bluuebunny/crossref_metadata_2025_split huggingface dataset:
Whole transcriptome sequencing in metastatic cancer: A review of expression outliers in 113 metastatic breast cancer patients.
Authors: LeVasseur Nathalie , Csizmok Veronika , Bonakdar Melika , Shen Yaoqing , Zibrik Lindsay , Zhao Eric Yang , Sun Sophie , Gelmon Karen A. , Laskin Janessa J. , Marra Marco A. , Chia Stephen K. L. 
Published: May 2019

3080 Background: The genomic profiling of breast cancers has led to a greater understanding of the mutational landscape of metastatic breast cancer (MBC) with potential therapeutic implications. Despite these advances, there is a paucity of data regarding the additive value and relevance of gene expression across histological and molecular subtypes, which represents the majority of informative and actionable findings identified in the BC Cancer personalized oncogenomics program (POG). Methods: Informative findings with potential clinical application from whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) in MBC patients between 2012-2018 were reviewed. Variants observed in pathway genes of potential clinical relevance, as defined by a curated list of genes, were examined across histological subtypes. High and low expression outliers relative to TCGA breast cases, defined as expression greater than 98th percentile and FC > 2 compared to Illumina breast dataset and lower than 25th percentile and FC < -2 compared to Illumina breast dataset, respectively, were then analyzed to establish how many outliers were observed in pathways of potential clinical relevance. Results: A total of 113 cases were included. WGS revealed that TP53 was the most frequent single nucleotide variant (SNV) in triple negative breast cancer (23/30, 77%), whereas PIK3CA (37/78, 47%), PTEN (11/78, 14%) and ESR1 (19/78, 24%) were most frequent in ER positive cases and CDKN2A (2/18, 11%) in HER2 positive cases. Across all subtypes, the mTOR and cell cycle pathways were found to have the highest frequency of SNVs, with the identification of 86 and 71 variants, respectively. Expression data for 113 RNA-sequenced patients revealed a high frequency of expression outliers in the mTOR pathway (26 high expression and 424 low expression outlier genes) and cell cycle pathways (35 high expression and 331 low expression outlier genes), but also in the WNT pathway (96 high expression and 490 lower expression outlier genes) and NOTCH pathway (84 high expression and 564 low expression outlier genes). Conclusions: Frequently identified SNVs across histological subtypes were correlated with expression outliers in pathways of clinical relevance in breast cancer. Additional informative findings, in pathways of potential clinical relevance not historically targeted in breast cancer, were identified with WTS. The clinical utility of these findings warrants further study.
Transcriptome-based cancer type prediction for tumors of unknown origin.
Authors: Michuda Jack , Igartua Catherine , Taxter Tim , Bell Joshua SK , Pelossof Raphael , White Kevin 
Published: May 2019

3081 Background: Tumors of unknown origin occur in approximately 5% of newly diagnosed cancers and are difficult to treat without establishing the tissue type from which they derive. Establishing tumor origin guides standard of care treatment for several NCCN targeted therapy guidelines. Leveraging tissue specificity in gene expression profiles, classification models based on RNA expression offer a promising approach to identify the likely primary cancer site in tumors of unknown origin. Methods: In this study, we developed a transcriptome-based cancer type classifier trained on over 10,000 tissue samples annotated by pathologists and sequenced for RNA expression to identify conserved patterns of expression characteristic of 30 tumor types across primary and metastatic tissue sites. The classifier probabilistically ranks cancer of origin. Results: Overall, the accuracy of the most probable cancer prediction was 85%, 88% within primary tumors and 77% within metastatic tumors. The top three cancers types with the highest accuracy were colorectal (accuracy in metastatic: 93%, accuracy in primary tumors: 99%), breast (95%, 96%) and lung (87%, 94%). Classifier performance was lower in low-purity metastatic tumors where the surrounding normal tissue obscures the tumor transcriptional profile, though the classifier still achieves 71% accuracy on metastatic tumors with less than 50% purity. Conclusions: We present a novel method to probabilistically predict tumor type for cancers of unknown origin using RNA-Seq. Our method achieves robust classification that is applicable to primary and metastatic tumors and demonstrates the value of utilizing RNA-Seq to aid cancer diagnosis and treatment decisions.
Machine learning algorithm analysis using a commercial 592-gene NGS panel to accurately predict tumor lineage for carcinoma of unknown primary (CUP).
Authors: Abraham Jim , Heimberger Amy B. , Gatalica Zoran , Korn Wolfgang Michael , Spetzler David 
Published: May 2019

