bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
NCI Breast Cancer Steering Committee Working Group (WG) report on meaningful and appropriate endpoints for clinical trials (CT) in metastatic breast cancer (MBC).
Authors: Seidman Andrew David , Regan Meredith M. , Hershman Dawn L. , Korde Larissa A. , Perlmutter Jane , Barlow William E. , Rubinstein Larry , Fehrenbacher Louis , Beaver Julia A. , Amiri-Kordestani Laleh , Wedam Suparna B. , Smith Mary Lou , Rastogi Priya , Bordeleau Louise , Butler Lynn Pearson , Hayes Jennifer Fallas , Zujewski Jo Anne
Published: September 2018

1073

Background: There is significant heterogeneity in the natural history of MBC. Several recent randomized CT have yielded statistically significant advantages for the experimental arm, but neither led to regulatory approval nor practice change. Formal guidance for industry on CT endpoints provided by the US FDA in 2007 was not disease-specific. Patient-focused drug development is mandated by Prescription Drug User Fee Act V. Our WG sought to create specific consensus on endpoints for MBC CT focusing on subtype and line of therapy, with sensitivity to various stakeholders. Methods: A WG composed of medical oncologists, statisticians, advocates, FDA and NCI liaisons performed a systematic literature review of MBC natural history, CT endpoints by subtype (HR+/HER2-, HR+/HER+, HR-/HER2-, HR-/HER2+), and line of therapy (n = 146 papers). External expertise was obtained on industry perspectives, big data and real world evidence (RWE), and patient reported outcomes (PROs). WG members voted anonymously on statements and positions generated from deliberation. Results: The WG reached consensus on definitions relevant to contemporary CT endpoints. WG recommendations on the appropriate choice of OS or PFS are sensitive to expected post progression survival (PPS), and proportional and absolute gains. Currently, for HR-/HER2- MBC, OS is preferred as the optimal primary endpoint regardless of line of therapy; PFS is preferred in settings where expected PPS is longer. Toxicity can outweigh modest gains in PFS; scant data exist to gauge how patients value PFS gain vs toxicity. Where new agents may prolong PFS without impacting OS, exploring/validating graphic approaches that capture grade and timing of toxicity and PROs is warranted. An overview of WG Consensus Statements will be presented in detail. Conclusions: CT design for MBC should be sensitive to natural history (PPS), availability of other effective agents, PROs and toxicity burden. As unique subtypes (e.g. AR+) and novel therapies (e.g. immunotherapy) emerge, reassessment of relevant benchmarks is indicated. Rigorous big data approaches providing insights from RWE may inform CT endpoints in the future.
Distribution of receptor tyrosine kinase (RTK) nsSNPs in breast cancer (BC) patients (pts) using next-generation sequencing (NGS).
Authors: Morris Lindsay Kaye , Stein Matthew , Karri Saradasri , Sareen Srishti , Patel Kruti , Vidal Gregory A. , Schwartzberg Lee Steven , Martin Michael Gary
Published: September 2018

