bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoscopic molecular imaging of early gastric cancer targeting transferrin receptor 1.
Authors: Tian Jie , Du Yang
Published: September 2018

e23093

Background: Gastric cancer is primarily managed endoscopically by white light gastroscope with suboptimal diagnostic accuracy. Emerging optical imaging technologies possess great potential for improving diagnostic accuracy but currently lack imaging agents for molecular specificity. In this study, a novel ligand of transferrin receptor 1 (TfR1), human H-ferritin (HFn), was labeled with fluorescent agents to enable in vivo real-time imaging by confocal laser endomicroscopy (CLE). Methods: In vivo fluorescence imaging was performed in tumor-bearing mice from human gastric cancer cell lines using fluorescently labeled HFn nanoprobe. The HFn-FITC as molecular imaging agent was applied to the gastric cancer with confocal laser endomicroscopy (CLE) in fresh endoscopic submucosal dissection (ESD) of early gastric cancer. Results: Intravital imaging of gastric xenograft tumors revealed a specific tumor targeting effects of HFn-IRDye800CW, whereas no specific signal was observed in mice injected with free dye. An ex vivo experiment on human specimens using a rigid confocal probe showed positive fluorescent staining in ESD samples diagnosed as early gastric cancers. Our CLE evaluation correlated well with immunohistochemical findings. Conclusions: CLE can be used for in vivo, molecular analysis of early gastric cancer and to identify TfR1 expression in xenografts and human tissue samples. HFn-targeted molecular imaging could improve early detection of gastric cancer.
Assessment of EGFR mutations in plasma from advanced NSCLC patients by modified cell-free DNA extraction method and blocker PCR assays.
Authors: Zhang Meiling , Gong Ziying , Li Chun , Hu Jie , Hong Qunying , Hou Yingyong , Zhang Daoyun , Zhang Xin
Published: September 2018

e23115

Background: Epidermal growth factor receptor (EGFR) mutation testing in plasma cell-free DNA (cfDNA) for lung cancer patients is an emerging clinical tool.However,the sensitivity of plasma testing,compared with tissue testing, is not high enough. We aimed to investigate the likelihood of improving the plasma testing sensitivity by increase the cell-free DNA(cfDNA )yields using a modified extraction method and blocker PCR. Methods: Blood samples were collected from 106 patients without EGFR-TKI treatment and 127 patients with acquired EGFR-TKI resistance.CfDNA was extracted from plasma by the modified extraction method and mutations were identified by blocker PCR.The yields of circulating tumor DNA (ctDNA) and cfDNA from 106 patients were quantified by standard curve.Next generation sequencing (NGS)was employed to verify the reliability of blocker PCR. Meanwhile,paired tumor tissues were examined by amplification refractory mutation system (ARMS). Results: The novel extraction method can extract small fragment less than 100bp.The yield of total cfDNA of 106 plasma was mostly between4 000and 200,000 copies per milliliter.With regard to exon 19 deletions(E19-DELs) , the ctDNA proportion of 85% samples (17/20)was from 0.1% to 5% . As for L858R mutations, the fraction of ctDNA of 84.6%(11/13)cases was calculated with the range of 0.01% to 0.1%.For 106 patients,the overall concordance rate,sensitivity and specificity between plasma and tumor tissue was 99.06%[k = 0.97; 95% confidence interval (CI), 0.87-0.99; P < 0.0001],94.87%(95% CI, 83.11%-98.58%) and 100 % (95% CI,94.58%-100%).Among the 127patients,40.16%(51/127)T790M was detected in the plasma, 78.44%(40/51) of which coexists with an EGFR activating mutation. Conclusions: The modified extraction method can improve ctDNA yields and thus improve the sensitivity of liquid biopsy.The blocker PCR offers the possibility of detecting mutations in cfDNA with high concordance with tumor tissues.
Tumor profiling from whole-genome and whole transcriptome sequencing to uncover gene fusions and structural variations in clinically relevant cancer genes.
Authors: Gylfe Alexandra E , Shinbrot Eve , Kakaradov Boyko , Delport Wayne , Lau Corine K , Krishnan Subha , Perlina Ally , Natarajan Thanemozhi G , Sainger Rachana , Pelak Kimberly , Choppa Paul , Cooc Janine , Biggs William , Smith Heather L , Perkins Brad , Jones Daniel G , Nehring Ramlah B , Cohen Ezra E.W. , Bloom Kenneth Joel
Published: September 2018

