bluuebunny/crossref_metadata_2025 huggingface dataset:
Post resection circulating residual disease monitoring in early stage lung and colorectal cancer patients using a circulating cell-free DNA assay with ultra-high accuracy and specificity.
Authors: Maslan Annie , Jaimovich Ariel , Rajagopalan Narsi , Tan Michelle , Mortimer Stefanie , Chudova Darya , Kennedy Drew , Kim Hee Cheol , Kim Seung Tae , Lee Se-Hoon , Lee Jeeyun , Eltoukhy Helmy , Kim Jhingook , Talasaz AmirAli
Published: September 2018

e23068

Background: Analysis of cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is a promising method for detecting and monitoring earlier stage cancers. Liquid biopsies have a large potential to detect cancer earlier upon initial recurrence and to aid in adjuvant decision making through a non-invasive and highly accurate mechanism. Methods: We developed a 30kb ctDNA capture panel based on the landscape of genomic alterations in ctDNA of over 10,000 advanced cancer patients with high theoretical clinical sensitivity for colorectal (96%) and lung (87-93%) cancers. The panel was validated with high analytical PPV (86% at MAFs < 0.025%, 96% at MAFs > 0.025%). We applied the panel to a clinical study of 63 healthy donors and also 40 early stage (II/III) CRC and lung cancer patients with both pre- and post-tumor resection blood draws. Tumor samples were also collected at the time of the surgical resection. Results: Overall, the detection rate of ctDNA in pre-op blood draws was 72% (13/18) in CRC and 67% (12/18) in lung cancer patients. In the post-op blood draws ctDNA was detectable in 11% (2/18) of CRC and 11% (2/18) of lung cancer cases. For lung cancer patients, the median MAF in pre-op was 0.06% (0.01%-8.47%, n = 51) and in post-op was 0.06% (0.02%-4.14%, n = 38). For CRC patients, the median MAF in pre-op was 0.18% (0.01%-9.26%, n = 51) and in post-op was 0.36% (0.04%-9.5%, n = 18). Sixty-three healthy donor plasma samples were screened at similar cfDNA input amounts and nine (14%) had mutations; the majority of the mutations were also detected in matched leukocyte DNA. To assess a clinically relevant biological false positive background rate in lung cancer patients, screening of cancer-free smokers is ongoing. Conclusions: We have developed a highly sensitive and specific universal assay for the detection of ctDNA in early stage CRC and lung cancer patients without the requirement of a priori knowledge of tumor mutations. This technology allows for a promising non-invasive route for molecular monitoring of residual disease post-surgery and for early detection of relapse compared to traditional methodologies.
Pembrolizumab in gastrointestinal (GI) malignancies with defective DNA mismatch repair (dMMR): A single institution experience.
Authors: Cavalieri Courtney Christine
Published: September 2018

e23081

Background: Defective DNA mismatch repair is associated with increased mutation load and expression of neoantigens. Increased activity of PD-1 inhibitor is reported in patients with GI cancers with dMMR. Here, we describe our experience at Huntsman Cancer Institute with PD-1 inhibition in subjects with GI malignancies with dMMR. Methods: Retrospective chart review of patients with metastatic GI malignancies with dMMR, treated with pembrolizumab at Huntsman Cancer Institute between July 15, 2015 and February 6, 2017. Results: A total of 9 patients were identified that received at least 1 dose of pembrolizumab [colorectal (CRC) n = 4; extrahepatic cholangiocarcinoma (EHCC) n = 2; pancreatic adenocarcinoma (PDAC) n = 2; adenocarcinoma of the appendix n = 1]. Five patients received concurrent cytoxic chemotherapy at some point in treatment. Median number of doses given: 6.5 (3-18). Median age: 61 years (33-73 years). Eight patients were evaluable for response per RECIST. Two patients had complete responses (EHCC and CRC). Two patients had a partial response: PDAC (-57%, time to progression [TTP] +11 months) and CRC (-38%, TTP +6 months). Three patients had stable disease: PDAC (-28%, TTP +5 months), CRC (-6%), and adenocarcinoma of the appendix. One patient with CRC died from upper GI bleeding. Two patients experienced toxicities requiring discontinuation of pembrolizumab. The first patient experienced grade 3 hyperthyroidism and adrenal insufficiency. The second patient had an incidental finding of pneumonitis and enlarged mediastinal lymph nodes on restaging CT scan, biopsy showed non-necrotizing granulomas consistent with sarcoidosis. One patient had grade 2 pneumonitis that was treated and resolved on steroids. This patient continues on pembrolizumab. Conclusions: Single-institution data seem to confirm activity of PD-1 inhibitor in GI malignancies that harbor dMMR. At time of abstract submission, six patients remain on single agent pembrolizumab. Complete responses were seen in CRC and EHCC. Two patients (PDAC and CRC) attained a partial response. Updated responses for all patients will be presented during the meeting.
Research on the diversity of T cell receptor repertoire in the process of malignant transformation of HBV chronic infection.
Authors: Zhang Henghui , Chen Yanhui , Li Guoli , Zeng Hui , Chen Hongsong
Published: September 2018