3083 Background: The diagnosis of a malignancy is typically informed by clinical presentation and tumor tissue features including cell morphology, immunohistochemistry, cytogenetics, and molecular markers. However, in approximately 5-10% of cancers, ambiguity is high enough that no tissue of origin can be determined and the specimen is labeled as a Cancer of Occult\Unknown Primary (CUP). Lack of reliable classification of a tumor poses a significant treatment dilemma for the oncologist leading to inappropriate and/or delayed treatment. Methods: 40,000 tumor patients with NGS data were used to construct a multiple parameter lineage-specific classification system using an advanced machine learning approach. The dataset for each classifier was split 50% for training and the other 50% for testing. The training task for each classifier was to identify the cases that were similar to the cases it was trained on against a backdrop of randomly selected cases of other histological origins. Results: Tumor lineage classifiers predicted the correct classifications where the primary site was known with accuracies ranging between 85% and 95%. When applied to CUP cases (n = 500), an unequivocal result could be obtained 100% of the time. Conclusions: Lineage predictors can render a histologic diagnosis to CUP cases that can inform treatment and potentially improve outcomes.
Design, engineering, and characterization of a novel long-acting (Pegylated) single isomer human arginase for arginine depriving anticancer treatment.
Authors: Yu Kuo-Ming , Pang Tammy Pui-Shi , Cutler Murray , Lau Johnson Yiu-Nam , Lo Thomas Wai-Hung , Leung Thomas Yun-Chung 
Published: May 2019

3090 Background: Arginine deprivation therapy is an attractive strategy to treat arginine-auxotrophic cancers with deficient expression of argininosuccinate synthetase, argininosuccinate lyase or ornithine transcarbamylase. We have designed and engineered a novel human arginase with single site pegylation exerting excellent preclinical pharmacologic profile to serve as a new class of therapy. Methods: Human arginase has three cysteines (at position 45, 168, 303) and none of them is in or close to the active site. Two cysteines were mutated to serines, leaving the only cysteine at 45 for the simple and cost-effective synthesis of a single isoform of pegylated human arginase. Different forms of PEG moieties were evaluated for the selection of a drug candidate (PT01), followed by extensive characterization. Results: Converting Cys at 168 and 303 to serine impacted least on enzymatic activity (with cobalt cation). Pegylation with different sizes and shapes showed that 20 and 40 kDa (linear and branched) had similar PK/PD profile without damaging enzymatic activity. Therefore, arginase modified with a linear 20 kDa PEG was chosen as the candidate. A single 0.4 mg/kg IV dose of PT01 in rats induced 4 days of near complete plasma arginine depletion, while 6–7 days of depletion between 1.2 and 2 mg/kg. Plasma arginine levels were reversible. First-order clearance of both plasma PT01 concentration and activity suggested a terminal half-life of about 20 hours. In vitro assay showed very potent cytotoxicity at sub-nM level against various cell lines of breast, prostate, and pancreas in origins. In two mouse cancer models (hard-to-cure pancreas and castration-resistant prostate), weekly infusion at 5 and 10 mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose. Conclusions: A novel single isoform of pegylated human arginase was created, showing excellent enzymatic activity, PK/PD profiles, and cytotoxicity in vitro. Mouse xenograft models showed good tumor growth inhibition activity with tolerable toxicity as manifested on transient weight loss during therapy.
Nanoparticle entrapped docetaxel (CPC634) enhances intratumoral docetaxel exposure compared to conventional docetaxel (Cd) in patients with solid tumors.
Authors: Atrafi Florence , van Eerden Ruben A.G. , van Hylckama Vlieg Marte A.M. , De Hoop Esther Oomen , de Bruijn Peter , Rijcken Cristianne J.F. , Hanssen Rob , Eskens Ferry , Mathijssen Ron H.J. , Koolen Stijn L.W. 
Published: May 2019