e23118

Background: Current targeted cancer therapies rely on the identification of clinically relevant somatic alterations in the tumor. Hotspot gene-panels and exome sequencing are designed to quickly assess somatic variations in frequently mutated regions and/or the coding regions of relevant genes, but they have limited ability to detect complex genomic rearrangements or novel structural variations. Here, we describe an integrative and comprehensive approach to fully characterize the genomic complexity of solid tumors using high throughput whole genome sequencing (WGS) and whole transcriptome sequencing (RNA Seq). Methods: We performed WGS and high-depth sequencing of known cancer genes in 14 paired tumor-normal samples of a variety of tumor types. Tumor-specific somatic alteration assessments included protein-coding mutations, copy number variations, gene fusions and structural variants. In addition, RNA Seq data was analyzed to identify expressed somatic alterations. Results: We identified 2 novel fusion genes as well as important structural alterations which could have clinical and therapeutic implications. We described a novel BRAF fusion gene in a cholangiocarcinoma devoid of other known driver mutations. BRAF fusions have not been described previously in cholangiocarcinoma; this fusion may represent an alternative mechanism for MAPK activation and could be a useful drug target. We also identified a novel NTRK3 fusion partner in a glioblastoma tumor. This fusion may imply a novel mechanism for NTRK3 activation. Finally, we identified numerous tandem duplications in an ovarian cancer. Recent advances describe tandem duplication hotspots in ovarian cancer as a potential driver mechanism characterizing a specific mutational signature. Conclusions: Comprehensive genomics assessment of paired tumor-normal samples through whole-genome and transcriptome sequencing can yield additional clinically actionable genomic characteristics that may not be detected in whole-exome or hotspot gene-panel sequencing. These findings have the potential to aid in clinical decision making.
HER2 activity in solid tumors.
Authors: Kujtan Lara Ann , Morris Scott , Subramanian Janakiraman
Published: September 2018

e23121

Background: ERBB2 is a member of the human epidermal growth factor receptor family. HER2 expression that is immunohistochemistry (IHC) 3+ or IHC 2+ with copy number gain is an effective predictor for treatment with trastuzumab in breast and gastroesophageal cancers. Here we present an analysis on HER2 activity measured by IHC, mRNA expression and copy number variation (CNV) across a variety of solid tumors. Methods: The study population consists of patients diagnosed with solid tumors (n = 856) that underwent a Paradigm Diagnostic Cancer Test during 2016. We then analyzed tumor types that tested positive for HER2 by IHC (3+), CNV and/or mRNA expression. Results: We identified 365 (43%) patients positive for HER2 by IHC, 258 (30%) had high HER2mRNA expression and 41 (5%) had amplification by CNV. Seventy-five patients were HER2 IHC 3+ or 2+/CNV positive. The proportion of HER2 IHC 3+ or 2+/CNV positive tumors in each tumor type was as follows: breast cancer 41 (18.5%), NSCLC 10 (8.1%), colorectal 6 (6.7%), esophago-gastric 3 (10%,) urothelial/bladder 3 (16%), biliary 2 (28.6%), ovarian cancer 2 (5.1%) and pancreas 1 (3.1%). Using copy number gain as the gold standard, across all tumor types, an IHC of 3+ had a 90.2% sensitivity and a 95.6% specificity. In the same analysis with breast cancers omitted, the sensitivity was 75%, and specificity 96.8%. Whereas high mRNA expression had a sensitivity of 97.6% and specificity of 73.3%, omitting breast cancers, the sensitivity was 93.8% and specificity 73.2%. Conclusions: HER2 activity was identified in a wide variety of solid tumors and a small but significant proportion of these tumors maybe candidates for treatment with HER2 inhibitors such as trastuzumab. Our analysis also identified that HER2 activity in breast cancers has a distinctive pattern which was not seen in other tumor types. HER2 IHC 3+ expression was much less sensitive among other tumor types compared to breast cancer. mRNA expression, while remaining sensitive among other tumor types, is not specific, even among breast cancer patients. Our analysis also identified that HER2 activity in breast cancers has a distinctive pattern which was not seen in other tumor types.
Radiomics features of ground glass nodules tailored different pathological grades of lung adenocarcinoma.
Authors: Zhang C , Zhai Haoran , He Lan , Liu Zai-Yi , Wu Yi-Long , Zhong Wenzhao
Published: September 2018

e23127

Background: Different pathological subtypes as well as different grades of adenocarcinoma based on the IASLC/ATS/ERS classification had been proven to be stage-independent predictor of survival. Radiomics features, as a novel analytic method, has been increasingly applied in variety cancer research and may be a potential predictor for preoperatively differentiating pathological grades of adenocarcinoma. Methods: Patients (pts) with radiological proved as solitary ground glass nodule were eligible in this study. Radiomics features derived from computed tomography (CT) images were extracted by Chinese Academy of Science. All pts will be categorized into three groups with lepidic predominance as low-grade, acinar and papillary predominance as intermediate-grade, micropapillary and solid predominance as high-grade. We used L1 penalized constrained continuation ratio model to select relevant radiomics features, and corresponding radiomics signature was constructed. Association between the radiomics signature and pathological grades of adenocarcinoma was explored using the Kruskal-Wallis test and C-index was performed to test the efficacy of differentiating. Results: 82 pts were included in this study. Low-grade, intermediate-grade and high-grade contained 15 (18.3%), 53 (64.6%), 14 (17.1%) pts respectively. 475 radiomics features were extracted from thin section CT image and 10 of them selected through L1 penalized constrained continuation ratio model composed radiomics signature which significantly associated with pathological grades (P < 0.0001). C-index for radiomics signature were 0.813 (95%CI 0.793-0.833). Since clinical characters including gender, age, smoking status, NSE, CEA and CYFRA21-1 were not associated with different grades of adenocarcinoma, we could not establish nomogram based on the radiomics signature and correlated clinical characters. Conclusions: Radiomics features only can be a potential predictor for preoperatively differentiating pathological grades of adenocarcinoma, which may be a more applicable clinical predictor for patients’ survival. Yet large sample sizes are warranted to confirm the results.
PAK4 as a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC).
Authors: Thillai Kiruthikah , Sarker Debashis , Wells Claire
Published: September 2018