1080

Background: Non-synonymous SNPs (nsSNPs) discovered by NGS occurring in RTKs’ conserved topology in pts with BC may promote oncogenic signaling and hence may be actionable. Methods: We analyzed BC pts for nsSNPs in 29 RTKs identified by tumor profiling with NGS from Caris during 2013-2015. Mutations were classified by location including the tyrosine kinase domain (TKD), extracellular domain (ECD), transmembrane domain (TM), juxtamembrane domain (JM) and carboxy-terminal (CT) regions. nsSNPs underwent in silico analysis using PolyPhen-2 (Harvard) to determine pathogenicity. Results: 79 pts were identified with a median age of 58 years (range 32-83); 99% female; 60% white, 38% black and 2% other. 77 pts were classifiable with 8 (10%) triple-positive, 35 (46%) ER+/PR+/HER2- (ER/PR+), 10 (13%) ER-/PR-/HER2+ (HER2+) and 24 (31%) triple-negative. 78 nsSNPs and 1 Caris-reported pathogenic substitution of ERBB3 (TKD S846I) were found. 52/79 (66%) pts had ≥1 RTK nsSNP (range 0-4); 28/29 RTKs had ≥1 nsSNP with median of 2 (range 0-15). In 28 pts (35%), 40% of nsSNPs were predicted to be damaging (pnsSNP) and 3 pts had 2 pnsSNPs. 17/29 RTKs had pnsSNPs, median 1 (range 0-9). The most commonly mutated RTKs were ROS1 (9/15 variants were pnsSNPs), ALK (3/4), EPHA5 (3/3), FLT4 (2/5), cKIT (2/4) and ERBB4 (2/3). ROS1 and ALK nsSNPs were most-frequently seen in ER/PR+ (9/15 pnsSNPs), triple-positive (3/3) and HER2+ (0/2) pts; no triple-negative pts had such variants. 100% triple-positive pts (6/8 pnsSNP), 69% ER/PR+ (18/35), 60% HER2+ (2/10) and 58% triple-negative (3/24) had RTK nsSNP. nsSNP were spread in all 5 RTK regions: 58% localized to the ECD (20/45 pnsSNPs), 17% TKD (8/13), 9% CT (2/7), 9% TM (1/7) and 8% JM (1/6) lesions were found. Of 9 ROS1 pnsSNPs, 7 were ECD, 1 CT and 1 TKD. Conclusions: 35% of BC pts had pnsSNP in RTKs across various phenotypes including frequent mutations in potentially actionable genes such as ROS1 and ALK. 26% of ER/PR+ pts had pnsSNPs in ROS1 or ALK. nsSNPs in the ECD or TKD were most likely to be damaging.
A phase 2 study of napabucasin with weekly paclitaxel in previously treated metastatic breast cancer.
Authors: Edenfield William Jeffery , Becerra Carlos , Langleben Adrian , Spira Alexander I. , Braiteh Fadi S. , Kossler Kimiko , Gao Yuan , Li Youzhi , Hitron Matthew , Li Chiang
Published: September 2018

1084

Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, Napabucasin plus weekly paclitaxel was well tolerated. A phase II expansion cohort was opened for pts with previously treated metastatic breast cancer (MBC). Methods: Pts with metastatic MBC for whom weekly PTX was a reasonable treatment option received Napabucasin 240, 480, or 500 mg orally, twice daily in combination with paclitaxel 80 mg/m2 IV weekly on 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks per RECIST 1.1 criteria. Results: A total of 50 pts were enrolled including 34 with triple-negative disease (negative for estrogen receptor [ER], progesterone receptor [PR], and Her2 and no prior history of positive receptor status). There were 9 pts positive for ER, PR, or Her2 and refractory to targeted agents, and 7 pts with conversion to triple-negative disease from pathology previously positive for ER, PR or Her2. Pts were heavily pre-treated, having received a median of 5 prior lines of systemic therapy. All but 3 patients had received previous systemic treatment with a taxane. Napabucasin + PTX was well tolerated. Grade 3 AE occurring in ≥ 5% patients was diarrhea (n = 4), and 1 pt had grade 4 diarrhea. The objective response rate (ORR), disease control rate (DCR), median progression free survival (mPFS), and median overall survival (mOS) for all pts and for each sub-group are summarized in the table. Conclusions: Napabucasin (BBI-608) plus weekly paclitaxel has demonstrated safety, tolerability, and encouraging signs of anti-cancer activity in pts with pretreated metastatic breast cancer. Further clinical evaluation of this combination regimen in controlled trials is warranted. Clinical trial information: NCT01325441. [Table: see text]
Extracellular matrix (ECM) protein fragments in serum and outcomes in two metastatic breast cancer cohorts.
Authors: Willumsen Nicholas , Leitzel Kim , Ali Suhail M. , Nagabhairu Vinod , Marks Eric , Polimera Hyma Vani , Richardson Angelique Ellerbee , Krecko Laura , Ali Ayesha , Leeming Diana Julie , Karsdal Morten Asser , Lipton Allan
Published: September 2018

