bluuebunny/crossref_metadata_2025 huggingface dataset:
Retroperitoneal lipo-leiomyomata in a woman with history of breast cancer and antiestrogen therapy.
Authors: Moon Jung Joo , Mais Daniel D
Published: September 2018

e22542

Background: Retroperitoneal lipo-leiomyomata are extremely rare. The usual-type retroperitoneal leiomyoma is itself a rare tumor that is mistaken preoperatively for malignant retroperitoneal tumors or thought of as an exophytic subserosal leiomyoma of the uterus. Lipo-leiomyoma is a variant of leiomyoma with an incidence in uterus ranging between 0.03% - 0.2%, but its presentation as a retroperitoneal mass has not been documented in literature yet. We present a unique case of retroperitoneal lipo-leiomyoma that presented as a diagnostic challenge due to its unique location and unusual histologic appearance. Methods: A 68-year-old female patient with a history of breast cancer diagnosed 4 years ago, currently on antiestrogen therapy (Fulvestrant) and Herceptin, presented to our university hospital with symptomatic left pelvic mass. An abdominal CT showed a heterogeneous low-density pelvic mass with foci of internal calcification and fat with surrounding intermixed intermediate and high density fluid in the expected location of the uterus. Results: A debulking surgery including radical hysterectomy was planned. Intraoperatively, a normal sized uterus was found, the myometrium of which contained multiple variable-sized intramural leiomyomata. In addition, a huge left retroperitoneal mass was found that had no connection to the uterus. Histopathological examination revealed abenign lipoleiomyomatous tumor, composed of an encapsulated proliferation of benign adipocytes and myoid cells intimately admixed. Immunohistochemistry confirmed myoid differentiation, with negative reactions for HMB45 and CKIT, and . MDM2 gene amplification by fluorescence in situ hybridization (FISH) was negative. Conclusions: Some unusually located extra-uterine leiomyomata have been reported; retroperitoneal leiomyoma being among them. Such a tumor with the added feature of lipomatous differentiation presents a differential diagnosis that includes leiomyosarcoma, liposarcoma, angiomyolipoma, and gastrointestinal stromal tumor. The association of an uncommonly located leiomyoma with subsequent lipomatous change withantiestrogen therapy is an unexplored issue that merits further investigation.
Effect of an anti-MARCKS peptide (BIO-11006) on metastasis of lung cancer in vivo.
Authors: Adler Kenneth B , Parikh Indu , Crews Anne , Fang Shijing , Yin Qi , Dickson Brian
Published: September 2018

e23017

Background: We have previously reported that administration of peptides that inhibit the function of MARCKS (myristoylated alanine-rich C Kinase Substrate) inhibit metastasis of human lung cancer cells orthotopically-injected into the left lung of SCID mice (Chen et al: Oncogene 33:3696–3706, 2014; Chen et al: Am J Resp Crit Care Med 190:1127-1138, 2015). Methods: Here, we administered an anti-MARCKS peptide, BIO-11006, as an inhaled aerosol in 2 models of lung cancer in SCID mice: PC-9 cells orthotopically injected into the left lung, and A549 cells injected into the tail vein. In the orthotopic model, initiation of treatment with BIO-11006 at day 4 post injection of cells and treatment every day thereafter for 4 weeks resulted in dramatic attenuation of tumor metastasis into the lung, heart and diaphragm, with similar attenuation whether the peptides were administered IP or via inhaled aerosol. In additional studies with this model, we waited until day 26 post orthotopic cell injection, a time when there was already extensive metastasis to the lung and distal organs, to begin daily treatment with BIO-11006 via inhalation. Results: There was complete inhibition of further metastasis and primary tumor growth when the animals were examined at day 38 post orthotopic injection of cells. Similar results with the tail vein model were observed: when the peptide was administered by aerosol starting at day 3 post tail vein inoculation, metastasis observed 8 weeks later in distal organs was inhibited by ~ 95% by treatment with inhaled BIO-11006. When PC-9 cells were examined via confocal microscopy, BIO-11006 was seen to cause a cytoskeletal rearrangement so that the cells took on a morphology favoring adherence to the substrate rather than movement. Conclusions: The results suggest that inhaled BIO-11006, already completed in phase 2 clinical trials in patients with COPD, appears to have potent antimetastatic effects in two different mouse models of lung cancer. Clinical trials of inhaled BIO-11006 in patients with advanced lung cancer were initiated in January of 2017.
Sensitivity of TargetSelector in clinical experience in ctDNA profiling of NSCLC 2000 cases.
Authors: Singh Veena M. , Daher Anthony J. , Chen Jeffery J. , Arnold Lyle , Vibat Cecile Rose T.
Published: September 2018