e23139

Background: PDAC is an aggressive cancer and metastatic spread requires reorganization of the actin cytoskeleton, a process dependent on Rho family GTPases and their interaction with downstream effectors. p21 activated kinases (PAK1-6) are effectors of Rho GTPases Cdc42 and Rac, and play a key role in cell migration and survival. PAK4 can be amplified in PDAC and can reciprocally activate the PI3K pathway. Hepatocyte growth factor (HGF), via c-Met, is an established activator of PAK4 and the PI3K pathway and may promote PDAC invasion. We hypothesized that there is a link between PAK4 and PI3K downstream of HGF and thus PAK4 is a potential therapeutic target in PDAC. Methods: Several invasive PDAC cell lines were used including PaTu 8988T, PaTu 8988S, Capan 1, Panc 1 and PaTu 8902. SiRNA transfection allowed transient loss of PAK4 and cell migration was measured using 2D time lapse microscopy. An organotypic model consisting of PDAC and stromal cells within an extracellular gel of collagen was developed to assess 3D invasion. Immunofluorescence staining of cytokeratin and smooth muscle actin allowed analysis of depth of invasion. Protein expression was measured using western blotting and protein interaction by pulldown assays. Results: Treatment with the c-Met ligand HGF increased migration speed, persistence of direction and importantly PDAC invasion. HGF also stimulated the phosphorylation of several proteins within the PI3K pathway including AKT and PRAS40. Loss of PAK4 expression resulted in a concomitant loss in PI3K signalling. Moreover, PAK4 directly binds to the p85α subunit of PI3K in PDAC cells. Reduced PAK4 expression in PDAC cells suppressed HGF-induced migration, and PAK4 depletion significantly inhibited the invasion response to HGF. Conclusions: We demonstrate a novel link between PAK4, PI3K and AKT, and show the significant effects of PAK4 on PDAC cell polarity, migration and invasion. Our results strongly support further investigation of PAK4 as a therapeutic target in PDAC, particularly given the minimal impact of PI3K-AKT pathway inhibitors in PDAC to date.
Understanding docetaxel and cabazitaxel modes of action in prostate cancer.
Authors: Nelius Thomas , Jarvis Courtney , Filleur Stephanie
Published: September 2018

e23149

Background: Despite the approval of several new agents, taxanes remains the main treatment with survival benefits for castration-refractory metastatic prostate cancer/mCRPC. Still their mechanisms of action and therapeutic efficacy remain incompletely characterized. In the present study, we proposed to compare docetaxel/Doc and cabazitaxel/Cab, delivered as monotherapy or in combination with the anti-angiogenic and anti-tumoral Pigment Epithelium-Derived Factor/PEDF, on CRPC cells in vitro and in vivo. Methods: CRPCcells were assessed for cell growth, cell cycle, and apoptosis under taxane/control treatment by cytotoxicity, PI incorporation and TUNEL assays. CL1 cells that express PEDF/control were used in vivo. Tumor cells were injected s.c. into CB17-SCID mice. After two weeks, mice were randomized into groups: 1) Placebo; 2) Doc 5mg/kg i.p. d4; and 3) Cab 5-1-0.5-0.1mg/kg i.p. d4, d1-7, d2, daily. To assess the anti-tumor effect of the combination, tumor cell migration and phagocytosis were measured by Boyden chamber and confocal microscopy analyses of CL1-RAW264.7 macrophages co-cultures. Results: Cab was more cytotoxic than Doc in all the cell lines tested.This effect was concomitant to increased cell death, but was not due to autophagy or necrosis. Inversely, we showed that apoptosis was superior in Cab-treated cells than in Doc treatment. In vivo, while 0.5 and 0.1 mg/kg Cab did not improve PEDF efficacy on tumor growth, 1mg/kg was very toxic. In contrast, PEDF combined with 5mg/kg Cab lead to stabilization of the disease and was also found to be drastically more efficient than PEDF/Doc in delaying the disease. In vitro, PEDF/Cab inhibited tumor cell migration at a significant superior level compared to PEDF/Doc. Finally, tumor cells phagocytosis was induced in PEDF/Cab suggesting that the combination may target macrophages within the tumor microenvironment. Conclusions: Our data demonstrated the greater anti-tumor efficacy of Cab compared to Doc. They also insist on the fact that PEDF/Cab could be used as a novel combined therapy for CRPC, and emphasize on the importance in evaluating the cytotoxicity of the novel combination tested and investigating the role of the tumor microenvironment in the anti-tumor effect.
NAMPT inhibition is a novel synthetic lethal therapeutic approach exploiting nuclear-mitochondrial crosstalk in ERCC1-deficient populations.
Authors: Touat Mehdi , Sourisseau Tony , Friboulet Luc , Dorvault Nicolas , Chabanon Roman , Morel Daphné , Adam Julien , Sauvaigo Sylvie , Enot David , Bigot Ludovic , Pontoizeau Clément , Bouillaud Frédéric , Olaussen Ken , Pierron Gérard , Sarasin Alain , Lombès Anne , Ashworth Alan , Lord Christopher J. , Soria Jean-Charles , Postel-Vinay Sophie
Published: September 2018