1085

Background: Extracellular matrix (ECM) is the non-cellular component of all tissues. Increased ECM formation and matrix metallo-protease (MMP) mediated ECM degradation are parts of tumorgenesis. The altered ECM remodeling generates specific ECM fragments that are released into the circulation. We evaluated the association of specific ECM/collagen fragments measured in serum with outcomes in two independent metastatic breast cancer (MBC) cohorts. Methods: C1M (MMP-degraded type I collagen), C3M (MMP-degraded type III collagen), C4M (MMP-degraded type IV collagen), and PRO-C3 (pro-peptide reflecting truetype III collagen formation) were measured by ELISA in pre-treatment serum from a phase III randomized clinical trial of 2nd-line hormone therapy (HR+, n= 153), and a 1st-line trastuzumab-treated cohort (HER2+, n=64). In both cohorts, all sites of metastases were included. The collagen-fragments were evaluated on continuous and categorical (75th percentile cut-off) bases by univariate Cox-regression analysis for their association with time-to-progression (TTP) and overall survival (OS). Results: In the HR+ cohort, Pro-C3 measured as a continuous variable was significantly associated with TTP; C1M, C4M and Pro-C3 were associated with OS. On a categorical basis, C1M and C3M were associated with TTP; all fragments were associated with OS (Table). In the HER2+ cohort, continuous measurements of all fragments were associated with TTP and OS. On a categorical basis (Table), all fragments were associated with TTP; C4M and Pro-C3 were associated with OS. Conclusions: ECM remodeling quantified in pre-treatment serum was associated with shorter TTP and OS in two independent MBC cohorts receiving systemic therapy. If validated, quantification of ECM remodeling in serum has potential as prognostic and/or predictive biomarkers in MBC. [Table: see text]
Paclitaxel plus carboplatin versus paclitaxel plus epirubicin as first-line treatment for metastatic breast cancer: Efficacy and safety results of a randomized, phase III trial.
Authors: Tong Zhongsheng , Li Shufen , Shi Yehui , Wang Xu , Wang Chen , Hao Chunfang , Wang Xiaorui , Meng Wenjin , Zhang Li
Published: September 2018

1087

Background: Paclitaxel/carboplatin combinations are highly active in metastatic breast cancer (MBC). We conducted a randomized, phase III, non-inferiority trial comparing paclitaxel/carboplatin (TP) with paclitaxel/epirubicin (TE) as first-line therapy for MBC. Progression-free survival (PFS) was the primary efficacy endpoint. Secondary endpoints included response rate, overall survival, tolerability, and quality of life (QoL). Methods: From June 2009 to January 2015, 231 patients were randomly assigned, 115 of whom were randomized to TP and 116 to TE. Baseline characteristics were relatively well-balanced in the two treatments. Results: After a median follow-up of 29 months, no significant difference was observed between the two treatments in objective response rate (ORR) (38.3% vs. 39.7%, respectively). Both the progression-free survival (p=0.158) and overall survival (p=0.369) were very similar between the two treatments. Both regimens were well tolerated. The main toxicities were myelosuppression, gastrointestinal reactions, and alopecia. TP showed higher grades 3–4 alopecia and higher nausea (p<0.05). TE showed higher incidence of myelosuppression than TP (p<0.05) (Table). Those patients whose epirubicin cumulative dose was more than 1000 mg/m2 did not suffer worse cardiotoxicity. Conclusions: Our study suggests that TP arm is an effective therapeutic alternative for patients with MBC, especially in those previously exposed to epirubicin in the adjuvant setting. TP has some advantages, such as less cost and less side effects (myelosuppression and fatigue). Clinical trial information: NCT02207361. [Table: see text]
Genome-wide copy number analysis of cell-free DNA from patients with chemotherapy-resistant metastatic triple-negative breast cancer.
Authors: Stover Daniel G. , Parsons Heather Anne , Ha Gavin , Freeman Samuel , Barry William Thomas , Guo Hao , Gydush Greg , Reed Sarah , Rhoades Justin , Rotem Denisse , Hughes Melissa E , Krop Ian E. , Tolaney Sara M. , Wagle Nikhil , Getz Gad , Meyerson Matthew , Love J. Christopher , Winer Eric P. , Lin Nancy U. , Adalsteinsson Viktor
Published: September 2018