3096 Background: Failure or resistance to chemotherapy may be caused by sub‐therapeutic intratumoral drug levels. Nanomedicine aim to improve intratumoral drug exposure. CPC634 is a nanoparticle entrapping docetaxel. We hypothesized that CPC634 increases intratumoral docetaxel exposure. Methods: In this randomized cross-over study we assessed intratumoral and plasma pharmacokinetics (PK) of docetaxel after intravenous administration of CPC634 and conventional docetaxel (Cd). The study was powered to identify an 25% increase in intratumoral docetaxel exposure of CPC634 relative to Cd. Patients (≥18 years) were randomized to receive 75 mg/m2 CPC634 in cycle 1 and Cd in cycle 2 or vice versa. After drug administration, patients underwent tumor biopsies during both cycles. Total docetaxel was determined for both drugs and released docetaxel for CPC634 in tumor tissue and in plasma with a validated LC-MS/MS method. PK data were analyzed with mixed model analysis. Results: Sixteen evaluable patients were included. Intratumoral PK revealed a 323% (95% CI: 148,621) higher total docetaxel (p < 0.001) for CPC634. Released docetaxel for CPC634 was comparable to total docetaxel levels for Cd (95% CI: -35-,67) (p = 0.43). Plasma released docetaxel for CPC634 exhibited an 89% (95% CI: 86, 91) lower (p < 0.001) peak plasma concentration (Cmax) and 81% (95% CI: 46, 125) higher (p < 0.001) area under the curve (AUC) relative to Cd. Conclusions: CPC634 resulted in higher intratumoral total docetaxel and comparable released docetaxel levels relative to total docetaxel for Cd. CPC634 had a favorable plasma PK profile with a lower Cmax and prolonged higher systemic exposure relative to Cd. These results indicate that CPC634 could improve intratumoral docetaxel exposure compared to Cd. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) are currently ongoing.
Patient-derived organoid (PDO), a new personalized therapy selection tool for prompt clinical decision making in metastatic gastrointestinal (mGI) cancer patients.
Authors: Xie Hao , Hogenson Tara L , Horn Isaac P , Almada Luciana , Marks David , Koenig Amanda , Tolosa Ezequiel , Barrett Michael T. , Boyum James H , Mahipal Amit , Hubbard Joleen Marie , Scheffler Hanson Temperance J , Yin Jun , Petersen Gloria M. , Revzin Alexander , Billadeau Daniel D. , Bekaii-Saab Tanios S. , Adjei Alex A. , Ma Wen Wee , Fernandez-Zapico Martin 
Published: May 2019

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 < 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAFV600E-mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.
Host transcriptomic signatures associated with dysbiosis in a preclinical model of lung cancer.
Authors: El-Ashmawy Mariam , Wu Benjamin , Tsay Jun-Chieh , Franca Brendan , Perez Luisanny , Sulaiman Sheik Mohammad Imran , Rom William , Wong Kwok-Kin , Segal Leopoldo 
Published: May 2019