e23086

Background: The progression of liver inflammation resulted from HBV infection is the main cause of HBV-related liver cancer. T cells play a central role in anti-HBV and anti-tumor specific immune response during disease progression, and the T cell receptor (TCR) repertoire can quantitatively reflect the immune function of T cells. The accurate information of TCR repertoire change in the progression from chronic hepatitis B to tumor was obtained in this study. Methods: CD4+ T cells from the spleens of mice and CD8+ T cells from 50ml peripheral blood of the patients with chronic hepatitis B and liver cancer were sorted by flow cytometry for establishing next generation sequencing (NGS) and the related bioinformatics research system of TCR repertoire. The sequence in V region of TCR was amplified bu using 5 'RACE technology with the mRNA as template. The sequences of TCRα and TCRβ were determined by the NGS technology, and the sequence data with 6Gb were obtained for each chain of each individual. Results: Acoording to analysis of TCR repertoire in mouse CD4+ T cells, the V-J pairing and diversity of CDR3 sequence in TCRβ were higher than TCRα; With the increasing of the recombination number in D gene fragments in the TCRβ chain, a higher diversity of V-J pairing could be introduced in TCRβ.Acoording to analysis of TCR repertoire in human CD8+ T cells, the effects of chronic hepatitis and HCC condition on the overall diversity of TCR receptor repertoire were not significant; The level of receptor repertoire in patients with chronic hepatitis and HCC showed major difference only at the level of low frequency ratio compared with healthy volunteers; the distinctive V-J paring and CDR3 could be detected in the group of patients with chronic hepatitis and HCC based on the above TCR clone at the level of low frequency. Conclusions: NGS sequencing and the related bioinformatics research system of mouse and human TCR repertoire were established. The level of receptor repertoire in patients with chronic hepatitis and HCC showed major difference only at the level of low frequency ratio compared with healthy volunteers.
Regulation of PD-L1 in breast cancer.
Authors: Zerdes Ioannis , Tsesmetzis Nikolaos , Lovrot John , Rolny Charlotte , Bergh Jonas C. S. , Rassidakis Georgios , Foukakis Theodoros
Published: September 2018

e23088

Background: Programmed death ligand 1 (PD-L1, CD274) is currently being investigated as a therapeutic target in breast cancer (BC), however its transcriptional regulation has not been elucidated. Methods: Three BC cells lines, one negative (MCF7) and two positive (MDA-MB-231, BT549) for PD-L1 were used. Protein expression of potential regulators of PD-L1, including Myc, STAT3, p-rpS6 (mTOR effector), Erk and p53 was assessed by western blotting and immunohistochemistry. Furthermore, transfections with small interfering RNAs (siRNAs) of selected proteins or plasmids and pharmacologic inhibition were performed. Fluorescent in situ hybridization (FISH) analysis was used for PD-L1 gene amplification studies. Publically available gene expression data derived from The Cancer Genome Atlas (TCGA) database (cBioportal) were analyzed for correlations between mRNA levels of PD-L1 and potential regulators. Results: PD-L1 gene amplification was not detected in BC cells expressing PD-L1, suggesting non-genetic regulation of PD-L1 expression. Additionally, the correlation between CD274 transcript levels and copy-number alterations (CNA) in primary BC was weak. Pharmacological treatment with either Myc (expressed in MDA-MB-231) or mTOR (p-rpS6 expressed in all three cell lines) inhibitors did not affect PD-L1 expression. STAT3 protein was expressed in all cell lines and STAT3 mRNA levels had a weak positive correlation with PD-L1 (Spearman’s rho = 0.25) in the TCGA dataset. Both gene silencing using STAT3 siRNA and pharmacologic inhibition of STAT3 activity resulted in decreased PD-L1 protein levels in BT549 and MDA-MB-231 cells respectively. Multiple DNA binding sites for STAT3 were identified in silico on the PD-L1 gene promoter suggesting that the observed regulatory effects are likely transcriptional. Conclusions: STAT3 can act as an inducer of PD-L1 expression, while Myc and mTOR seem to have no effect in PD-L1 regulation in BC.
Comprehensive analysis of germline and somatic BRCA1/2 mutations in ovarian cancer population: Interim results of OVATAR prospective study.
Authors: Tyulyandina Alexandra , Kekeeva Tatiana , Karaseva Vera , Gorbunova Vera , Kolomiets Larisa , Filipenko Maxim , Demidova Irina , Lyubchenko Liudmila , Imianitov Evgenii , Cherdyntseva Nadezhda , Moliaka Yuri , Vodolazhky Dmitriy , Andreev Sergei , Statsenko Galina , Saevets Valeria , Khokhlova Svetlana , Tkachenko Svetlana , Koroleva Irina , Lisyanskaya Alla , Tjulandin Sergei
Published: September 2018

e23109

Background: The most promising method for the detection of BRCA 1/2 mutations is next-generation sequencing (NGS). There is no enough data about prevalence of large deletions of BRCA mutations and somatic alterations in ovarian cancer (OC). NGS technology is important approach for somatic mutations search in tissue samples. Methods: 498 pts with serous and endometrioid OC were enrolled in OVATAR study (NCT02122588). NGS testing of BRCA1/2 in blood and tumor tissue, multiplex ligation-dependent probe amplification (MLPA) for large deletions in blood were employed. Results: Interim analysis included pair tumor and blood samples from 336 pts (median age 54 (22 - 84) years; family history in 79 (23.5%). The total rate of BRCA1/2 mutations was 29.2% (98/336) pts including 80.6% (79/98) germline mutations and 19.4% (19/98) somatic mutations. Hotspot mutations were detected in 42/98 (42.8%) pts, among them 5382insC mutation was observed in 29.6% (29/98). Blood MLPA was performed in 142 (42.2%) pts; germline large deletions were found in 2 (1.4%) cases. Differences in NGS results for tumor and blood are listed in the table. Conclusions: Application of NGS revealed rare mutations in 57.2% among all detected mutations in OC pts; moreover, NGS in tumor tissue provided a significant increase in BRCA mutations of 19% due to somatic alterations. Large deletions in BRCA1/2 are rare event in OC in our study. [Table: see text]
Enhancing targeted therapy of tumors with activating FGFR alterations.
Authors: Bockorny Bruno , Rusan Maria , Piccioni Federica , Tan Li , Bass Adam Joel , Hammerman Peter S.
Published: September 2018