1092

Background: Triple-negative breast cancer (TNBC) is a poor prognosis breast cancer subset characterized by relatively few mutations but extensive copy number alterations (CNAs). Cell-free DNA (cfDNA) offers the potential to overcome infrequent tumor biopsies in metastatic TNBC (mTNBC) and interrogate the genomics of chemotherapy resistance. Methods: 506 archival or fresh plasma samples were identified from 164 patients with mTNBC who had previously received chemotherapy. We performed low coverage sequencing to determine genome-wide copy number and estimate ‘tumor fraction’ of cfDNA (TFx). In patient samples with TFx >10%, we identified regions that were significantly gained or lost using GISTIC2.0. We compared CNAs of mTNBCs with primary TNBCs from a publicly-available dataset, METABRIC (TNBC n=277). Results: We successfully obtained high quality, low coverage whole genome sequencing data for 478 (94.5%) plasma samples from 158 patients, with 1 to 14 samples per patient. Archival samples had significantly higher average cfDNA per mL plasma and TFx than fresh samples, potentially due to later average line of therapy. Average TFx of first blood draw was significantly higher in patients with liver metastases (TFx 28.3% vs. 14.4%, p=1.1e-7). 101/158 patients (63.9%) had at least one sample with TFx >10%, our threshold for high confidence CNA calls. Most alterations significantly enriched in chemotherapy-resistant mTNBCs were chromosomal gains, including NOTCH2 and ERCC1. Median overall survival from time of first blood draw was 9 months, and TFx was highly correlated independent of metastatic line of therapy, age at metastatic diagnosis, BRCA status, and primary stage: adjusted hazard ratio between 4th and 1stquartiles = 4.29 (95% CI 1.66-11.1; p=0.0008). Conclusions: It is feasible to perform genome-level copy number analysis from cfDNA in both archival and fresh samples from patients with mTNBC. Copy number alterations enriched in mTNBC may have implications in the understanding of metastasis, therapeutic resistance, and novel therapeutic targets. ‘Tumor fraction’ of cfDNA is correlated with overall survival and may be an independent prognostic marker in mTNBC.
Investigating tumoral and temporal heterogeneity through comprehensive -omics profiling in patients with metastatic triple negative breast cancer.
Authors: Szeto Christopher , Parulkar Rahul , Sedgewick AJ , Benz Stephen Charles , Cecchi Fabiola , Hembrough Todd A. , Vaske Charles Joseph , Sanborn Zack , Rabizadeh Shahrooz , Mahen Elisabeth , Burton Kimberly , Soon-Shiong Patrick , Kuderer Nicole Maria , Senecal Francis Mark , Blau Sibel , Blau C. Anthony
Published: September 2018

1093

Background: The “Intensive Trial of OMics in Cancer”-001 (ITOMIC-001; Clinicaltrials.gov ID: NCT01957514) enrolls patients with metastatic triple negative breast cancer (TNBC) who are platinum-naive and scheduled to receive cisplatin. Multiple biopsies (up to 7 metastatic sites) are performed under carefully controlled conditions prior to and upon completion of cisplatin treatment and following any subsequent therapies. Samples are chosen for DNA sequencing, RNA sequencing, and quantitative proteomics (GPS Cancer). Here we describe the -omic alterations acquired during treatment. Methods: We analyzed 74 biopsies from 17 patients taken at various clinical timepoints (e.g. initial diagnosis, initial trial recruitment, following cisplatin treatment, etc.) spanning 2 years on trial and over 8 years before recruitment. This dataset includes 64 whole genomes (with matched-normal blood samples), 44 RNAseq expression profiles, and 23 proteomic sets. GPS Cancer, which comprises whole genome sequencing, whole transcriptome sequencing, and targeted quantitative proteomics was used to detect somatic alterations, measure mutational burdens, and estimate expression profiles of both transcripts and proteins. PARADIGM pathway analysis was used to identify network-level changes through integration of all available data types. Results: While mutational profiles within patients were largely stable over time, we observed up to a 10-fold difference in the magnitude of mutational burden between patients. Following cisplatin treatment, the expression of over 300 genes were significantly perturbed, and an average of 270 mutations per patient were introduced. PARADIGM integrated pathway analysis shows differential activity in the MYC/MAX and ETS1 pathways during tumor progression. Conclusions: Using GPS Cancer we provide detailed characterizations of the molecular profiles of metastatic TNBC across space and over time. We demonstrate the potential for using this information to discover mechanisms underlying treatment resistance and disease progression. Our findings form the basis for molecularly informed QUILT trials for combination therapy.
Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer: ERIGE trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).
Authors: Musolino Antonino , Porzio Rosa , Rubino Daniela , Frassoldati Antonio , Caldara Alessia , Schirone Alessio , Gori Stefania , Piacentini Federico , Berardi Rossana , Brandes Alba Ariela , Cavazzini Giovanna , Foglietta Jennifer , Villa Federica , Pellegrino Benedetta , Camisa Roberta , Todeschini Renata , Tognetto Michele , Naldi Nadia , Baldari Daniela , Montemurro Filippo
Published: September 2018