e23033

Background: Targeted cancer therapy relies on identifying specific DNA mutations from a patient’s tumor. Tyrosine kinase inhibitors (TKIs) tend to be effective for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations, of which exon 19 deletions (Del19) and L858R are most common. Acquired resistance to TKI therapy is associated with a T790M mutation. Standard biomarker analyses may not reflect tumor heterogeneity; they entail tissue biopsies often with surgical complications. To address these limitations, Biocept developed a minimally invasive method to characterize cancer biomarkers in blood. Biocept's proprietary TargetSelector assays selectively amplify relevant mutations from circulating tumor DNA (ctDNA). Clinical validations demonstrated high concordances between molecular tests in blood vs tissue. As further validation, EGFR mutation detection frequencies were compared to US averages (mycancergenome.org). Here we analyze 2000 blood samples received at Biocept from 1Mar 2016 to 4Jan 2017 from late stage NSCLC patients. Methods: Blood was collected in Biocept OncoCEE BCT validated to preserve DNA ≤ 8 days. TargetSelector was used to detect ctDNA L858R, Del19 and T790M.EGFR allele copy numbers for wild type and each mutant were calculated. The prevalence of each mutation was compared to US averages. Results: Del19, L858R, and T790M mutations were detected in 12.9%, 8.5%, and 9.9% of the analyzed blood samples, respectively. This is concordant with US averages, which are 10% for each mutation. Median copy numbers/ml of blood were 30 for Del19 (range: 1 – 91974), 15 for L858R (range: 1 – 91200), and 10 for T790M (range: 1 – 137360). The median wild type EGFR copy number detected/ml blood was 2304 (range: 8 – 2498725). In ~80% of T790M cases, ≥ 1 concomitant activating mutation was detected. Conclusions: Biocept's TargetSelector detects EGFR mutations (Del19, L585R, and T790M) at a very high level of sensitivity down to 1 mutant copy/ml in advanced NSCLC patients at frequencies consistent with cited US rates. Moreover, the underlying activating mutation was detected in ~80% of T790M cases.
Analysis of lymphocyte-neutrophil relationship in patients with advanced kidney cancer and the response to one-line treatment with target therapies.
Authors: Acosta Luciana Paola , Richardet Martin Eduardo , Molina Matias , Richardet Eduardo
Published: September 2018

e23034

Background: In kidney cancer, some important prognostic factors of survival are known and inflammation plays a key role. It has been proven that cancer progress is not only determined by the characteristics of the tumor but also by the response of the host. It is known that a high RNL has been identified as an independent prognostic factor associated to poor survival in several/different types of cancer, including breast cancer, colon cancer, gastric cancer, mesothelioma and pancreas. The primary aim was to evaluate if RNL can be used as a prognostic indicator of SLP in patients with advanced CCR with 1st line treatment with tirosin-kinasa inhibitors. The secondary aim was to evaluate whether there was a relationship between prognostic factors, smoking habits, BMI, anemia, calcemia, KPS and nephrectomized patients as opposed to those who were not operated with RNL and SLP. Methods: Retrospective and analytical study. The medical histories from patients with metastatic kidney cancer diagnosis were analyzed as well as those who were undergoing treatment with Sunitinib and Pazopanib. The cut value of > ó < 3 was taken as a reference point for RNL. Overall survival analysis will be evaluated through the Kaplan-Meier curve and the meaning will be verified by the log-rank test. The multivariate analysis will be done through the Chi-square test. Results: A total of 65 patients were included in this study. 50 patients (75.38%) received treatment with Sunitinib and 15 patients (24.62%) with Pazopanib. It was observed that RNL < 3 was correlated with a higher SLP 21,6 months vs 8.9 months, p = 0,00002 and it was statistically significant. In subgroup analysis, those patients with normal values of corrected calcium the survival was 20 months vs 12, 2 months (p: 0.01), non-smokers 21 months vs 12 months (p: 0.05), KPS > 1 17,72 months Vs 8,8 months (p: 0.03) and a RNL < 3 showed a higher survival in a statistically significant way. There were no differences in survival when we performed the anemia analysis, BMI, smoking habits and KPS 0 to 1. Conclusions: We can conclude that those patients with RNL < 3 and who had already undergone treatment with ITK revealed a better SLP in a statistically significant way.
Circulating tumor DNA profiling of lung cancer patients treated with EGFR inhibitors.
Authors: Ortiz-Cuaran Sandra , Swalduz Aurelie , Green Emma , Avrillon Virginie , Epstein Michael , Howarth Karen , Marteau Solène , Morris Clive D. , Perol Maurice , Saintigny Pierre
Published: September 2018

e23060

Background: The presence of a targetable driver mutation in nearly 50% non-small cell lung cancer (NSCLC) patients has enabled tailoring therapy regimens to improve survival. Serial repeat biopsies can offer an instrumental indication into the longitudinal evolution of cancer. However, tissue biopsies are invasive and can provide insufficient material for molecular testing. Mutation detection in plasma DNA as a “liquid biopsy” has been suggested as non-invasive approach to monitor tumor dynamics over time. Methods: We established an institutional protocol (NCT01511288) for the collection of liquid biopsies from stage IIIB/IV NSCLC patients either untreated, under therapy or progressive on therapy with a TKI. This protocol has included 134 NSCLC patients for whom clinical, pathological and genomic information is collected prospectively. Analyses were performed by Inivata using InVision (enhanced tagged-amplicon sequencing). Results: So far, samples from 50 patients have been analyzed. InVision allowed the detection of driver mutations in 20 plasma samples obtained at diagnosis. Tissue was unavailable for molecular analysis in 8/20 samples. We observed a concordance rate in mached plasma and tissue samples, of 92,3% (n = 12). In plasma samples from patients that relapsed under erlotinib or gefitinib we evidenced the EGFR T790M mutation in 57% of patients, with a concordance rate of 90,9%. Interestingly, analysis of serial samples collected from 3 patients under EGFR-targeted therapy showed the emergence of an EGFR T790M mutation 11 weeks before the radiographic confirmation of progression (P1); differential dynamics in the allelic fractions of mutated clones that reflected the pattern of dissociated tumor response to treatment (P2) and the presence of concomitant EGFR activating and T790M mutations, together with an EGFR C797G, BRAF V600E and KRAS G12D in a patient who progressed under osimertinib (P3). Conclusions: Our preliminary results provide further evidence on the use of liquid biopsies for monitoring disease response, resistance to treatment and tumor heterogeneity. Subsequently, we will evaluate the utility of liquid biopsies in the clinical setting to understand the dynamics of mutant clones over time.
Serum thioredoxin reductase 1 as a diagnostic marker for non-small cell lung cancer.
Authors: Kang Xiaozheng , Dong Chaoran , Shen Bocun , Yin Hanwei , Xu Guobing , Chen Ke-Neng , Zeng Huihui
Published: September 2018