e23134

Background: Emerging evidence points to the Fibroblast Growth Factor Receptor (FGFR) kinase family as a promising target in multiple cancer types including lung squamous cell carcinoma, cholangiocarcinoma, gastric, bladder and breast cancer. Although several FGFR kinase inhibitors have entered clinical trials, single agent clinical efficacy has been modest and resistance invariably occurs. A comprehensive understanding of the molecular basis of resistance to FGFR inhibitors is urgently needed to enable the successful application of anti-FGFR therapy in the clinic. Methods: We utilized a systematic genome-wide open reading frame (ORF) screen to identify genes whose upregulation confers resistance to the FGFR inhibitors BGJ398 and FIIN-3 in FGFR1-amplified H2077 lung cancer cells. In an orthogonal approach, we established resistant clones of FGFR1-amplified and FGFR3-translocated cell lines by chronic exposure to BGJ398, and characterized these by high-throughput gene expression analysis. Results: We identified 34 candidate genes, including expected findings such as a mutant KRAS allele and MET overexpression. Intriguingly, we also identified novel candidate resistance mechanisms involving the genes of the TAM family, which encode the transmembrane receptors Tyro3, Axl and Mertk. These tyrosine kinases may serve as a secondary target to augment FGFR therapy. We validated that the TAM family confers resistance to FGFR inhibitors in different FGFR dependencies including FGFR1-amplified lung cancer, FGFR2-amplified gastric and colon cancer and FGFR 3-translocated bladder cancer, with AXL having the greatest rescue. Notably, gene profiling of resistant clones also implicates the TAM family, with both receptors and their ligands upregulated in the majority cases. Moreover, concurrent TAM blockade augments the response to FGFR inhibition in vitro and provides a promising therapeutic strategy to overcome resistance. Conclusions: TAM kinases are important mediators of resistance to FGFR inhibitors and the dual blockade of FGFR and TAM provides a novel approach to enhance the efficacy of anti-FGFR therapy.
Comprehensive analysis of tumor NGS data to demonstrate pathways pointing to therapeutic targeting options.
Authors: Krishnan Subha , Perlina Ally , Thomas Alex , Kakaradov Boyko , Delport Wayne , Nehring Ramlah B , Shinbrot Eve , Natarajan Thanemozhi G , Lau Corine K , Gylfe Alexandra E , Sainger Rachana , Pelak Kimberly , Smith Heather L , Biggs William , Perkins Brad , Cohen Ezra E.W. , Bloom Kenneth Joel
Published: September 2018

e23153

Background: Recent advancements in NGS technology have enabled precision medicine based on tumor-specific genomic alterations. However, the complex nature of tumor biology demands an integrative analysis of genomic variations to identify converging downstream targets potentially regulated by multiple pathways. Methods: Genomic alterations from whole-genome sequencing results were interpreted in the context of pathways. Beyond listing the implicated known pathways based on genomic alterations, we explored protein interactions cross-linking the pathways to converging downstream targets. An in-house analytical pipeline was used to prioritize candidate pathways from MetaBase™, which contains manually curated pathways and interactions based on published experimental results. Custom pathway diagram was then designed manually to depict the most actionable pathways. The manual review consists of context-checking and addressing the concordant/discordant nature of all interactions. Factor such as mutational impact, directionality, mechanism of interaction and known targeted action are taken into account. Results: Comprehensive analysis of the genomic variations in three tumors types revealed activation of multiple oncogenic signaling pathways. Key events driving the tumor in a melanoma sample were NF1/RAS/MEK/ERK, WNT/beta-catenin pathway, and MITF signaling. Three interconnected signaling pathways, WNT, PI3K/AKT, and P53 were impacted by genomic alterations in a colorectal sample, which point to activation of converging downstream targets- CDK6, VEGFA, and COX-2. Integrated discovery of genomic alterations in an esophageal adenocarcinoma sample suggested potential activation of PI3K/AKT/MTOR and p16/Cyclin D1/CDK pathways. This could synergistically activate downstream converging targets- VEGFA, Cyclin D1, CDK6, CDK4, AURKA; some of which also showed relative RNA overexpression, supporting our pathway findings. Conclusions: Comprehensively analyzing the genomic alterations in context of cell signaling pathways provides us insights on how the pathways synergistically affect downstream targetable events, which in turn can impact therapeutic decisions.
Association of activated B-cell infiltration in the tumor microenvironment with regulatory T-cell (Treg) infiltration, but not macrophages polarization in immunogenic human cancers.
Authors: Chae Young Kwang , Bae William Han , Kim Young Suk , Anker Jonathan Forrest , Matsangou Maria , Giles Francis J.
Published: September 2018