e23159

Background: ERCC1 (Excision Repair Cross-Complementation group 1) deficiency is the most frequent DNA repair defect in non-small cell lung cancers (NSCLC), making this enzyme an attractive therapeutic target for synthetic lethal (SL) approaches. Previous data support that DNA damage response is involved in regulation of metabolic homeostasis. We hypothesized that ERCC1 deficiency resulted in metabolic reprogramming of cancer cells that in turn generated specific vulnerabilities. Methods: High-throughput proteomic SILAC (stable isotope labeling by aminoacids in cell culture) and metabolomic (LC-MS, GC-MS, LC-QTOF) profiling were performed on a in-house generated NSCLC model of ERCC1 deficiency. Nicotinamide phosphoribosyltransferase (NAMPT) was selected as main hit and revalidated in low-throughput. Sensitivity to NAMPT inhibition was assessed in several NSCLC models. Potential SL interactions were investigated using functional DNA repair and metabolic assays, and transmission electronic microscopy (TEM). Results: We found marked metabolic rewiring in ERCC1-deficient populations, including decreased NAMPT and NAD+ levels and defects in the tricarboxylic acid cycle. These caused exquisite selective sensitivity to NAMPT inhibition in several in vitro and in vivoNSCLC models; these effects were reversed by the restoration of a functional ERCC1 isoform, establishing a causal link with the ERCC1 defective state. TEM, functional DNA repair and metabolic studies revealed structural and functional defects in the mitochondria of ERCC1-deficient cells, and allowed us to propose a model for this nuclear-mitochondrial SL link. A correlation between NAMPT expression and ERCC1 expression was observed in NSCLC patient samples. Conclusions: These findings open novel therapeutic opportunities that exploit a previously undescribed nuclear/mitochondrial SL link between ERCC1 deficiency and NAMPT inhibition in NSCLC. This highlights the potential for targeting DNA repair / metabolic crosstalk for cancer therapy, and support the evaluation of NAMPT inhibitors in ERCC1-deficient tumors.
Satellite alpha transcripts as a biomarker to predict the development of breast cancer with bilateral or multiple primary malignancies.
Authors: Kakizawa Nao , Suzuki Koichi , Yoshizawa Ayuha , Ichida Kosuke , Saito Masaaki , Futsuhara Kazushige , Rikiyama Toshiki
Published: September 2018

e23202

Background: The impaired stability of chromosomal structure promotes the abnormal segregation of chromosomes, increasing the risk of carcinogenesis. Chromosomal stability during segregation is managed by appropriate methylation in the centromeric region of chromosomes. Satellite alpha transcripts (SatA) is a non-coding RNA transcribed from the centromere, which could be involved in this machinery. We reported that overexpression of SatA led to chromosomal instability, which was observed in not only cancer regions (CR) but also noncancerous regions (NCR). It was enhanced in NCR of patients with multiple primary malignancies (MPM), suggesting the involvement of SatA in genomic damage in regions where multiple cancers may arise. In this study, we determined whether SatA is involved in breast cancer development with bilateral or MPM. Methods: We constructed lentiviral vectors expressing SatA and control viruses, which were used to infect human mammary epithelial cells. SatA levels were determined by real-time quantitative PCR (qRT-PCR) and copy number alterations were evaluated by array comparative genomic hybridization (CGH). Then, we investigated the levels of SatA in clinical specimens in 135 breast cancer (BC) patients including 128 tumors and 83 matched normal tissues. Results: qRT-PCR showed higher expression levels of SatA in cells infected with SatA virus than in the control. Array CGH analysis indicated frequent copy number alterations at several specific chromosomes in infected cells, despite no alterations in the control. Among the 135 patients, 24 had bilateral breast cancer (BBC) and 18 had MPM. SatA was much higher in CR in BBC and in MPM than in SBC. SatA was also higher in NCR in MPM than without MPM. Considering human epidermal growth factor receptor type2 (HER2), hormone receptor (HR), family history and other factors, the levels of SatA in CR were a significant independent factor predicting the development of BBC patients. Conclusions: Chromosomal instability induced by SatA is involved in the development of BBC and BC with MPM.
In silico validation of a prostate cancer recurrence prognostic signature based on pathways related to stem cells.
Authors: Espinoza-Portocarrero Miguel Arturo , Araujo Jhajaira M. , Pinto Joseph A. , Casado Fanny Lys
Published: September 2018

e23205

Background: Prostate cancer has the highest incidence in Peruvian male population with mortality close to 50% as opposed to countries with strong preventative programs were mortality is between 10-15%. Early detection and close follow up to avoid or detect recurrence as soon as possible is considered to be the best strategy to reduce this high mortality. However, this is not always the case due to limitations in prevention programs and cultural characteristics of male behavior. Therefore, there is a need to develop better biomarkers and targets. We hypothesize that recurrence occur due to the existence of cells that have acquired stem cell behavior that we denominate prostate cancer stem cell, which are not affected by first-line therapies. Methods: We curated a list of stem-cell genes meshing the WNT Signaling Pathway (KEGG entry: hsa04310) and the Signaling Pathways Regulating Pluripotency of Stem Cells (KEGG entry: hsa04550). We used data from 497 samples of primary tumors whose expression for 231 genes was quantified with NanoString from a public genomic information database (TCGA, provisional). The validation set (GSE21032) consisted of 131 primary tumors cases of prostate cancer. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected FZD3, PLCB2, PLCB3 and TP53 as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a four-genes signature using the regression coefficients for each gene. Results: The signature was: -0.363 × FZD3 + 0.432 × PLCB2 + 1.313 × PLCB3 - 0.237 × TP53. The percentile seventy-five score in the discovery set (0.6734) identified two subgroups with different DFRS (P < 0.05). The same score we used in the validation set and was also able to discriminate patients with different DRFS (P = 0.000003). Conclusions: Our in silico validation of a prostate cancer recurrence prognostic signature supports the involvement of stem cell-related pathways in prostate cancer genomics.
Lung cancer genomic alterations in cell free DNA in pleural effusion compared to plasma.
Authors: Zhou Zhenzhen , Chen Rongrong , Chu Yuxing , Hu Xingsheng , Yang Ling , Yi Xin , Zhang Hongbing , Zhang Dongmei , Xia Xuefeng , Liao Zhongxing X.
Published: September 2018