e23069

Background: Non-invasive diagnostic markers for patients with suspicious non-small cell lung cancer (NSCLC) may provide needed guidance on invasive diagnostic and therapeutic decisions. Thioredoxin reductase 1 (TrxR1) is a pivotal intracellular redox sensor and antioxidant enzyme, and plays an important part in tumor growth, progression, metastasis, and chemotherapy resistance. The goal of this study is to test the feasibility of developing plasma TrxR1 as a novel diagnostic marker for NSCLC. Methods: The plasma TrxR1 activity was determined spectrophotometrically by monitoring the NADPH-dependent production of 2-nitro-5-thiobenzoate at 412nm and at 37℃. All detection kits and automatic analyzer possess independent intellectual property rights, and have been widely used in breast cancer screening. Results: In this study, the plasma levels of TrxR1 were measured in 109 treatment-naïve resectable NSCLC patients and 15 individuals with benign tumor-like pulmonary diseases. Taking plasma TrxR1 activity of 5.0 as reference, the overall concordance rate was 58.1%, while those of CEA, CA199, CA125, NSE, CYFRA21-1 and SCC were 19.2%, 8.2%, 2.1%, 45.9%, 25.3% and 9.5%, respectively. Furthermore, using TNM staging (AJCC 7th ed.) as classifier, the concordance rates of TrxR1 in benign tumor-like pulmonary diseases, local and regional stage NSCLC subgroups were 53.3% (8/15), 57.5% (46/80) and 63.0% (17/27), respectively. A multipoint linear fitting correlation model was created, and the equation was TrxR1 = 5.716 + 0.4898*Stage. Conclusions: Our data suggest that plasma TrxR1 activity is a useful non-invasive diagnostic marker for NSCLC, and there may be a linear correlation between TrxR1 activity and pathological stage.
Association of mesenchymal subtype with the presence of immune infiltrates in squamous cancer classifier.
Authors: Seitz Rob , Hout David Richard , Ring Brian Z , Bailey Dan B
Published: September 2018

e23073

Background: Lehmann and colleagues (Lehmann 2011) devised a classification system for triple negative breast cancer (TNBC) consisting of seven subtypes—IM, BL1, BL2, LAR, M, MSL, and UNS. Recent work has shown the IM group (characterized by the presence of immunomodulatory genes) is due to tumor infiltrating lymphocytes (TILs), and should be measured independently of the other subtypes. Furthermore, the m subtype (characterized by genes associated with epithelial-mesenchymal transition (EMT)) was shown to have a highly inverse relationship with the IM group (Lehmann 2016). We (Ring 2016) modified the original algorithm into a 101-gene algorithm that also confirmed this inverse relationship between IM and m signatures (Grigoriadis SABCS 2016). While this is a novel and interesting finding, we wanted to know whether this inverse relationship applies to other epithelial cell origin cancers such as squamous lung cancer. Methods: We downloaded gene expression data from 548 squamous cell lung cancers from the TCGA database, and applied the 101-gene TNBC algorithm to the lung cohort without optimization or adjustment. Results: Of the 548 samples, 389 (71%) were able to be classified by the 101-gene algorithm. Of these, 82 (21%) had an m phenotype. 128 patients (33%) were positive for the IM signature. The expected overlap of patients positive for both IM and m was 27 patients (7%). The observed overlap was 0 patients (chi-squared = 29; p < 0.001). Conclusions: The unoptimized 101-gene TNBC algorithm validated the observation that gene expression signatures for IM and m are inversely correlated. While any attempt to apply a TNBC algorithm to squamous lung cancer would need careful optimization and validation, these data support that the inverse relationship noted in TNBC may transcend the tissue of origin.
Reduction of immune inhibitory myeloid derived suppressor cells by low dose sunitinib combined with a cancer vaccine to provide therapeutic benefit to tumor-bearing mice.
Authors: Cho Helen Kim , Cockle Paul , Li Cindy Wei , Burgess Steve , Coleman Terrence , Harder Terri , Xu Dan , Chan Kam , Kurzyniec Steve , Guo Joan , Maldonado Oscar , Merson James , Jooss Karin
Published: September 2018