3107 Background: Enrichment of the lower airway microbiota with oral commensals has been associated with transcriptomic changes affecting several inflammatory pathways associated with non-small cell lung cancer (NSCLC) development and progression. Using a mouse model of NSCLC, we evaluated the effects of lower airway dysbiosis on tumor progression and host transcriptomics. Methods: Preclinical model of lung cancer was constructed by introducing luminescence-tagged Kras mutated cells into C57/B6 mice, causing lung cancer to develop. Lower airway dysbiosis was induced by weekly intratracheal challenge with either PBS or Veillonella parvula in wild type and lung cancer mice. Experiments were repeated twice to evaluate for survival as well as lower airway host response using flow cytometry and RNA sequencing (HiSeq). Sequence data was processed using a validated mouse gene expression signature matrix with cibersort from https://cibersort.stanford.edu and DESeq using FDR correction. Results: In wild type mice, lower airway dysbiosis with Veillonella did not affect the survival, weight gain or airway lumen diameter. Among lung cancer mice, dysbiosis led to increased mortality, weight loss, and tumor burden. Multiple transcriptomic signatures were identified among the dysbiosis groups (both in WT and lung cancer mice). Unsupervised hierarchical clustering of immune cell profiles using cibersort on whole transcriptome showed near perfect separation between the four experimental conditions. Amongst the most differentially enriched immune cell subsets, we identified that lung dysbiosis upregulates genes annotated to Th1 and Th2 cells (p < 0.01, q < 0.2). Using flow cytometry, we identified that PD-1, IL-17, and ROR-gamma are differentially expressed in CD4+ cells in dysbiosis conditions, and these patterns are consistent in whole RNA transcriptome. Conclusions: Transcriptomic signatures reveal immune profiles associated with dysbiosis, an experimental condition associated with worse outcomes in lung cancer. This investigation provides novel insights into how disruption of the lower airway microbiome may contribute to the pathogenesis of NSCLC.
A modeling and simulation study of less frequent dosing of nivolumab 480 mg.
Authors: Peer Cody J. , Goldstein Daniel A. , Ratain Mark J. , Figg William Douglas 
Published: May 2019

3115 Background: Nivolumab was originally approved at 3 mg/kg q2w. However, there is abundant evidence that doses as low as 0.1 mg/kg q2w are effective, and a randomized trial in RCC demonstrated equivalence across a dose range of 0.3-10 mg/kg q3w. Modeling and simulation have been used to amend the labeled dosage to 240 mg q2w or 480 mg q4w, with the latter yielding an estimated steady-state trough concentration (Ctrough) of ~50 ug/mL. Given the high cost of nivolumab and the lack of a dose-response relationship, we hypothesized that less frequent dosing of 480 mg would maintain therapeutic serum concentrations. The objective of this study was to use modeling and simulation to develop alternative dosing strategies. Methods: A simulation model was built from a published population pharmacokinetic model, incorporating time-dependent clearance. Various alternative dosing schedules were simulated, beginning with the third dose (doses 1 and 2 were 480 mg at wk 1 and 5). We conservatively chose 4.5 mg/mL as the target concentration (TC), slightly above the mean simulated Ctrough at 0.3 mg/kg q3w (4.1 ug/mL), although even lower levels are likely efficacious. The simulated dose schedules were q8w, q10w, q12w and q14w, beginning with the third dose. Simulations were performed on 50 simulated patients, with each simulation replicated 5 times. Results: The simulated Ctrough following doses 2-4 are presented in the table below. Dosing q12w should maintain TC in > 70% of patients, and q14w dosing should achieve TC in > 55% of patients. Conclusions: Modeling and simulation provide evidence that nivolumab can be effectively dosed q8-14w (after the first 2 doses), resulting in a potential 70% cost savings. As responding patients generally have a 35-45% decrease in clearance over the first 6 months of treatment, even less frequent dosing may be required for subsequent doses. Randomized trials of this interventional pharmacoeconomic strategy are indicated. Similar opportunities may exist for other checkpoint inhibitors. [Table: see text]
Concomitant intake of abiraterone and food to increase pharmacokinetic exposure: Real-life data from a therapeutic drug monitoring program.
Authors: Groenland Stefanie L. , Bergman Andre M. , Huitema Alwin , Steeghs Neeltje 
Published: May 2019