e23206

Background: Circulating tumor DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in lung cancer and has been used to guide tumor treatment and monitor tumor progression. However, patients with lung cancer, even in advanced stage, usually present with small numbers of cancer-related genetic aberrations and low mutation allele frequency (MAF) on average. Malignant pleural effusion is one of common complications for lung cancer patients in advanced stage. Cell free DNA (cfDNA) in pleural effusion may be extensively diluted once entering into the peripheral circulation system. Methods: We implemented targeted capture NGS with a gene panel of 180 lung cancer-relevant genes on 23 paired plasma ctDNA and matched pleural cfDNA samples extracted simultaneously from the same patient with advanced lung cancer (n = 23), including 17 adenocarcinoma. Results: Overall, actionable variations with on label, off-label, or experimental drugs available, were identified in 87% (n = 20) of pleural effusion samples, whereas plasma was 48% (n = 11). Median number of pleural somatic mutations was 4, predominantly located in TP53, EGFR, and ALK; while the median number was 2 in plasma samples. Of that, 39% and 74% of plasma ctDNA and pleural cfDNA samples were observed at an average MAF above 1%, respectively. In addition, 48% and 78% of plasma ctDNA and pleural cfDNA samples were observed with the highest MAF above 1%. The concordance rate for EGFR and ALK alterations with plasma NGS was 83% and 87%, respectively. Conclusions: Our results suggest that pleural effusion-derived cfDNA is more sensitive than plasma for advanced lung cancer patients. With higher MAF and detection rate of actionable variations, pleural effusion-derived cfDNA might guide more precise lung cancer treatment.
Clinical significance of FDG-PET/CT in assessment of recurrence in breast cancer patients before surgery.
Authors: Yoshizawa Ayuha , Futsuhara Kazushige , Suzuki Koichi , Okochi Tomohisa , Rikiyama Toshiki , Kakizawa Nao
Published: September 2018

e23215

Background: FDG-PET/CT is widely used for the detection of primary breast cancer and metastasis, although its clinical significance is somewhat restricted to appropriate higher-risk populations. We attempted to apply maximum uptake values (SUVmax) of FDG-PET/CT to assess the malignant potential of breast cancer before surgery. Methods: We retrospectively reviewed 187 consecutive patients with invasive breast cancer and no distant metastasis recruited from 2009 to 2011 in our hospital who underwent PET/CT before surgery, and determined the representative PET imaging features by SUVmax. Correlation of SUVmax with several clinicopathological factors was evaluated by regression analysis. Relapse-free survival (RFS) and overall survival (OS) were compared among these factors and SUVmax using univariate and multivariate Cox analysis, Kaplan-Meier curves, and log-rank tests. Results: All patients were women of median age 60 years. The median follow-up period was 72 months. A logarithmic transformation was applied to SUVmax, which resulted in exclusion of 32 patients with no FDG uptake on PET/CT. Regression analysis revealed that SUVmax significantly correlated with ER (P = 0.0138), HER2 (P = 0.0153), lymph node metastasis (P < 0.0001), and tumor size (P < 0.0001). Multivariate analysis showed that tumor size was a significant independent factor. As regression analysis showed a strong correlation between SUVmax and tumor size < 5 cm (P < 0.0001), the 11 patients with tumor > 5 cm were excluded. Concerning the malignant potential of tumors, RFS was evaluated by univariate analysis whereby the median log SUVmax (0.6) was the only significantly independent factor to predict recurrence (P = 0.045). Patients with log SUVmax > 0.6 showed poor RFS (11 patients with recurrence) compared with log SUVmax < 0.6 (2 patients with recurrence) (P = 0.0064). OS showed no significant correlation. Conclusions: PET/CT is potentially a valuable modality to predict tumor recurrence in patients with breast cancer whose tumor size is < 5 cm and demonstrates uptake before surgery.
Safety of pregnancy in patients (pts) with history of estrogen receptor positive (ER+) breast cancer (BC): Long-term follow-up analysis from a multicenter study.
Authors: Lambertini Matteo , Kroman Niels , Ameye Lieveke , Cordoba Octavi , Pinto Alvaro , Benedetti Giovanni , Jensen Maj-Britt , Gelber Shari I. , Del Grande Maria , Ignatiadis Michail , De Azambuja Evandro , Paesmans Marianne , Peccatori Fedro , Azim Hatem A.
Published: September 2018

LBA10066

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.
APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC).
Authors: Von Minckwitz Gunter , Procter Marion Jennifer , De Azambuja Evandro , Zardavas Dimitrios , Knott Adam , Viale Giuseppe , Suter Thomas M. , Arahmani Amal , Rouchet Nathalie , Clark Emma , Benyunes Mark , Lang Istvan , Levy Christelle , Yardley Denise A. , Bines Jose , Gelber Richard D. , Piccart-Gebhart Martine J. , Baselga Jose
Published: September 2018