e23084

Background: Sunitinib is a receptor tyrosine kinase inhibitor (RTK) approved as a monotherapy for the treatment of advanced RCC, gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. At the approved doses, it inhibits angiogenesis in tumors and targets RTKs (PDGF receptor, VEGF receptor, KIT, FLT-3, and RET) involved in tumor cell growth. Sunitinib also has been shown in murine studies and patients, to exhibit immunomodulatory properties that reduce a heterogeneous population of cells termed myeloid derived suppressor cells (MDSCs) and restore the immune stimulatory Th1 cytokine profile of T cells. The approved anti-angiogenic sunitinib dosing regimens in RCC have a safety profile that is overall manageable with the most commonly reported sunitinib-related grade 3 adverse events including hypertension, fatigue, diarrhea and hand-foot syndrome. Although the tolerability of sunitinib as monotherapy was acceptable in advanced stage diseases, the drug’s side effect profile could potentially pose challenges for use in combination with other oncology therapies. Thus, if the dose of sunitinib could be lowered to improve the side effect profile without impacting its immune modulatory properties, it could be combined with cancer vaccine regimens, offering a better tolerated and highly potent immunotherapy for patients with cancer of all stages. Methods: To evaluate the relationship of dose of sunitinib on its immunomodulatory properties, the pharmacokinetic profile, the frequency of MDSCs, cytokine profile, vaccine induced immune responses and anti-tumor efficacy were monitored in a subcutaneous tumor bearing BALB-neuT mice in the presence or absence of a cancer vaccine. Results: The data suggested that sunitinib doses below the approved daily dose of 50 mg may maintain the drug’s immune modulatory properties and improve overall survival when given concurrently with a cancer vaccine. Conclusions: The data suggested that low dose sunitinib can be administered as an immunomodulator to reduce MDSCs safely in combination with potent, multi-component cancer vaccine regimens.
Spatial concordance of tumor proliferation and accelerated repopulation from pathologic images to 18F-FLT PET images.
Authors: Meng Xue , Zhang Xiaoli , Sun Xindong , Yu Jinming
Published: September 2018

e23100

Background: PET imaging with 18F-fluorothymidine (18F-FLT) can potentially be used to identify tumor subvolumes for selecting dose escalation in radiation therapy. The aim of this study was to monitor tumor cell proliferation and repopulation during fractionated radiotherapy and investigated the spatial concordance of tumor cell proliferation and repopulation with 18F-FLT tracer uptake. Methods: Mice bearing A549 xenograft tumors were assigned to 5 different irradiated groups (3f/6d, 6f/12d, 9f/18d, 12f/24d and 18f/36d) with 2 Gy/fractions and non-irradiated group. Serial 18F-FLT micro PET scans were performed at different time points, the maximum of standard uptake value (SUVmax) were measured to detect the feasible time of tumor repopulation during irradiation. Ex vivo images of the spatial pattern of intratumor 18F-FLT uptake and Ki-67 labeling index (LI) were obtained from thin tumor tissue sections. A layer-by-layer comparison between SUVmax and Ki-67 LI results, including the thresholds at which maximum overlap occurred between FLT-segmented areas and areas of active cell proliferation, were conducted to evaluate the spatial imaging pathology correlation. Results: The SUVmax were observed decreases in the 3f/6d group (P = 0.000), compared to these for non-irradiated tumors. However, it was significantly increased in the 6f/12d later, and then gradually reduced with treatment time prolonged again after 6f/12d group. Proliferation changes on pathology imaging at 6f/12d were also confirmed. Significant correlations were found between the SUVmax and Ki-67 LI of all ROIs in each in vitro tumor of cell proliferation group (Ps < 0.001). Similar results were also found in each tumor of accelerated repopulation group (Ps < 0.001). Furthermore, both of the mean ORRs were more than 50% in all layer of the tumor cell proliferation and accelerated groups. Regions of high-intensity 18F-FLT uptake in the autoradiographs exhibited prominent staining for Ki-67. Conclusions: 18F-FLT PET may be a promising imaging surrogate of tumor proliferative response to fractionated radiotherapy and might help make adaptive radiation oncology treatment plan.
Comprehensive genomic sequencing for triple negative breast cancer in Japan.
Authors: Nagahashi Masayuki , Hayashida Tetsu , Kitagawa Yuko , Futamura Manabu , Yoshida Kazuhiro , Kuwayama Takashi , Nakamura Seigo , Toshikawa Chie , Yamauchi Hideko , Kaneko Koji , Sato Nobuaki , Tsuchida Junko , Yuza Kizuki , Shimada Yoshifumi , Ichikawa Hiroshi , Ring Jennifer E. , Lyle Stephen , Okuda Shujiro , Takabe Kazuaki , Wakai Toshifumi ,   NGST-Japan
Published: September 2018