1095

Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Methods: We performed an open-label, national multicenter phase 2 study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC. The Simon's optimal two-stage design was used for estimating objective response rate (ORR) as study primary endpoint. A prospective, molecular correlative study was carried out on germinal DNA of study population to assess the role of germinal DNA polymorphisms and BRCA mutations in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016 , 83 (37 in the first stage, 46 in the second one) assessable patients were enrolled. Median age at baseline was 56 years. Sixty-six and 17 patients were in first or second-line treatment, respectively. All patients were previously treated with an anthracycline and/or a taxane. With regard to the first stage of study enrolment, patients received a median number of 6 cycles of treatment. The ORR (CR+PR) was 43.24% (90% CI 29.3-58.0) and the clinical benefit rate (CR+PR+SD) was 64.9% (90% CI: 50.1%-77.8%). The most common grade 3/4 AEs ( > 10% of patients) were neutropenia without febrile neutropenia and liver toxicity. Grade 1/2 AEs were fatigue, anemia, thrombocytopenia, diarrhea, alopecia, peripheral neuropathy, and oral mucositis. Conclusions: The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. More mature toxicity and outcome data of the final study population and correlation with genome analysis will be presented at the meeting. Clinical trial information: 2012-003505-10.
A multi-center phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401).
Authors: D'Angelo Sandra P. , Mahoney Michelle R. , Van Tine Brian Andrew , Atkins James N , Milhem Mohammed M. , Tap William D. , Antonescu Cristina R. , Horvath Laura E. , Schwartz Gary K. , Streicher Howard
Published: September 2018

11007

Background: Patients (pts) with metastatic sarcoma (SAR) have limited options. Nivolumab(N), a fully human anti-PD-1 mAb and ipilimumab (I), a humanized anti-CTLA-4 mAb, have favorable safety & efficacy in other tumors. Pembrolizumab demonstrated a response rate (RR) of 12% in SAR pts. We evaluated N, independently from N+I, in SAR pts. Methods: This open-label multi-center phase II study enrolled pts failing prior regimens. Randomized (non-comparative) pts received either N3 [N (3 mg/kg q2W)] or N3+I1 [N(3 mg/kg Q3W x4, then Q2W) & [I(1 mg/kg q3W x4)]. Treatment continued beyond progressive disease (PD) in 1st12 weeks. 5 confirmed responses in 38 evaluable pts yielded 90% power (0.05 1-sided alpha) to detect a 20% (vs 5%) confirmed RR. Other endpoints: adverse events (AEs), progression-free, overall survival (PFS, OS), and correlative studies including PD-L1 expression by IHC, mutational burden/neoantigen analysis, TCR clonality and TIL characterization. Results: 85 pts (43 - N3; 42 - N3+I1) were enrolled [mean age 54 yrs (21–81), 52% female). No significant differences in histological subtypes across cohorts: 36% LMS, 4% LPS, 10% UPS/MFH, 6% synovial, 5% bone, 5% Ewing’s, and 34% other. Pts were refractory to 1(20%), 2(22%), and ≥3 (58%) regimens. Grade 3-4 treatment related adverse events (TRAE) occurred in 7% (N3) and 14% (N3+I1) and 0 Gr 5 TRAEs. 8% of pts stopped due to AEs (2% N3, 14% N3+I1). 2/3 confirmed responses on N3, with 2 ongoing (range 1.1-3.2 months). 6/7 confirmed responses (2 complete) on N3+N1, with 5 ongoing (range 6-13 months). Responses occurred in 7 histologies. See Table for pt outcomes. Conclusions: N + I showed acceptable safety and encouraging antitumor activity with most responses ongoing across multiple SAR histologies, passing efficacy criteria. There was minimal activity observed with N alone. Increased TRAEs were observed in N3+I1. Correlative analyses ongoing. NCT02500797. Support: U10CA180821, U10CA180882, Conquer Cancer Foundation, BMS. Clinical trial information: NCT02500797. [Table: see text]
The sarculator stratified prognosis of patients with high-risk soft tissue sarcomas (STS) of extremities and trunk wall treated with perioperative chemotherapy in a randomised controlled trial (RCT).
Authors: Pasquali Sandro , Colombo Chiara , Bottelli Stefano , Verderio Paolo , Martin Broto Javier , Lopez-Pousa Antonio , Ferrari Stefano , Poveda Andres , De Paoli Antonino , Quagliuolo Vittorio , Cruz Josefina , Comandone Alessandro , Grignani Giovanni , De Sanctis Rita , Palassini Elena , Llombart-Bosch Antonio , Dei Tos Angelo Paolo , Casali Paolo Giovanni , Picci Piero , Gronchi Alessandro
Published: September 2018