LBA500

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Monday, June 5, 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 Monday edition of ASCO Daily News.
Trastuzumab emtansine (T-DM1) and ribociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 (CDK 4/6), for patients with metastatic HER2-positive breast cancer: Phase 1b clinical trial.
Authors: Spring Laura , Goel Shom , Juric Dejan , Isakoff Steven J. , Haddad Stephanie , Habin Karleen R. , Krop Ian E. , Moy Beverly , Tolaney Sara M. , Bardia Aditya
Published: September 2018

TPS1106

Background: Despite the availability of multiple effective therapies, most patients with metastatic HER2-positive breast cancer will experience disease progression and death. While traditionally the focus has been targeting the HER receptor family itself, combinations involving targets downstream of the HER2 pathway, particularly CDK 4/6, could potentially enhance therapeutic efficacy. In pre-clinical models of acquired resistance to HER2-targeted therapies, inhibition of CDK4/6 has been shown to result in tumor inhibition. Trial Design: This phase Ib, single arm, open-label clinical trialis investigating the combination of Trastuzumab emtansine (T-DM1) and the CDK4/6 inhibitor, ribociclib (LEE011). Eligible patients include patients age ≥ 18 years with HER2-positive metastatic breast cancer. Prior treatment with at least one regimen containing trastuzumab and a taxane is required. Ribociclib is given orally for two weeks of a 21-day cycle (days 8-21), with T-DM1 given at standard dose every 3 weeks on day 1. Trial Objectives: 1. To estimate the MTD and/or RP2D of ribociclib in combination with T-DM1. 2. To assess the safety and tolerability of ribociclib in combination with T-DM1. 3. To explore the clinical activity of T-DM1 and ribociclib in HER2-positive metastatic breast cancer. 4. To assess potential biomarkers of response to ribociclib in combination with T-DM1. Statistical Methods: A standard 3+3 dose escalation design is being used to evaluate various doses of ribociclib in combination with T-DM1 to determine the maximum tolerated dose (MTD) and/or recommended phase-2 dose (RP2D). Once MTD/RP2D is determined there will be a dose-expansion cohort (N = l5) to confirm the safety profile and evaluate preliminary evidence of efficacy, including objective response rate (ORR) by RECIST 1.1 and progression-free survival (PFS). Clinical trial information: NCT02657343.
Individualized screening trial of innovative glioblastoma therapy (INSIGhT).
Authors: Alexander Brian Michael , Trippa Lorenzo , Gaffey Sarah C. , Arrillaga Isabel , Lee Eudocia Quant , Tanguturi Shyam Kumar , Ahluwalia Manmeet Singh , Colman Howard , Galanis Evanthia , De Groot John Frederick , Drappatz Jan , Lassman Andrew B. , Nabors Louis B. , Reardon David A. , Schiff David , Welch Mary Roberta , Ligon Keith L. , Wen Patrick Y.
Published: September 2018

TPS2079

Background: Patient with glioblastoma (GBM) with unmethylated MGMT promoters derive limited benefit from temozolomide (TMZ) and have dismal outcome. Prioritizing the numerous available therapies and biomarkers for late stage testing requires an efficient clinical testing platform. INSIGhT (NCT02977780) is a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters. Methods: INSIGhT compares experimental arms to a common control of standard concurrent TMZ and radiation therapy (RT) followed by adjuvant TMZ. The primary endpoint is overall survival (OS). Patients with newly diagnosed, unmethylated GBM that are IDH R132H mutation negative, and with genomic data available or who consent to whole exome sequencing through the ALLELE companion study for biomarker grouping are eligible. Two experimental arms consist of concurrent RT/TMZ followed by adjuvant neratinib (EGFR, HER2, and HER4 inhibitor) or abemaciclib CDK 4/6 inhibitor), respectively, in place of TMZ. The other experimental arm is CC-115 (TORC1/2 and DNA PK inhibitor), which replaces TMZ in both the concurrent and adjuvant phases. Biomarker groups include: EGFR + patients with EGFR amplification/mutation; PI3K + patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3amplification, PIK3C2B > 1 copy gain, or PTEN dual loss; CDK: + patients with wild-type RB1 and CDK4 amplification, CDK6 amplification, or CDKN2A > 1 copy loss. Given the lack of pretrial biomarker data and the anticipated overlap of the groups, randomization will initially be equal. As the trial progresses, randomization probabilities will be adapted based on the Bayesian estimation of the probability of treatment impact on progression-free survival (PFS). These randomization probabilities can vary among the biomarker groups so predictive biomarkers will be identified and utilized if present. Treatment arms may drop due to low probability of treatment impact on OS, and new arms may be added. Experimental arms are compared only with control and should be thought of as discrete experimental questions, with INSIGhT being open to new investigators with proposed therapeutic hypotheses. Clinical trial information: NCT02977780.
Nivolumab combined with hypofractionated stereotactic irradiation (HFSRT) for patients with recurrent high grade gliomas: A phase I trial (NCT02829931).
Authors: Sahebjam Solmaz , Forsyth Peter A. J. , Arrington John , Tran Nam D. , Jaglal Michael Vishal , Mokhtari Sepideh , Long Wendy , Macaulay Robert J , Wicklund Melissa , Drury-Sibiga Ali , Gatewood Tyra , Robinson Timothy J. , Raval Raju R. , Yu Michael
Published: September 2018