e23174

Background: We reported an inverse association between tumor-infiltrating B and CD8 T cells in human cancers. Preclinical studies suggested that B cells regulate T cell activities via activation of Treg cells and alternative polarization of macrophages. In this study, we investigated the relationship between B cell infiltration, Treg cell infiltration, and macrophage polarization in five human cancers approved for the use of immune checkpoint inhibitors by the FDA. Methods: mRNA expression scores of 812 immune-related genes from the TCGA database were analyzed to calculate tumor infiltrating cells in 2951 patients with bladder urothelial carcinoma, renal cell carcinoma, skin melanoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (Angelova et al., 2015). Expression patterns of Treg markers and M1/M2 phenotypic macrophage polarization markers were compared in relation to the presence of activated B cells (ActB) in human tumor tissues. Odds ratios (OR) of the numbers of tumors with versus without Treg cell infiltration by the presence of ActB cells were calculated. Results: Infiltration by ActB cells was significantly correlated with Treg cell infiltration in human cancers (OR=10.86, p<0.001). In lung adenocarcinoma, ActB cells also demonstrated a significant association with myeloid derived suppressor cells (MDSCs, p<0.05). Tumors infiltrated by ActB cells had significantly elevated expressions of Treg markers and suppressive cytokines (Table), but not macrophage polarization markers. No significant changes in survival outcomes were noted. Conclusions: We report for the first time an association between B cells and Treg cells in human immunogenic cancer tissues. ActB cell infiltration in the tumor microenvironment was positively correlated to Treg cell infiltration, but not macrophages polarization in immunogenic human cancers. [Table: see text]
The correlation between immune status of patients and their prognosis in non-small cell lung cancer.
Authors: Ding Xiao , Cui Jiuwei , Yan Xu , Niu Chao , Tian Huimin
Published: September 2018

e23192

Background: In order to investigate the association of immune status with the prognosis in patients with lung cancer and to screen the potential prognostic markers, the immune status including the expression levels of tumor surface molecules, tumor infiltrating lymphocytes (TIL) and cytokines, sMICA and sMICB in serum were detected in this study. Methods: Tissue and serum samples of 125 patients with NSCLC were obtained from the First Hospital of Jilin Universtiy. 50 serum samples of healthy volunteers were obtained as controls. Surface molecules of cancer cell, such as MHC-I, PD-L1, MICA/B and CD8+ TIL were detected with immunohistochemistry. Cytokines such as IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α levels in serum were detected with Luminex. sMICA and sMICB levels were examined by ELISA. The association between their expression levels and patients’ prognosis was analyzed by SPSS 17.0 software. Results: MHC-I was down-expressed, PD-L1 and MICA/B were up-regulated in NSCLC. CD8+ TIL could be seen in tumor stroma and nest. In univariate analysis, we found that patients with down-expression of MHC-I and up-regulation of PD-L1 had a poor prognosis (P < 0.05). MICA/B expression had no correlation with patients’ prognosis (P > 0.05). Patients with more stromal CD8+ TIL might have better prognosis. In multivariate analysis, we found that MHC-I and stromal CD8+ TIL might be independent prognostic factors in NSCLC (P < 0.05). TNF-α and IFN-γ were significantly decreased, IL-6 was increased in NSCLC patients (P < 0.05). There were no connections between the cytokines levels with patients’ prognosis (P > 0.05). Serum sMICA was significantly higher in NSCLC patients than healthy controls (P < 0.05). sMICB tented to be elevated in NSCLC compared with health controls, but there was no significant difference (P > 0.05). High sMICA expression had an association with poor prognosis (P < 0.05). There was no connection between the sMICB level with patients’ prognosis (P > 0.05). Conclusions: The immune status of patients with NSCLC had a close association with their prognosis in this study. It worths further study to confirm the clinical value of MHC-I expression, stromal CD8+ TIL and serum sMICA as prognostic marker in the patients with NSCLC.
A new unsupervised clustering algorithm applied to genome-wide profiles of breast cancers in The Cancer Genome Atlas proper subsets triple-negative samples.
Authors: Mezey Jason , Schwager Steven , Shenoy Sushila , Benbanaste Jef , Elashoff Michael , Kelkar Anuja , Somashekar Pramod , Lee David S.
Published: September 2018

e23195

Background: Clustering algorithms have identified subtypes of major cancers from analysis of genome-wide gene expression (GE) and somatic mutation (SM) profiles. These algorithms almost never discover a proper subset cluster, a recovered cluster that includes all the samples of a specific subtype. For breast cancer (BC), clustering of genome-wide profiles has been unable to proper subset triple negatives (TNs), TN subtypes, or other major subtypes. Methods: To search for a proper subset cluster for TNs, we applied a new clustering algorithm to the public domain GE and SM data of BC samples in The Cancer Genome Atlas (TCGA). A module of Medidata’s Clinical Trial Genomics (CTG) platform for automated clinical and genomic data integration and analysis, it uses a hierarchical component with tree learned cut points applied to a principal component dimension reduced similarity matrix calculated from a genome-wide data profile. Results: Our analysis of 540 TCGA BC samples run without human supervision produced a proper subset cluster that included all 55 TN samples and only 74 non-TN samples. GE data have previously indicated TN status, but this is the first demonstration that these TCGA BC data contain enough information to proper subset TNs, implying that this broad BC subtype has a strong, quantifiable impact on GE. We show that the genome-wide SMs of TCGA BC samples can be used to proper subset 4 novel subtypes distinguished as classes “TP53 mutated”, “PIK3CA mutated”, “both TP53 and PIK3CA mutated”, and “neither mutated”, signifying an important role for these known driver mutations in producing the subtypes’ genome-wide mutation profiles. We find that most ( > 80%) TN BCs are in “TP53 mutated” but only 1 TN sample ( < 2%) is in “PIK3CA mutated”, indicating distinct biology for these TNs with potential implications for TN therapy. Conclusions: CTG clustering achieves proper subset cancer subtype clustering of TCGA BC samples. These results illustrate the therapeutic discovery potential possible from genomic data of the high quality present in TCGA if combined with detailed clinical data with the Medidata CTG integration and annotation platform.
Molecular classification with NanoString nCounter system in triple-negative breast cancer.
Authors: Ahn Sung Gwe , Kim Seung Joon , Lee Hak Woo , Yoon Hyo Jeong , Kim Chungyeul , Jeong Joon
Published: September 2018