11016

Background: Patients with extremity and trunk wall STS with high malignancy grade and size larger than 5cm are considered at high risk of death, but in fact this risk varies broadly depending on histologic subtype and size. The Sarculator, a nomogram for STS, can improve prognostic assessment of these patients. This tool was evaluated for stratifying risk of distant metastasis (DM) and overall survival (OS) in a RCT investigating perioperative chemotherapy. Methods: High-risk STS patients were randomly assigned to receive either three cycles of preoperative chemotherapy with epirubicin (120 mg/m2) and ifosfamide (9 g/m2) or the same three preoperative cycles followed by two further postoperative cycles. The Sarculator was used to stratify patient risk according to predicted 10-year cumulative incidence of DM and OS rates. Results: The Sarculator identified three different prognostic groups of patients at low (N = 101), intermediate (N = 102), and high (N = 107) risk. Cumulative incidence of DM was 0.26 (SE: 0.04), 0.31 (SE: 0.05), and 0.48 (SE: 0.05) for low, intermediate, and high risk patients, respectively. Similarly, OS rates were 0.78 (95%CI 0.68-0.85), 0.63 (95%CI 0.53-0.72), and 0.42 (95%CI 0.32-0.52), respectively. Patients in the low risk group were at significantly lower risk of death compared to those in the intermediate (HR 0.51, 95%CI 0.34-0.78, P = 0.002) and high (HR 0.28, 95%CI 0.17-0.46, P < 0.001) risk groups. Subgroup analysis performed by jointly considering these three groups and the two study arms did not identify statistically significant survival differences between the treatment arms within each risk category. Conclusions: Patients with high-risk STS included in this RCT were not a homogeneous population. The Sarculator identified different risk groups for DM and OS even in patients included in a RCT investigating perioperative treatments. This tool should be considered for redefining high-risk STS and stratifying patient risk in future RCT investigating perioperative chemotherapy. Clinical trial information: 2004-003979-36.
Factors impacting contemporary management of high-grade extremity sarcoma: An analysis of 12,020 patients.
Authors: Ramey Stephen , Asher David , Zhao Wei , Kodiyan Joyson , Chinea Felix , Patel Vivek , Wang Lily , Wilky Breelyn A. , Subhawong Ty , Trent Jonathan C. , Yechieli Raphael
Published: September 2018

