clinical practice in Italy in HR+ve pts. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve MBC pts receiving at least one CHT (SABCS 2016, P5-15-07 & P5-14-09) in the years 2012-2015. For the present analysis, we focused on the use of T from the AdJ to the metastatic setting. Results: So far, 791/1500 pts have been registered into the study, 651 of them (82,3%) evaluable with HR+ MBC. Main characteristics are: Mean age 52 years; pN: UK 64 (9.8%) N+=405 (62.2%); Adj CHT=397 (61 %), mean DFI=96,99 months. T were used in 60.3% of the cases in the Adj setting, alone or in combination with other drugs, mainly anthracyclines (82.6%), with a mean DFI of 56.9 months. In the metastatic setting, across 1st to 3rd line, 460 pts (70.6%) received T, alone (49.7%) or in combination with Bevacizumab (38.2%), or other CHT drugs (11.9%). Details of the use of T in MBC are described in the table below. Conclusions: T have been used in more than 60% of cases of Luminal tumours in the Adj setting. In this population DFS is significantly shorter as compared with the non-T treated luminal population, as previously suggested by different Authors. Re-challenge with T is very frequent across different lines for MBC. Paclitaxel is the most used T, Docetaxel the less used and Nab-paclitaxel, labelled for MBC only, shows an increasing use from 1st-to 3rd line of treatment. [Table: see text]
Mental healthcare use and severe psychiatric diagnoses in adult survivors of childhood cancer: A population-based study using health services data.
Authors: Gupta Sumit , Nachman Alex , Kurdyak Paul , Sutradhar Rinku , Pole Jason D , Nathan Paul C. 
Published: September 2018

10565 Background: Though physical late effects in childhood cancer survivors are well documented, their risk for adverse mental health outcomes is less clear; existing evidence is contradictory. Health services data offer an objective method for measuring population-based mental health outcomes. Methods: Using a provincial registry with detailed patient, disease, treatment, and outcome data, we assembled a cohort of all five-year survivors of childhood cancer diagnosed before age 18 years and treated in an Ontario pediatric cancer centre between 1987-2008. Patients were linked to population-based healthcare data capturing inpatient, outpatient, and emergency department (ED) visits. The primary outcome was the rate of mental healthcare visits (primary care, psychiatrist, ED or hospital). Secondary outcomes included the time to a severe mental health event (ED visit, hospitalization, or suicide) both overall and by psychiatric diagnostic categories. Outcomes were compared between survivors and matched controls using recurrent event and survival analyses, and predictors of adverse outcomes modeled. Results: When compared to 20,269 controls, 4,117 survivors had a significantly higher rate of mental health visits [47.1 vs. 36.1 visits/100 person years; adjusted relative rate (RR) 1.3, 95% confidence interval (CI) 1.2-1.5]. Higher rates of visits were associated with female gender (RR 1.4, CI 1.1-1.7; p = 0.008) and adolescent age at diagnosis (RR 2.0, CI 1.3-3.0; p = 0.004). Cancer type, treatment intensity or treatments targeting the central nervous system were not significant predictors. The hazard of a severe mental health event did not differ between survivors and controls. Though rare in both groups, survivors were at increased risk of a severe event due to a psychotic disorder (HR 1.8, CI 1.1-2.8; p < 0.05). Conclusions: Childhood cancer survivors experience higher rates of mental health visits than the general population, but are no more likely to experience a severe mental health event. Their risk is not attributable to a specific diagnosis or aspect of treatment. An increased risk of severe psychotic disorders requires confirmation in other cohorts.
Impact of a formal human papilloma virus (HPV) education program in a childhood cancer survivor center.
Authors: Burns Karen Cristly , Kent Debra A. , Correll Judy , Cole-Jenkins Cheri , Nagarajan Rajaram 
Published: September 2018