e23198

Background: Previous studies have shown that several distinct subtypes identified by gene expression profiling (GEP) consisted of triple-negative breast cancer (TNBC). Compared with the subtypes defined by GEP, we developed molecular classification with NanoString nCounter system in TNBC. Methods: GEP was conducted on 188 FFPE containing chemotherapy-naïve TNBC tumors collected at Gangnam Severance Hospital. To select core genes for classification, other 120 samples from public GEP database were used. Correlation between nCounter system and GEP using identical RNA was done. In a part of tumors, BRCA1 methylation, homologous recombination deficiency (HRD) assay, and drug response assay with ATP was comprehensively assessed. Results: To classify TNBC into 4 major subtypes (Basal-like: BL, Luminal androgen receptor: LAR, Mesenchymal: M, and Immune-modulatory: IM) according to the Vanderbilt classification, we selected 110 genes in 220 samples with GEP (100 from Gangnam Severance Hospital and 120 from public database). In other 88 samples, the classification with the 110 genes were validated. In 149 tumors excluding UNS subtype by the Vanderbilt, a correlation between 110 genes-classification and the Vanderbilt system was 74.4% (111 of 149, Pearson’s R = 0.726). In 180 tumors with GEP and nCounter assay, a correlation between them was 85.0% (153 of 180, Pearson’s R = 0.827). Compared with tumors of the IM type by 110-genes, the recurrence-free survival was significantly reduced in tumors of the non-IM type by 110-genes ( P= 0.049). In cases with BRCA1 methylation test (n = 147), a significant higher rate of BRCA1 promoter methylation was found in BL type by nCounter system (BL: 41.0% vs. non-BL: 19.4%). In cases with HRD test, a significant lower rate of HRD was found in nCounter-identified LAR type (LAR: 0% vs. non-LAR: 79.3%). In patients with in vitro drug response assay with cisplatin (n = 36), tumors with nCounter-BL had a significant higher responsiveness than tumors with others ( P= 0.028). Conclusions: Our work shows the feasibility of molecular classification with nCounter system in TNBC. Future study warrants the clinical utility of this classification to guide the subtype-specific therapy in patients with TNBC.
PI3K mutation and effect of aspirin use in breast cancer.
Authors: Tang Shou-Ching , Raval Priyanka , Sonbol Mohamad Bassam , Simmons Josh David , Chintalapally Rohini , Savage Natasha , Kolhe Ravindra B. , Kitamura Eiko , Chang Chang-Sheng , Keaton Mark Robert , Maihle Nita J. , Kim Sangmi
Published: September 2018

e23209

Background: Increasing literature suggests a protective role of aspirin in breast cancer. PI3K mutation is prevalent in 30% of estrogen receptor positive and 50% of HER2 receptor positive breast cancers. Aspirin inhibits prostaglandin-endoperoxide synthase 2 (PTGS2) through down-regulation of phosphatidylinositol 3-kinase (PI3K). A study in colorectal cancer demonstrated that regular use of aspirin was associated with superior survival among patients with PI3K mutated tumors. The aim of this study was to retrospectively examine the presence of PI3K mutation in breast cancer tissue in patients who used aspirin during treatment, and compare survival between those with and without PI3K mutations. Methods: Among 1259 patients diagnosed with breast cancer between year 2002 to 2013 at Augusta University (AU), 47 patients who used at least 81 mg of aspirin daily during cancer treatment were identified, and their breast cancer tissue blocks were analyzed for PI3K mutation by gene sequencing technique. Genomic DNAs were extracted from formalin fixed paraffin-embedded tissues using GeneRead DNA FFPE kit (Qiagen) and sequenced on Miseq sequencer (Illumina). We selectively analyzed five genes involved in the PI3K pathway, including PIK3CA, AKT, PIK3R1, PTEN, and TP53. The presence of mutation was correlated to overall survival, using Kaplan-Meier and Cox Regression analyses. Results: Of the 47 patients, 53% were Caucasian and 47% were African American. 70% were early stage (TNM stage I, II) and 30% were late stage (TNM stage III, IV). 69% were never smokers, 31% were current or former smokers. ER, PR and HER2 were expressed in 84%, 79%, and 86% patients respectively. 66% had PI3K mutation, and 34% were PI3K wild type. There was no significant difference (log-rank test p = 0.28) in overall survival (OS) of patients with PI3K mutation versus those without, although the former group had longer survival numerically. The multivariable-adjusted hazard ratio (HR) for PI3K mutation was 0.53 (p = 0.29). Conclusions: Our project supports justification for a larger study to explore the role of aspirin in prevention, treatment and prognosis of breast cancer, and to validate biomarkers such as PI3K and related genes mediating the aspirin effect.
RNA turbulence by tumor type: Overexpression of actionable mRNA signaling pathways by histology.
Authors: Patel Sandip Pravin , Morris Scott , Chae Young Kwang , Clarke Jeffrey Melson
Published: September 2018