TPS2084

Background: Nivolumab is an IgG4 monoclonal antibody that targets the PD-1 immune checkpoint pathway and prevents binding of PD-1 with PD-L1 and PD-L2. Expression of PD-1 and PD-L1 is found in the microenvironment of high grade gliomas and correlates with worse outcome providing a rationale for investigating nivolumab in this group of patients (pts) with very limited treatment options. Nivolumab monotherapy is well tolerated in recurrent glioblastoma pts. Preclinical studies have demonstrated that radiotherapy synergizes with anti PD-1/PD-L1 blockade and produces tumor regression and long-term survival in orthotopic murine models of glioma. This report describes an ongoing phase I trial of nivolumab in combination with HFSRT in pts with recurrent WHO grade III or IV gliomas. Methods: This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 20 pts (NCT02829931). Pts with bevacizumab naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior radiation therapy is required unless there is a new recurrence outside of the previous radiotherapy treatment field. Eligible patients will be treated with HFSRT to the recurrent tumor (30 Gy delivered in 5 fractions). Nivolumab will be started 5 days after HFSRT. It will be administered intravenously every 2 weeks (at 240 mg flat dose) for 4 months. After 4 months, nivolumab will be administered every 4 weeks at 480 mg flat dose. The primary study objectives are to determine safety and tolerability of nivolumab administered in combination with HFSRT to recurrent high grade gliomas. Secondary endpoints include determination of the preliminary antitumor activity (response rate, 6-months survival and 9-months survival rates), and exploring tissue and imaging biomarkers. Study Progress: At deadline for abstract submission, 5 patients have been treated on this study. Clinical trial information: NCT02829931.
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of BAL101553, a novel tumor checkpoint controller (TCC), administered as 48-hour infusion in adult patients with advanced solid tumors.
Authors: Joerger Markus , Stathis Anastasios , Metaxas Ioannis , Hess Dagmar , Omlin Aurelius Gabriel , Mayer Gisela , Gaggetta Sheila , Anderson Stephanie , Pasqualotto Marco Gioele , Hutter Franziska , Levy Nicole , Stuedeli Silvia , Landau-Salzberg Michèle , McKernan Phil , Lane Heidi A , Larger Patrice , Scheerlinck Rudi , Engelhardt Marc Frederick , Von Moos Roger , Sessa Cristiana
Published: September 2018

TPS2602

Background: BAL101553 (prodrug of BAL27862), is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 has shown potent antitumor activity in diverse preclinical tumor models, including models refractory to standard therapies. In a completed Phase 1 study using 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. JCO 34, 2016 suppl; 2525) dose-limiting vascular effects were observed and appeared Cmax related. The recommended Phase 2 dose for 2-h IV BAL101553 is 30 mg/m2. Vascular toxicity was not observed in an ongoing study with oral BAL101553 (NCT02490800, CDI-CS-002) at daily doses up to 30 mg (QD). Preclinical data suggest that antiproliferative effects of BAL101553/27862 are driven by exposure (AUC); thus vascular toxicity and antitumor activity are mediated by different PK drivers. BAL27862 has a half-life of ~15 h. Based on PK-modeling, extending the infusion from 2 h to 48 h was expected to result in ~4-fold higher AUC at a given Cmaxlevel and thereby improve the therapeutic window. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study (NCT02895360, CDI-CS-003/SAKK67/15) using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of 48-h infusions of BAL101553 in consecutive 28-day cycles at a starting dose of 30 mg/m2 administered on Day 1, 8 and 15 (q28d). The dose escalation scheme foresees up to ~ 50% dose increments depending on observed toxicities. During cycle 2, patients receive 7 days oral (QD) BAL101553 (Day 15–21) instead of the weekly IV infusion to assess absolute oral bioavailability. Patients with histologically-confirmed advanced or recurrent solid tumors are eligible for enrollment. Adverse events are assessed using CTCAEv4; tumor response by RECIST 1.1 (every 2 cycles). PD assessments include optional tumor biopsies and circulating tumor cells. PK profiles are assessed during the first 2 cycles. Two dose cohorts (30 and 45 mg/m2) have completed without DLTs or signs of vascular toxicity. Clinical trial information: NCT02895360.
A phase 1, multicenter, dose-escalation study of PRN1371, an irreversible covalent FGFR1-4 kinase inhibitor, in patients with advanced solid tumors, followed by expansion cohorts in patients with FGFR genetic alterations.
Authors: Piha-Paul Sarina Anne , Hierro Cinta , Boni Valentina , Moreno Victor , Hahn Noah M. , Bitting Rhonda L. , Bauer Todd Michael , Aggarwal Rahul Raj , Gourlay Steven , Smith Patrick , Venetsanakos Eleni , Meric-Bernstam Funda , Brameld Ken , Karr Dane , Tabernero Josep
Published: September 2018