e23122

Background: Breast cancer is the leading cancer among women both in US and Japan. Triple negative breast cancer (TNBC) is the subset of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and HER2. While the selective ER modulator tamoxifen or anti-HER2 therapy for breast cancer patients with ER positive or HER2 protein overexpression are the most successful examples of targeted therapies, only limited therapies are available for patients with TNBCs, which are associated with a poor prognosis. Advance in next-generation sequencing enables us to identify actionable driver mutations that can be potentially treated by targeted therapies in each cancer patient. The aim of this study is to examine actionable driver mutations in TNBCs in Japan by comprehensive genomic sequencing (CGS) with 435 gene panel, and compare the driver events in Japan with TCGA database to validate the utility of CGS. Methods: We examined all exons of 435 known cancer genes in Japanese TNBC patients (N = 53) by CGS and evaluated for concordance among independent data obtained from The Cancer Genome Atlas-TNBC whole exome sequencing database (N = 123). Results: Oncogenic driver mutations were identified in 51 of 53 Japanese patients (96%) with TNBC and 36 of 53 patients (67%) harbored mutations in genes associated with FDA-approved targeted therapies, indicating the potential clinical utility of a large gene panel for evaluating patients with TNBC. Among 80 total genetic alterations, frequently mutated genes ( > 10% patients) were TP53, PIK3CA and PTEN. Overall, the mutation spectrum of the Japanese patients is similar to that of the TCGA population, except amplification of MYC. Conclusions: Use of a CGS panel of 435 genes can reliably identify all of the critical mutations in TNBC patients, which are similar as TCGA data. The information derived from CGS can be used to determine the optimal treatment for TNBC patients.
Evaluation of the correlations between patient-derived xenograft (PDX) model-based mouse trials and cancer patient-based clinical trials.
Authors: Gu Zhenyu , Jiang Jingjing , Yan Ying , Tan Tingting , Yu Tengfei , Liu Zhenhua , Du Wei , Yang Xuqin , Qiu Ling , Ye X. Katherine
Published: September 2018

e23140

Background: Clinical trial to evaluate the safety and efficacy of an oncology drug candidate in general is a long and expensive process required for regulatory approval in drug development. High failure rates and difficulties to predict the outcome of clinical trials have wasted the resources and hindered the progress to bring more cancer drugs to patients. PDX models have been widely used recently in preclinical efficacy studies of new cancer agents. Comparing with tumor cell line derived xenografts, PDX models showed more similarities to cancer patients in tumor pathological features, molecular changes and drug responses. More importantly, the large number of available PDX models make it feasible to do preclinical tests in large scales which can represent cancer complexity similar to clinical trials with cancer patients. Methods: At GenenDesign, we have established over 1000 PDX tumor models in various cancer types and derived about 200 acquired drug resistance models. In our in house studies, we have tested near 40 treatments with standard of cares (SoCs) and late stage clinical drug candidates either as mono-therapies or combination therapies, and have generated over 3300 drug response datasets. Many tests with targeted drugs are based on cancer gene aberrations as predictive biomarkers. The drug responses were analyzed by Modifying Response Evaluation Criteria in Solid Tumors (mRECIST) method. Results: By comparing the mRECIST scores in mouse trials with results from about two dozens of historical clinical trials at phase 3 or phase 2, we found that there are high correlations in the rates of objective response (OR), stable disease (SD) and progressive disease (PD) between the mouse trials and their counterpart clinical trials. Progression-free survival also showed similar patterns in these analyses. Conclusions: PDX based mouse trials have advantages in flexibility of study design, quickness in testing new drug candidates and direct comparison of multiple drug treatments in the same models. It can provide valuable information on clinical trial outcome prediction and support clinical study design and patient selection.
Salinomycin reduces the viability of circulating epithelial tumor cells (CETCs) and tumorspheres cultured from circulating cancer stem cells (cCSC) and may potentially prevent progression in patients with solid cancer.
Authors: Pizon Monika , Schott Dorothea , Pachmann Katharina , Pachamnn Ulrich , Szalus Norbert
Published: September 2018

e23143

Background: Recently the hypothesis has been proposed that a more aggressive subpopulation of circulating tumor cells, circulating cancer stem cells are the source of metastatic spread from the primary tumor. These cells are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. The antibiotic Salinomycin has been shown to reduce the expression of markers for stemness and spheroid-forming ability. In this study, we evaluated the cytotoxic effect of salinomycin on CETCs and tumorspheres cultured from cCSC. Methods: 20 patients with solid tumors in different stages of disease were included. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. To evaluate the cytotoxic effect of salinomycin on CETCs and spheroids they were exposed to different concentrations of salinomycin in short time culture for different periods of time. Results: 80% of patients had detectable CETCs but sphere formation was observed in 95% of solid cancer patients. Growth of spheroids was detected also in patients without CETCs. The number of tumorspheres increased significantly with tumor progression. Treatment with salinomycin showed an 80% reduction in spheroid formation compared with control. Salinomycin reduced the viability of spheroids in a dose–dependent manner. Salinomycin had stronger cytotoxic effect on CETCs in non-metastatic as compared to metastatic patients (median of dead CETCs 85% vs. 34%, p < 0.001). Patients without chemotherapy responded better to salinomycin treatment than patients after several lines of chemotherapy (median of dead CETCs 87%vs.35%, p < 0.001) Conclusions: Using a method for cultivation of tumorspheres from blood of cancer patients and an effective in vitro platform for screening anti-cancer stem cells drugs was developed. Thus it could be shown that salinomycin targets not only more differentiated circulating cancer cells but also cancer stem cells from peripheral blood. It may evolve as a novel and promising therapeutic strategy for future cancer treatment
Concordance between comprehensive cancer genome profiling in plasma and matched tumor specimens.
Authors: Menon Roopika , Müller Judith N , Falk Markus , Lakis Sotirios , Mariotti Erika , Leenders Frauke , Bertrand Miriam , Neemann Nicole , Netchaeva Maria , Heukamp Lukas C. , Gloeckner Christian , Tiemann Markus , Heuckmann Johannes , Griesinger Frank
Published: September 2018