e23213

Background: Overexpression of mRNA provides an oncogenic mechanism, downstream of DNA level changes detected by sequencing, that can be treated with targeted therapies. It is still unknown why a subset of patients experience substantial responses to targeted therapies, while others experience minimal benefit. We hypothesize that the occurrence of multiple mRNA drivers may segment by cancer type in a similar manner to mutation burden. Methods: We examined results from 2088 patients with the 23 most common histologies that had received molecular testing at Paradigm Diagnostics by a panel of 56 mRNA targets, including 21 from the MAPK pathway, 14 from the P53 pathway, and 18 from the PI3K pathway. We calculated RNA turbulence, defined as the number of mRNA overexpressed in each case, as well as the pathway-specific RNA turbulence for the MAPK, PI3K and TP53 pathways. Results: Significant differences in overall and pathway-specific RNA turbulence across cancer types was observed. Colon and rectal cancers had high turbulence in the MAPK and TP53 pathways, with 87% having multiple putative drivers in the MAPK pathway and 29% having multiple drivers in the PI3K pathway. Small cell lung cancer and kidney cancers had high turbulence in the PI3K pathway, with 33% and 39% having multiple RNA drivers respectively. Overall, pancreatic, kidney and colon cancers had the highest turbulence and GIST, melanoma and cholangiocarcinoma had the lowest. There was a slight inverse relationship in tumor type when ranked by mutation burden vs. RNA turbulence Conclusions: RNA turbulence represents a unique mechanism by which to analyze tumors and correlates with disease type. Multiplex diagnostics assaying DNA, RNA, and protein level tumor changes will likely be needed to guide cancer therapeutics.
Alectinib versus crizotinib in treatment-naive advanced ALK-positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX study.
Authors: Shaw Alice Tsang , Peters Solange , Mok Tony , Gadgeel Shirish M. , Ahn Jin Seok , Ou Sai-Hong Ignatius , Perol Maurice , Dziadziuszko Rafal , Kim Dong-Wan , Rosell Rafael , Zeaiter Ali Hassan , Liu Ting , Golding Sophie , Balas Bogdana , Noé Johannes , Morcos Peter N. , Camidge D. Ross
Published: September 2018

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. On site at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.
Phase II study of apatinib plus vinorelbine, a novel combination of all-oral regimen in heavily pretreated patients with metastatic HER2-negative breast cancer.
Authors: Zhu Anjie , Yuan Peng , Wang Jiayu , Ma Fei , Luo Yang , Fan Ying , LI Qing , Zhang Pin , Xu Binghe
Published: September 2018

TPS1123

Background: Antiangiogenic therapy in combination with chemotherapy is effective in control advanced breast cancer(ABC). Apatinib is an oral, highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Phase II clinical trials of Apatinib single agent had presented objective response and manageable toxicity in heavily pretreated, metastatic breast cancer. The median progression free survival (PFS) and median overall survival (OS) of single agent in both triple-negative and non-triple-negative breast cancer were 3.3-4.0 months and 10.3-10.6 months, respectively. The overall response rate and disease control rate (DCR) reached 16.7% and 66.7%, respectively. This all-oral phase II study aims to investigate the efficacy and safety of the oral vinorelbine-Apatinib combination in pre-treated metastatic breast cancer(MBC). Methods: This single arm prospective study enrolled patients with HER2(Human epidermal growth factor receptor-2 ) negative advanced breast cancer, pretreated with anthracycline and taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimen. The estimated Enrollment was 40 patients.The primary end point of this study was PFS. Secondary end points included objective response rate (ORR), DCR, OS and safety. Patients were treated with apatinib 500/425mg daily plus oral vinorelbine 60-80 mg/m2 day1,8,15 every 3 weeks/cycle. Starting doses of Apatinib were chosen according to age, weight and patient status. Patients eligible were evaluated by CT or MRI scan at baseline and every 2 cycles (6 weeks) there after until disease progressed. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs, version 4.0. Clinical trial information: NCT02768415.
Phase II trial of pembrolizumab in combination with nab-paclitaxel in patients with metastatic HER2-negative breast cancer.
Authors: Kwa Maryann J. , Iwano Alyssa , Esteva Francisco J. , Novik Yelena , Speyer James L. , Oratz Ruth , Meyers Marleen Iva , Axelrod Deborah M. , Hogan Rebecca , Mendoza Sandra , Goldberg Judith D. , Muggia Franco , Adams Sylvia
Published: September 2018