3117 Background: Abiraterone acetate is registered for the treatment of metastatic castration resistant prostate cancer. Pharmacokinetic (PK) exposure has been linked to efficacy, since patients with Cmin ≥ 8.4 ng/mL have a significantly longer progression free survival compared to patients with a Cmin below this threshold (7.4 vs. 12.2 months, p = 0.044) (Carton, 2017). At the recommended fixed dose of 1000 mg QD administered in a modified fasting state, 35% of patients do not reach this efficacy threshold (Carton, 2017), providing a strong rationale for therapeutic drug monitoring (TDM). Since a clinically relevant food effect has been established, concomitant intake of abiraterone and food could offer a cost-neutral solution in case of low exposure (Chi, 2015). This study aims to evaluate whether PK-guided abiraterone dosing is feasible and results in an increased proportion of patients with concentrations above the target. Methods: Patients starting regular treatment with abiraterone were included. PK sampling occurred 4, 8 and 12 weeks after start of treatment, and every 12 weeks thereafter. Abiraterone concentrations were measured and Cmin was calculated. In case of Cmin < 8.4 ng/mL and acceptable toxicity, a PK-guided intervention was advised. As a first step, concomitant intake of abiraterone and a light meal or a snack was advised. Results: In total, 35 patients were included, of which 18 patients (51%) had at least one Cmin < 8.4 ng/mL. These patients were advised to take abiraterone concomitantly with food, after which Cmin increased significantly from 5.6 (47%) ng/mL [mean (CV%)] to 40.6 (110%) ng/mL (p = 0.006) without additional toxicities. This intervention led to adequate exposure in 15 patients (83%). Seventeen patients had all Cmin levels ≥ 8.4 ng/mL, in these patients mean Cmin was 31.5 (65%) ng/mL. Conclusions: TDM of abiraterone was applied in clinical practice and proved to be feasible. Concomitant intake with food resulted into a significant increase in Cmin and offers a cost-neutral opportunity to optimize treatment for patients with low PK exposure. Up to 100 patients will be included to evaluate the effect of PK-guided abiraterone dosing on treatment efficacy. Clinical trial information: NL6695.
Boosting pazopanib exposure by splitting intake moments: A prospective pharmacokinetic study in cancer patients.
Authors: Groenland Stefanie L. , van Eerden Ruben A.G. , Verheijen Remy B , Huitema Alwin , Mathijssen Ron H.J. , Steeghs Neeltje 
Published: May 2019

3119 Background: Pazopanib is approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). Due to high (40-70%) interpatient variability in pharmacokinetic (PK) exposure, 16-20% of patients do not reach the 20 mg/L exposure threshold related to prolonged progression free survival (20 weeks versus 52 weeks, respectively) with the currently used fixed dose of 800 mg QD (Suttle, 2014; Verheijen, 2017). PK simulations showed that, due to non-linear absorption of pazopanib, splitting the intake (400 mg BID) leads to an increase in Cmin and AUC0-24h of 75% and 59%, respectively (Yu, 2017). This study aimed to show whether switching patients from an 800 mg QD to a 400 mg BID dose schedule will lead to a significant increase in PK exposure. Methods: We performed a prospective PK trial (NL6137) in which PK sampling at the 800 mg QD dose schedule occurred at day 1, after which the intake moments were split into 400 mg BID during one week, followed by PK sampling at day 8. Paired samples t-tests were used to assess differences in Cmin, Cmax and AUC0-24h between these two dose schedules. To detect an increase in PK exposure of 50% (2-sided α = 0.05 and β = 0.20), 10 evaluable patients were needed. Results: Eleven patients (6 RCC and 5 STS) have been included, of whom ten were evaluable for PK analyses. Using the 800 mg QD dose schedule mean Cmin, Cmax and AUC0-24h were 26.7 mg/L (coefficient of variation (CV%) 44.7), 46.1 mg/L (CV% 37.1) and 809 mg h/L (CV% 42.1), respectively. Switching to 400 mg BID resulted in an increase of both Cmin and AUC0-24h to 40.7 mg/L (CV% 37.0, p = 0.013) and 1059 mg h/L (CV% 33.1, p = 0.068), respectively, while Cmax did not significantly change (56.5 mg/L, CV% 33.2, p = 0.185). One patient (9%) experienced grade 3 diarrhea after splitting intake moments, leading to treatment interruption. This strategy could potentially save up to 2000 USD/patient/month compared to conventional dose increments. Conclusions: This study demonstrates that boosting pazopanib exposure by splitting intake moments leads to a significant increase in Cmin, of 52%, with acceptable tolerability. Therefore, this new dose schedule offers a safe and cost-neutral opportunity to optimize treatment for patients with low PK exposure. Clinical trial information: NL6137.