e23146

Background: The importance and clinical use of liquid biopsies to identify somatic, targetable alterations in the plasma of cancer patients is steadily increasing. However, their concordance with alterations identified in cancer specimens tested in routine diagnostics is not being monitored. In a cohort of non-squamous cell lung cancer patients, our aim was to systematically compare alterations found by a massively parallel sequencing liquid biopsy assay covering 39 cancer related genes (NEOliquid) with alterations identified by routine diagnostics in a certified central pathology laboratory. Methods: Routine Diagnostics: DNA mutational analysis was performed using cobas or Sanger-Sequencing. Rearrangements were identified using immunohistochemistry or FISH. NEOliquid assay: Cell-free DNA from plasma was subjected to hybrid-capture based next-generation sequencing to detect point mutations, small insertions and deletions, copy number alterations and genomic translocations in 39 clinically relevant genes in a single assay. To evaluate and compare the performance of liquid biopsies, we applied the NEOliquid tests on blood samples of 82 non-squamous NSCLC patients and correlated them with results of routine diagnostics of matched tissue samples. Results: Routine diagnostics for lung cancer related oncogenes (EGFR, ALK, ROS1, KRAS, BRAF) identified a total of 50 somatic alterations of which 37 were point mutations, 11 InDels and 2 gene fusions. NEOliquid analysis of the corresponding plasma sample revealed a total of 34 alterations, including 21 targetable driver alterations. Overall, the concordance of mutation calls between routine diagnostic testing and NEOliquid was 97.6%, with a sensitivity of > 70% and a specificity of 100%. Importantly, NEOliquid identified additional clinically relevant genomic alterations, not covered by routine testing. Conclusions: We have shown high concordance of genomic alterations identified from liquid biopsies and tumor tissue specimens. The excellent specificity of actionable alterations identified by NEOliquid offers analytical performance for routine diagnostic use.
Three dimensional organotypic ex vivo culture of tissues from post-operated tumor samples: Strengths and limitations.
Authors: Dey Nandini , Sun Yuliang , Krie Amy K. , Rojas Luis , Starks David , Lin Xiaoqian , Williams Kirstin Anne , Megan Quast Megan , Carlson Jennifer , Jepperson Shelby Hintze , Lazar Vladimir , De Pradip , Williams Casey B. , Leyland-Jones Brian
Published: September 2018

e23151

Background: Evolution of tumor occurs in two phases, pretreatment phase, and posttreatment phase.Tumorigenic history and path of tumorigenic evolution determine the response of tumor cells to antitumor drug and thus the outcome of treatment. Carcinomas from the same organ-site with similar genomic alterations in different patients may vary in their tumorigenic history and their diverse paths of tumorigenic evolution which cause them respond differently to the same antitumor drugs. Uniqueness of tumorigenic history and paths of tumorigenic evolution in individual patient makes it ideal to test drugs, N-of-1. Here we present our experience with 3D organotypic ex vivo culture of tumor tissue from post-operated tumor samples. Methods: Informed consent was obtained from patients ( NCT02470715). The investigation was approved by IRB of the Avera Cancer Institute and the Western IRB. Surgically resected tissue was obtained from patients with different tumors of different organ sites including ovarian, breast, lung, endometrium, and cervix at the Avera Cancer Institute, SF, SD. Tissues from patients were collected in two formats, paired samples (tumor and tumor-adjacent normal) and unpaired samples. Results: As extracellular matrix lost in cell cultures, provide important signals for cell survival, differentiation and drug resistance we have established a protocol to culture slices in the 3D format. We have established 3D slice cultures (3x3 mm) of tumor-derived tissues which can be maintained ex vivo for at least three days. Tumor cells / normal cells from different tumors/tumor-adjacent normal tissues from day zero (non-cultured) were used to compare day1, day2, and day3 cultures. At the end of the culture period, slices were embedded in paraffin for histological analysis following H&E staining as well as IHC-staining for proliferation index (Ki-67), cellular proliferation signals (pS6RP), apoptosis (activated caspase 3), or tumor angiogenesis (CD31). Ki67 staining was characteristically different in cultured normal and cultured tumor tissues. Conclusions: Here, we show that tumor-derived tissues survive in 3D Matrigel culture for a minimum of 6 hours and maximum up to 3 days. Clinical trial information: NCT02470715.
CT20p as a therapeutic for lung cancer with elevated chaperonin containing TCP1 (CCT) expression levels.
Authors: Vishnubhotla Priya , Carr Ana C , Khaled Amr , Bassiouni Rania , Khaled Annette R.
Published: September 2018