TPS1124

Background: Immunotherapy has shown therapeutic promise in several cancers, including breast cancer. Monotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated durable responses in patients with metastatic triple-negative breast cancer (mTNBC) (Nanda et al, JCO 2016) and metastatic estrogen receptor-positive (mER+)/HER2-negative breast cancer (Rugo et al, SABCS 2015). Furthermore, response rates have been increased with combination approaches with chemotherapy (Adams et al, ASCO 2016). Based on these results, we seek to study the anti-tumor efficacy and safety of pembrolizumab (anti-PD-1 antibody) and nab-paclitaxel, the impact of therapy on the tumor microenvironment, and predictive markers of response. Methods: This is an ongoing single-arm open-label multi-cohort phase II study of pembrolizumab and nab-paclitaxel in patients treated with ≤2 prior lines of therapy for metastatic HER2-negative breast cancer (n = 50) (ClinicalTrials.gov: NCT02752685). Thirty patients with mTNBC and 20 patients with mER+/HER2-negative breast cancer will be enrolled. Enrollment of patients with metaplastic breast cancer is encouraged. Patients will receive pembrolizumab 200 mg IV on day 1 plus nab-paclitaxel 100 mg/m2 IV on day 1 and 8 (21-day cycle). Prior taxane therapy given > 3 months before cycle 1 is allowed. Primary objective is treatment efficacy, as determined by overall response rate (RECIST 1.1). Secondary objectives include safety, progression-free survival, overall survival, and duration of response. Serial tumor biopsies will be performed to assess changes in the tumor microenvironment from baseline with chemotherapy alone (cycle 1) and then with chemoimmunotherapy (cycle 2 and subsequent cycles). Mutational and neoantigen load, TILs by histopathological assessment, TCR by immunosequencing, and immune gene profiles in tumors will be evaluated. PD-L1 expression in tumor tissue is not required for enrollment but will be assessed as a predictive marker. The potential role of the gut microbiome in modulating the immune response will also be evaluated by 16S rRNA. An initial safety run-in with 12 subjects has been completed with no unexpected toxicity. Clinical trial information: NCT02752685.
A phase 0/II study for ribicoclib in patients with recurrent glioblastoma.
Authors: Sanai Nader , Tien An-Chi , Honea Norissa , Mehta Shwetal , Li Jing
Published: September 2018

TPS2083

Background: Disruption of CDK4/6-dependent G1-S cell cycle regulation is a hallmark of glioblastoma (GBM) progression in 78% of cases. Newly-developed CDK4/6 inhibitors have shown promise in non-CNS cancer trials and glioma animal models. To explore the utility of Ribociclib, a specific CDK4/6 inhibitor, in treating recurrent GBM patient, we designed a phase 0/II clinical trial to examine the pharmacokinetic (PK) and pharmacodynamics (PD) of Ribociclib. Methods: 24 adult patients are allocated to 3 time-escalation arms and receive 5 days of daily Ribociclib prior to planned GBM resection. Eligible patients are selected based on intact Rb expression and loss of Ink4a/Arf locus. Intensive PK sampling of blood, CSF, and tumor is performed intraoperatively and Ribociclib concentrations are determined by a validated LC-MS/MS method. PD endpoints, including RB phosphorylation and FoxM1 expression, are compared to matched archival tissue. Patients exhibiting positive PK and PD outcomes will graduate to a therapeutic regime of Ribociclib as part of the Phase II component of the study with a primary endpoint of progression-free survival, as determined by Response Assessment in Neuro-Oncology (RANO) criteria. Clinical trial information: NCT02933736.
REGOMA: A randomized, multicenter, controlled open-label phase II clinical trial evaluating regorafenib (REG) activity in relapsed glioblastoma (GBM) patients (PTS).
Authors: Lombardi Giuseppe , De Salvo Gian Luca , Eoli Marica , Brandes Alba Ariela , Ruda Roberta , Faedi Marina , Pace Andrea , Lolli Ivan , Pasqualetti Francesco , Rizzato Simona , Germano Domenico , Maiello Evaristo , Indraccolo Stefano , Cabrini Giulio , Gardiman Marina Paola , Zagonel Vittorina
Published: September 2018

TPS2085

Background: GBM is the most common and malignant form of primary brain tumor with a high recurrence rate after surgery, radiation therapy and temozolomide. Currently, there is no established regimen for the treatment of recurrent GBM. GBMs are highly vascularized tumors with high expression of pro-angiogenic factors and activation of multiple signaling pathways in the tumor microenvironment, including the receptor tyrosine kinases, VEGFR, FGFR, and PDGFR, which control the tumor vasculature. REG, an oral multikinase inhibitor, inhibits these angiogenic kinases and the mutant oncogenic kinases KIT, RET and B-RAF. REG was demonstrated to be safe and effective in metastatic colon-rectal cancer, hepatocellular carcinoma and GIST PTS. It was shown that REG inhibits tumor angiogenesis and tumor cell proliferation in rat GBM tumor xenografts (Wilhelm S.M, et al. Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer:129,245-255.2011). Methods: Primary aim of the study is to assess the role of REG activity in prolonging the overall survival in relapsed GBM PTS after surgery and Stupp regimen; secondary aims are to analyze progression free survival, objective response rate, disease control rate and quality of life. Eligible PTS with ECOG PS 0-1, documented progression of disease (after Stupp treatment) as defined by RANO criteria, adequate bone marrow, liver and renal function are randomized in a 1:1 ratio to REG 160 mg/die (3 weeks on, 1 week off) or lomustine 110 mg/m2 (every 6 weeks). A total of 112 PTS will be randomized (α = 0.20, β = 0.20) and stratified based on surgery at recurrence. Disease evaluation is performed with gadolinium brain MRI every 8 weeks according to RANO criteria. Additional exploratory objectives include analysis of specific angiogenic and metabolic biomarkers in tissue as possible predictors of response to REG. The trial started in Nov 2015; as of Jan 2017, 105 PTS have been enrolled. Final analysis is planned in Dec 2017. Clinical trial information: NCT02926222.
A phase 1, open-label, dose escalation study of enoblituzumab (MGA271) in pediatric patients with B7-H3-expressing relapsed or refractory solid tumors.
Authors: Desantes Kenneth , Maris John M. , McDowell Kimberly , Mackall Crystal , Shankar Sadhna , Vasselli Jim , Chen Francine , Loo Deryk , Moore Paul A. , Wigginton Jon M. , Sondel Paul M.
Published: September 2018