TPS2616

Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 clinical trial explores ascending doses of PRN1371 in adult patients with advanced solid tumors in a "3 + 3" design, where cohorts of three patients are studied at each level until additional patients need to be added to better assess safety, establish the maximum tolerated dose and define the recommended phase 2 dose (RP2D). PRN1371 is dosed once or twice daily in continuous, 28-day cycles until disease progression. Part B studies include two or three expansion cohorts of different tumor types, 10 patients each with FGFR1-4 gene mutations, fusions, or amplification at the RP2D. The on-target effect of serum phosphorus and FGF23 increases are measured as potential pharmacodynamic biomarkers. Elevated serum phosphorus is managed with oral phosphate binding medications and a low phosphate diet, with dose interruptions and use of acetazolamide if certain thresholds are exceeded. Circulating tumor DNA from patients at baseline and during follow up is analyzed for FGFR genetic alterations. Pre and on-treatment tumor biopsies in Part B will be tested for a panel of pharmacodynamic biomarkers of FGFR inhibition. Clinical trial information: NCT02608125.
A phase I/IIa, open label, clinical trial evaluating the safety and efficacy of autologous T cells expressing enhanced TCRs specific for NY-ESO-1 in patients with recurrent or treatment refractory ovarian cancer (NCT01567891).
Authors: Odunsi Kunle , Cristea Mihaela C. , Dorigo Oliver , Jazaeri Amir A. , Slomovitz Brian M. , Chagin Karen , Van Winkle Erin , Kari Gabor , Iyengar Malini , Norry Elliot , Bartlett-Pandite Arundathy N. , Amado Rafael G.
Published: September 2018

TPS3094

Background: Epithelial ovarian cancer comprises the majority of malignant ovarian neoplasms (~80%) and is the leading cause of death from gynecologic cancer in the US. Due to lack of effective screening strategies, the majority (63%) of patients are diagnosed with ovarian cancer at advanced stages. New therapies are needed to address the unmet medical need of patients with ovarian cancer. 11-40% of ovarian cancers express NY-ESO-1 cancer testis/antigen. This study is evaluating affinity enhanced autologous NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 in ovarian cancer. Methods: This single arm, open label clinical trial is evaluating safety and tolerability, antitumor activity (response rate by RECIST v1.1, progression free survival, overall survival, duration of response), and translational research endpoints. The study evaluates two lymphodepleting regimens: cyclophosphamide (enrolment completed; n = 7) and cyclophosphamide plus fludarabine (at least 10 subjects to be enrolled). Subjects must be ≥ 18 years old; HLA-A*02:01, *02:05, or *02:06 positive; have recurrent epithelial ovarian, primary peritoneal or fallopian tube carcinoma with refractory or platinum-resistant disease expressing NY-ESO-1 by IHC; have measurable disease; have ECOG status 0 or 1; and have adequate organ function. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259 TCR, and 1 – 6 × 109 transduced T cells are infused intravenously on Day 0 after lymphodepletion with fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day on days -7 to -5. Response is assessed at weeks 4, 8, 12 and 24, and then every 3 months until confirmation of disease progression. Clinical trial information: NCT01567891.
A phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of the OX40 agonist MEDI0562 in combination with tremelimumab or durvalumab in adult aubjects with advanced solid tumors.
Authors: Curti Brendan D. , Bauer Todd Michael , Steeghs Neeltje , Lockhart A. Craig , Giles Francis J. , Powderly John D. , Rizvi Naiyer A. , Goldman Jonathan Wade , Khleif Samir , Gribbin Matthew Joseph , McDevitt Jennifer T. , Hammond Scott A , Chiou Victoria L , Marabelle Aurelien
Published: September 2018

TPS3100

Background: Recent advances in treatment of solid tumors include single or combined use of monoclonal antibodies (mAbs) against the immune checkpoints CTLA-4 or PD-1/PD-L1 that can reactivate antitumor cytotoxic tumor-infiltrating lymphocytes (TILs) and significantly improve OS (Menon S, et al. Cancers (Basel). 2016;8:E106.) (Antonia S, et al. Lancet Oncol. 2016; 17:299-308). Activation of TILs via the costimulatory OX40 (CD134) molecule, may offer an alternative and non-redundant pathway for increasing antitumor immunity. OX40 costimulation promotes effector T cell expansion and longevity, overcomes regulatory T cell suppression and provides survival benefit in animal models of tumor challenge (Linch SN, et al. Front Oncol. 2015;5:34). MEDI0562 is an investigational, humanized IgG1κ anti-OX40 mAb that triggers OX40 signaling. Coadministration of an OX40 agonist and either a CTLA-4 or PD-1/PD-L1 pathway inhibitor may promote synergistic effects against certain solid tumors and may be tolerable administered in combination. Methods: A Phase 1, multicenter, open-label study (NCT02705482) is underway to evaluate safety (primary endpoint), pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity (secondary endpoints) of MEDI0562 in combination with either anti-PD-L1 mAb durvalumab or anti-CTLA-4 mAb tremelimumab in adult subjects with previously treated advanced solid tumors. Subjects with primary CNS tumors and hematologic malignancies are excluded. The study includes a dose escalation and expansion phase, with 2 treatment arms in each: MEDI0562/durvalumab combination (Arm A) and MEDI0562/tremelimumab combination (Arm B). Safety assessments include AEs, serious AEs, dose-limiting toxicities, abnormal laboratory parameters, vital signs, and electrocardiogram results. Antitumor efficacy will be assessed as OR, disease control, duration of response, PFS, and OS using RECIST Version 1.1. Subjects will remain on treatment until unacceptable toxicity, progressive disease or other reasons for discontinuation. Clinical trial information: NCT02705482.