e23163

Background: We previously reported, in breast cancer, the effectiveness of a novel therapeutic peptide called CT20p that displays cancer-selective cytotoxicity. CT20p targets for inhibition a macromolecular complex called Chaperonin-Containing TCP-1 (CCT) that is responsible for folding actin and tubulin and other proteins, like STAT3, into their active forms. CCT is composed of 8 subunits (CCT1-8) that are highly conserved among species. In breast cancer cases, we found that the genes for CCT were frequently amplified (CCT2), upregulating the chaperonin’s activity, which correlated with decreased patient survival. Methods: To determine whether CCT is active in other cancers and thereby a broad therapeutic target, we examined the protein levels of CCT2 in colon, liver, prostate and lung cancer by immunohistochemistry (IHC), using human tissue microarrays (TMAs). Genomic data from The Cancer Genome Atlas (TCGA) was used to support IHC findings. Immunoblot probing of three CCT subunits (CCT2, CCT4, CCT5) was performed to determine their relative expression level in five small cell lung cancer (SCLC) cell lines compared to normal lung cells and these cells tested for susceptibility to killing by CT20p. Results: Results of IHC staining for CCT2 were interpreted on a scale of 1 to 4 (with 4 being the strongest staining). We found that with the exception of colon cancer, all cancers expressed high levels of CCT2 with advancing stage. We identified a significant correlation with cancer progression in both small cell lung carcinoma (SCLC) and squamous cell lung carcinoma (SqCLC). While individual levels of the three probed CCT subunits varied amongst the SCLC cell lines, overall CCT expression was higher in the SCLC cells when compared to normal lung cells and correlated with susceptibility to killing by CT20p. Using the TCGA database, CCT gene alterations were detected in clinical lung cancer cases, with amplification of CCT4 gene in SqCLC cases linked to decreased survival. Conclusions: These results indicate that targeted inhibition of CCT through CT20p treatment is a promising treatment approach for those cancers like SCLC that currently lack effective therapeutics to sustain progression-free survival.
A lung cancer-derived CRAF mutation to activate ERK pathway and to predict sensitivity to LY3009120 and trametinib.
Authors: Noeparast Amir , De Greve Jacques , De Brakeleer Sylvia , Bahadur Shahi Rajendra , Teugels Erik
Published: September 2018

e23197

Background: During the Belgian FIELT II clinical study, two non-small cell lung cancers among 41 were found to harbor a CRAF mutation. One of these mutations (P207S) was previously found in fibrosarcoma and characterized as not activating the ERK pathway at higher levels compared to the wild-type CRAF. The other mutation (P261A) has never been reported in cancer but found in Noonan syndrome. CRAF mutations can be oncogenic thereby activation of the ERK pathway. Serine 259 is a negative regulatory site and its phosphorylation is essential for keeping the CRAF auto-inhibited. P261A CRAF prevents phosphorylation of S259 but its role in cancer and its possible response to small molecule inhibitors has yet to be uncovered. Methods: We generated recombinant CRAF expression vectors by site-directed mutagenesis and investigated the ERK pathway activation status induced by CRAF mutants, in HEK293T cells and BEAS-2B (lung epithelial) cells. We tested the effect of candidate inhibitors at a clinically relevant dose on ERK pathway activity in BEAS-2B cells expressing CRAF mutants. Results: Expression of P261A CRAF in both HEK293T and BEAS-2B cells leads to increased ERK pathway activation compared to wtCRAF, accompanied by decreased phosphorylation of S259. P207S CRAF induces ERK pathway activity at levels comparable to wtCRAF and we observed that co-expression of BRAF with P207S CRAF does not lead to increased ERK activity compared to wtCRAF/BRAF. RAF-inhibitors LY3009120 and AZD-628 suppress ERK pathway activity induced by P261A CRAF in BEAS-2B cells. LY3009120 showed stronger ERK-inhibitory effect compared to AZD-628. In contrast, Dabrafenib (RAF-inhibitor) treatment of mutant or wtCRAF expressing cells leads to paradoxical ERK activation. Combinatorial treatment of LY3009120 with Trametinib (MEK-inhibitor) leads to stronger ERK-inhibitory effects compared to either single agent treatment in cells expressing mutant CRAF. Conclusions: The P261A CRAF mutation is ERK pathway activating and predicts sensitivity to LY3009120 and Trametinib. CRAF inhibition should be clinically explored in lung cancers and perhaps other cancers with sensitizing CRAF mutations.
Exploring a possible relationship of germline CDKN2A mutations with breast cancer in a multigene panel cohort.
Authors: Horcasitas Darling J , LaDuca Holly , Yussuf Amal , Chisholm Ginger , Chavez Jonah R , Campbell Fontaine Annette , Panos Smith Laura
Published: September 2018

e23218

Background: Germline mutations in CDKN2A have been known to increase the risk of melanoma and pancreatic cancer compared to the general population. With the advent of multi-gene panels, individuals who may not have melanoma or pancreatic cancer are undergoing CDKN2A analysis. Previous studies in homogenous populations have suggested that breast cancer risks may also be increased in CDKN2A. This study aims to further evaluate a possible relationship of CDKN2A mutations with breast cancer through a series of case-control comparisons. Methods: Clinical histories and molecular results were retrospectively reviewed for patients undergoing CDKN2A analysis as part of two diagnostic pan-cancer panels at a single laboratory to ascertain CDKN2A mutation carriers (n = 104) and patients negative for all genes analyzed (n = 20,280). Patients with a personal and/or family history (1st and 2nd degree relatives) of pancreatic cancer and/or melanoma were excluded from case-control analysis. Results: The majority of CDKN2A mutation carriers (82.6%, n = 86/104) had a personal history of cancer documented on the test requisition form. The most common cancers were breast (n = 38, 52.8%), melanoma (n = 37, 43.0%) and pancreatic (n = 6, 7.1%). The average age of breast cancer diagnosis in this cohort was 49.3 years (range 25-84). Family history of breast, melanoma, and/or pancreatic cancer was reported for 54.9%, 46.1%, and 34.3% of CDKN2A mutation carriers, respectively. Females with breast cancer were not more likely to test positive for a CDKN2A mutation than females with cancer other than breast (OR = 0.84, p = 0.79) or unaffected females (OR = 1.02, p = 1). Conclusions: Although CDKN2A mutations were not significantly associated with breast cancer in this cohort, these findings do not necessarily rule out an association of CDKN2A mutations with breast cancer, particularly if risks are moderate or if genotype-phenotype correlations exist. Additional studies involving breast cancer cases unselected for age and family history and/or longitudinal studies of CDKN2A carriers are needed to better understand the relationship between CDKN2A and breast cancer risk.
Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.
Authors: Shi Qian , Sobrero Alberto F. , Shields Anthony Frank , Yoshino Takayuki , Paul James , Taieb Julien , Sougklakos Ioannis , Kerr Rachel , Labianca Roberto , Meyerhardt Jeffrey A. , Bonnetain Franck , Watanabe Toshiaki , Boukovinas Ioannis , Renfro Lindsay A. , Grothey Axel , Niedzwiecki Donna , Torri Valter , Andre Thierry , Sargent Daniel J. , Iveson Timothy
Published: September 2018