11017

Background: Previous studies noted racial/ethnic disparities in high-grade extremity soft tissue sarcoma (ESS) treatment and overall survival (OS). Retrospective series have noted worse OS for Amputation (Amp) vs limb salvage surgery (LSS) and for LSS alone vs LSS plus radiation (RT). Given superior functional outcomes, LSS is now favored over Amp when possible. This study examines racial/ethnic disparities in receipt of Amp vs LSS and impact on OS using modern data from a national registry. Methods: The National Cancer Database was used to identify patients (pts) with stage II-III, high-grade ESS diagnosed between 2004-2014 and treated definitively with 1) Amp alone, 2) LSS alone, 3) Preoperative RT [pre RT] + LSS or 4) LSS + Post-operative RT [post RT]. Multivariate analyses (MVA) utilized logistic regressions for patterns of local treatment and Cox proportional hazards regression for OS. The Kaplan-Meier method was used to estimate 5-year OS. Results: Among 12,020 pts, receipt of LSS vs Amp did not differ significantly by race, ethnicity, age, insurance status, income, or educational attainment on MVA. The rate of Amp was higher in academic centers (OR 2.42; p = .006) or integrated network programs (OR 2.30; p = .014) vs community programs and rural vs. Metro settings (OR 1.88; p = .035). Actuarial 5-year OS by treatment was Amp 43%, LSS 59%, pre RT + LSS 61%, and LSS + post RT 66% (p < .001). On MVA, OS was worse with Amp vs. LSS alone (HR 1.37; p < .001) while pre RT + LSS (HR 0.70; p < .001) and LSS + post RT (HR 0.72; p < .001) had improved OS vs LSS alone. Treatment at a comprehensive community, academic, or integrated network programs vs community program; private insurance vs none; Hispanic vs. non-Hispanic (HR 0.85, p = .048); and higher educational attainment were associated with improved OS. More comorbidities, other primary cancers, older age, and no transitions in care were associated with worse OS. Conclusions: The only racial/ethnic disparity identified when evaluating rates of Amp and OS for ESS was a small OS benefit for Hispanic pts. OS was inferior with Amp and best with LSS with either pre RT or post RT. OS was improved at non-community programs, potentially indicating a need for referral to experienced centers.
Analysis of osteosarcoma subtypes by clinical genomic testing to identify clinically actionable alterations.
Authors: Livingston John Andrew , Posey Kristi , Subbiah Vivek , Daw Najat C. , Somaiah Neeta , Ravi Vinod , Patel Shreyaskumar , Benjamin Robert S. , Wang Wei-Lien , Lazar Alexander , Broaddus Russell , Meric-Bernstam Funda , Shaw Kenna Rael , Roszik Jason , Conley Anthony Paul
Published: September 2018

11019

Background: Genomic testing is being utilized with increasing frequency to identify matched therapies for patients (pts) with advanced disease; however, the utility of such testing has not been defined in osteosarcoma (OS). We report our experience with 36 pts with recurrent/metastatic OS who underwent testing on a genomic testing protocol, including actionable alterations across multiple histologic subtypes of OS. Methods: Standardized hotspot mutation analysis was performed in 36 pts with recurrent/metastatic OS, using either a 46-, 50-gene, or 128-gene CLIA certified multiplex platform. 12 pts had a 200-gene analysis on a companion research protocol. We used the Catalogue Of Somatic Mutations In Cancer (COSMIC) database to identify alterations that are in mutation hotspots in OS or in other cancers. Clinical outcomes were retrospectively collected. Histologic subtype classifications were made by an experienced sarcoma pathologist based upon the pre-treatment and resection specimens. Cases with only metastatic samples available were classified as “other high-grade osteosarcoma.” Additional clinical correlations are ongoing. Results: A total of 36 pediatric and adult pts were analyzed. All osteosarcomas were high grade; the most common osteosarcoma histologic subtypes were chondroblastic, osteoblastic, and other. Samples analyzed were from primary tumor in 15/36 (42%), with the remaining from metastatic specimens (58%). Mutations were identified in 26 pts (72%). The most common mutations were in TP53. An activating PIK3CA E545K mutation was found in chondroblastic OS. Other notable hotspot mutations include a GNAS R201 mutation in osteoblastic osteosarcoma and a KRASG12V mutation in a fibroblastic osteosarcoma. Conclusions: Clinical gene panel sequencing can identify a limited number of potentially actionable mutations in patients with osteosarcoma. Given the heterogeneity of osteosarcoma at the molecular level, clinical genomic testing may be warranted to identify patients for participation on matched clinical trials.
Clone evolution and genomic alteration analysis of osteosarcoma and matched lung metastasis.
Authors: Wang Di , Wang Jie , Niu Xiaohui , Huang Zhen , Wang Zhijie , Zhang Qing , Duan Jianchun , Bai Hua , Hao Lin
Published: September 2018