10568 Background: The HPV vaccine has proven efficacy in preventing secondary cancers. It was approved for females age 11-26 in 2006 and for males age 11-21 in 2011. Despite this, vaccination rates in the US have been poor. The Cancer Survivorship Center (CSC) at Cincinnati Children’s Hospital Medical Center (CCHMC) instituted an education program in July, 2016 to improve education and vaccination rates in a childhood cancer survivor population. The following is a summary of program effectiveness. Methods: Providers in the CSC identified females age 11-26, and males age 11-21, presenting for annual visit from 7/1/16 thru 12/31/16. Patients received HPV education materials published by the CDC at registration. Materials were also displayed in exam and waiting rooms. During the visit, providers reviewed and documented vaccination history and discussed the importance of the HPV vaccine in preventing cancer. Patients interested in starting the vaccine series received the first vaccine in clinic and a follow-up schedule for further vaccination. Education and immunization status was documented in the electronic medical record using smart phrase trackable format. All patients were asked to sign a release to obtain vaccine records from the primary physician. A comparison group consisted of HPV eligible patients seen in the CSC during the six months prior to program initiation. Groups were compared for education completed and vaccination rate. Results: A total of 156 eligible patients were seen in the comparison group. None received HPV-directed education during their visit. Only 37 (23.7%) had any HPV vaccine, with 5 given during the clinic visit (13.5%). By comparison, 176 eligible patients were seen after initiation of the education program. All patients received materials at registration and 89% had documented education completed by a health care provider. Ninety one (55%) had any HPV vaccine, with 30 given during the clinic visit (33%). Conclusions: Through the implementation of a standardized education program in the CSC, we saw more than a 200% increase in rate of HPV vaccination. This demonstrates the importance of knowledgeable providers and the value of a dedicated HPV education program.
Genetic causes of resistance to entinostat in luminal breast cancer model systems.
Authors: Tanioka Maki , Garay Joe , Fan Cheng , Carey Lisa A. , Perou Charles M. 
Published: September 2018

1065 Background: Based on promising phase II data, the histone deacetylase inhibitor Entinostat (ENT) is in phase III trials for patients with metastatic ER-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown. Methods: Luminal cell lines SKBR3 (ER-/HER2+), BT474 (ER+/HER2+) and MCF7 (ER+/HER2-) were treated with or without ENT at their IC50 doses and their gene expression profiles determined. In addition, a total of 27 MMTV-Neu mouse tumors (luminal) were untreated (N = 8), or treated with ENT at 12 mg/kg for 3 weeks (N = 5), 6 weeks (N = 6), or until progression after complete response (N = 8). We investigated their gene expression profiles by microarray and copy number (CN) by arrayCGH, and utilized the Dawnrank analysis, a network-based bioinformatics tool that integrates DNA and RNA data to identify driver genes, to find predictors of resistance to ENT. Results: Supervised analysis of gene expression data coming from the 3 treated cell lines showed significant upregulation of multiple MYC gene signatures. Therefore, we constitutively overexpressed MYC using lentiviral MYC shRNA in SKBR3 and MCF7, and MYC overexpression made cell lines more resistant to ENT. In MMTV-Neu mice, both MYC gene mRNA and gene signatures were downregulated while cells responded to ENT, and became upregulated when the tumors progressed. aCGH CN analysis revealed that a large portion of mouse Chromosome 4 had DNA CN loss and low gene expression in tumors that progressed while on ENT. Within this region, JUN was computationally identified to be a top driver gene associated with resistance. JUN was next knocked down using lentiviral JUN shRNA in BT474 and T47D, and JUN knock-down repeatedly made cell lines more resistant to ENT. MYC gene-expression was also upregulated in JUN-knockdown BT474 and T47D. Finally, JUN CN loss was found in 22% (132/588) of luminal tumors in The Genome Cancer Atlas breast cancer, and all the MYC signature scores were significantly higher in JUN-deleted TCGA samples. Conclusions: ENT was an effective drug for all of our luminal models, both in vitro and in vivo. Using these models, we selected for resistant variants and identified MYC signature expression, and JUN CN deletion as being associated with resistance.