LBA1

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Routine molecular screening of advanced refractory cancer patients: An analysis of the first 2490 patients of the ProfilER Study.
Authors: Tredan Olivier , Corset Veronique , Wang Qing , Varnier Romain , Pacaud Camille , Torroja Alexia , Luppi Nicolas , Ezzalfani Monia , Myard Magali , Jiang Xiaojun , Attignon Valéry , Pissaloux Daniel , Baudet Christian , Cassier Philippe Alexandre , Fayette Jérôme , Carbonnaux Mélodie , Bonneville-Levard Alice , Viari Alain , Pérol David , Blay Jean-Yves ,   LYric Profiler Author's Group
Published: September 2018

LBA100

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Web-based stress management for newly diagnosed cancer patients (STREAM): A randomized, wait-list controlled intervention study.
Authors: Hess Viviane , Grossert (equal contributor) Astrid , Alder Judith , Scherer Sandra , Handschin Barbara , Borislavova Borislava , Degen Sven , Faessler Alexandra , Hartung Jennifer , Schibli Sarah , Werndli Celine , Gaab Jens , Berger Thomas , Zumbrunn Thomas , Urech Corinne
Published: September 2018

LBA10002

The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.
Authors: Hyman David Michael , Laetsch Theodore Willis , Kummar Shivaani , DuBois Steven G. , Farago Anna F. , Pappo Alberto S. , Demetri George D. , El-Deiry Wafik S. , Lassen Ulrik Niels , Dowlati Afshin , Brose Marcia S. , Boni Valentina , Turpin Brian , Nagasubramanian Ramamoorthy , Cruickshank Scott , Cox Michael Craig , Ku Nora C. , Hawkins Douglas S. , Hong David S. , Drilon Alexander E.
Published: September 2018

LBA2501

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the
Annual Meeting Proceedings
online supplement to the June 20, 2017, issue of the
Journal of Clinical Oncology
. Onsite at the Meeting, this abstract will be printed in the Saturday edition of
ASCO Daily News
.
OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm).
Authors: Robson Mark E. , Im Seock-Ah , Senkus Elżbieta , Xu Binghe , Domchek Susan M. , Masuda Norikazu , Delaloge Suzette , Li Wei , Tung Nadine M. , Armstrong Anne , Wu Wenting , Goessl Carsten Dietrich , Runswick Sarah , Conte Pier Franco
Published: September 2018

LBA4

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
A randomized phase II/III study comparing stereotactic body radiotherapy (SBRT) versus conventional palliative radiotherapy (CRT) for patients with spinal metastases (NCT02512965).
Authors: Sahgal Arjun , Myrehaug Sten , Dennis Kristopher , Liu Mitchell , Chow Edward , Wong Rebecca , Butler James B. , Greenspoon Jeffrey Noah , Fehlings Michael G , Maralani Pejman , Masucci Laura , Lee Young , Brundage Michael Donald , Liu Stanley K. , Ding Keyue , Hum Maaike , Parulekar Wendy R.
Published: September 2018

TPS10129

Background: Innovative radiotherapy technology and modern imaging capabilities enable the use of Stereotactic Body Radiotherapy (SBRT) to treat patients with spinal metastases to optimize tumour control and palliation compared to standard conventional radiotherapy. No randomized clinical trial evidence exists directly comparing the two treatment strategies. Methods: SC.24 is a Canadian Cancer Trials Group randomized phase II/III study comparing standard conventional radiotherapy (20 Gy/5fr) to SBRT (24 Gy/2fr) in patients with solid tumours and MRI documented, painful spinal metastases suitable for RT. The primary accrual objective for the phase II portion of the study was met in January 2017 and the study continues as a randomized phase III study with a primary outcome measure of complete pain response at 3 months post radiotherapy. Secondary objectives include: measurement of complete pain response at 6 months; radiation site progression free survival at 3 and 6 months; adverse event profile, health related QOL and compliance with RT QA measures. Biobanking for future correlative studies is included in study design. Statistical design: The statistical assumptions for the phase III study include estimated complete pain response rates of 10% and 30% for the CRT and SBRT treatment arms respectively. Using a two sided alpha = 0.05 and power = 80% the sample size for the phase III study is 152, taking into account a 5% drop out rate. Conduct to Date: Study activation: July 2015. Accrual to date: 58. Supported by CCSRI grant 021039 Clinical trial information: NCT02512965.