11032

Background: Lung metastasis (LM), as the most common metastatic site, is the main reason resulting in treatment failure and death of osteosarcoma (OS). But there was no report about the clone evolution and genomic alteration in the process of LM of OS. Methods: Multiregion whole-genome sequencing and whole-exome sequencing were performed on ten patients with primary OS and matched lung metastatic tumors. A set of high confident somatic nucleotide variants (SNV), small insertion and deletion (indel) and copy number variation (CNV) in each sample were identified, then the n-dimensional Bayesian Dirichlet process was applied to define the constituent mutation clusters as clone or subclone. Neoantigen prediction and HLA typing were performed using NetMHC3.0 and POLYSOLVER algorithm, respectively. Results: There were diversified metastatic progression during lung metastasis of OS including linear evolution (7/10) and parallel evolution (3/10), and metastasis-to-metastasis spread was also found in a patient with multiple metastasis; Mutation accumulative effect during the metastasis of OS was evident, LM had much higher mutation load (fold change = 4.1, P-value < 0.01) and neoantigen burden (fold change = 4.5, P-value < 0.001) than the primary tumor; DNA mismatch repair (MMR) genes relevant deleterious mutation events were found in germline in 8/10 metastatic OS cases and MMR genes mutation were much more in LM than primary cancer; The genome instability of LM was prevalently much more significant than primary tumor, with higher copy number variation frequency (fold change = 7.01, P-value < 0.01). Conclusions: The evolution of OS during LM was very complex with diversified metastatic progression. For the LM of OS, the novel therapy should be considering the much higher mutation load, especially those causing tumor neoantigens, higher genomic instability which were associated with tumor immune therapy. Furthermore, the findings of germline MMR genes mutation in primary OS which had occurred LM and more MMR genes mutation in LM of OS indicated potential clinical benefit on immune checkpoint inhibitor therapy and other small molecular drugs for MMR genes.
A DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas.
Authors: Wu Shengyang , Cooper Benjamin Thomas , Bu Fang , Bowman Christopher , Killian Keith , Serrano Jonathan , Wang Shiyang , Jackson Twana , Gorovets Daniel , Gorlick Richard Greg , Ladanyi Marc , Thomas Kristen , Snuderl Matija , Karajannis Matthias A.
Published: September 2018

11034

Background: Bone sarcomas present a unique diagnostic challenge because of the considerable morphologic overlap between different entities. The choice of optimal treatment, however, is dependent upon accurate diagnosis. Genome-wide DNA methylation profiling has emerged as a new approach to aid in the diagnosis of brain tumors, with diagnostic accuracy exceeding standard histopathology. In this work we developed and validated a methylation based classifier to differentiate between osteosarcoma, Ewing’s sarcoma, and synovial sarcoma. Methods: DNA methylation status of 482,421 CpG sites in 15 osteosarcoma, 10 Ewing’s sarcoma, and 11 synovial sarcoma samples were measured using the Illumina HumanMethylation450 array. From this training set of 36 samples we developed a random forest classifier using the 400 most differentially methylated CpG sites (FDR q value < 0.001). This classifier was then validated on 10 synovial sarcoma samples from TCGA, 86 osteosarcoma samples from TARGET-OS, and 15 Ewing’s sarcoma from a recently published series (Huertas-Martinez et al., Cancer Letters 2016). Results: Methylation profiling revealed three distinct molecular clusters, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were correctly classified as synovial sarcoma (10/10, sensitivity and specificity 100%). All but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and all but one sample from the Ewing’s sarcoma series was classified as Ewing’s sarcoma (14/15, sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample was classified as Ewing’s sarcoma, and was later determined to be a misdiagnosed Ewing’s sarcoma based on RNA-Seq demonstrating high EWRS1 and ETV1 expression. An additional clinical sample that was misdiagnosed as a synovial sarcoma by initial histolopathology, was accurately recognized as osteosarcoma by the methylation classifier. Conclusions: Osteosarcoma, Ewing’s sarcoma and synovial sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide an accurate diagnosis when histological and standard techniques are inconclusive.