TPS2596

Background: Enoblituzumab, is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family. It is Fc-engineered to enhance effector function including antibody dependent cellular cytotoxicity (ADCC). IHC analyses with the parental anti-B7H3 mAb specificity incorporated in enoblituzmab revealed limited B7-H3 expression in normal tissues but high expression in many cancers (Loo et al., 2012). Among pediatric solid tumors, high expression of B7-H3 has been reported in neuroblastoma, rhabdomyosarcoma, osteosarcoma, Wilms tumor, Ewing’s sarcoma and desmoplastic small round cell tumor. B7-H3 overexpression correlates with poor prognosis in a broad range of cancers in adults suggesting a potential role in enabling tumor immune escape. ADCC and potential modulation of T cell function resulting in enhanced antitumor immune response are presumed mechanisms of action of enoblituzumab. Methods: This is an open-label, dose escalation / cohort expansion phase 1 study (NCT02982941) designed to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of enoblituzumab in children and young adults with B7-H3-expressing relapsed or refractory malignant solid tumors. A 3+3 design is used in escalating dose cohorts of weekly intravenous (IV) enoblituzumab starting at 10 mg/kg. Response is first determined at 8 weeks. irRECIST is used for response assessment for patient management. Enoblituzumab may continue up to 2 years based on response. Cohort expansion phase, to further define the safety and initial antitumor activity of enoblituzumab, will start after maximum tolerated dose is determined. The patients are assigned to 1 of 5 cohorts based on disease type as follows: 1) neuroblastoma - measurable disease, 2) neuroblastoma - non-measurable disease, 3) rhabdomyosarcoma, 4) osteosarcoma, and 5) Ewing’s sarcoma, Wilms’ tumor and desmoplastic small round cell tumors. Enrollment is ongoing. Ref : Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Loo D, Alderson RF, Chen FZ, Huang L et al. Clin Cancer Res. 2012; 18:3834-45. Clinical trial information: NCT02982941.
A phase I study to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activities of daily oral BAL101553, a novel tumor checkpoint controller (TCC) in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.
Authors: Ingles Garces Alvaro Henrique , Plummer Elizabeth R. , Lopez Juanita Suzanne , Kristeleit Rebecca Sophie , MacDonald Julie , Sweeting Lorna , Devlin Michael-John , Drew Yvette , Hannah Alison L. , Aceto Nicola , Anderson Stephanie , Lane Heidi A , Larger Patrice , Maurer Martina , McKernan Phil , Engelhardt Marc Frederick , Greystoke Alastair , Coleman Niamh , Evans T.R. Jeffry , Mulholland Paul James
Published: September 2018

TPS2601

Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule (MW 387) shown in rats to penetrate the brain (1:1 plasma ratio) and has shown promising antitumor activity in orthotopic preclinical models of GBM as monotherapy or in combination with radiotherapy (RT) with/without chemotherapy. In a completed Phase 1 study with 2-h IV infusions (Days 1, 8, 15, q28d, NCT01397929 , CDI-CS-001, Lopez et al. J Clin Oncol 34, 2016 suppl; 2525), dose-limiting vascular effects were observed and appeared Cmax related. 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. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients; no vascular toxicities were observed at doses up to the MAD of 30 mg QD. Given this absence, the study was amended to enroll separate cohorts of patients with progressive or recurrent GBM or high-grade glioma. Methods: This is an ongoing multicenter, open-label, Phase 1 dose-escalation study using a 3+3 design to determine the MTD, characterize dose-limiting toxicities and assess the PK, PD and antitumor activities of daily oral administration of BAL101553 in consecutive 28-day cycles at a starting dose of 8 mg QD. Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, are eligible for enrollment. This includes patients with histologically-confirmed low-grade glioma with unequivocal evidence by imaging of transformation to high-grade glioma. Adverse events are assessed using CTCAEv4; tumor response by RANO (every 2 cycles). The dose escalation allows for doubling of dose levels depending on observed toxicities. PD assessments include circulating tumor cells. PK profiles are assessed throughout the first two treatment cycles. Clinical trial information: NCT02490800.
A phase Ib, first-in-human, dose escalation and expansion study of XMT-1522, a novel antibody-drug conjugate (ADC) directed against HER2, in patients with advanced breast cancer and other advanced tumors expressing HER2.
Authors: Burris Howard A. , Barve Minal A. , Hamilton Erika Paige , Bardia Aditya , Soliman Hatem Hussein , Jarlenski Donna , Mosher Rebecca , Bergstrom Donald Alan
Published: September 2018

TPS2606

Background: XMT-1522 is an ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to an auristatin-based cytotoxic payload (AF-HPA). An average of 12 AF-HPA molecules is conjugated to each antibody via a biodegradable polymer. In pre-clinical xenograft experiments XMT-1522 achieved complete, durable tumor regressions in models of HER2-positive and HER2 1+/2+ breast cancer, HER2 2+/3+ NSCLC, and HER2-positive and HER2 1+ gastric cancer. Methods: This study (NCT02952729) is comprised of two parts: a dose escalation segment (DES) and an expansion segment (EXP). The primary objectives of the DES are determination of the maximum tolerated dose and recommended Phase 2 dose (RP2D) and assessment of safety and tolerability. The DES will enroll patients with advanced or metastatic breast cancer who have progressed following standard therapies and have HER2 protein at least 1+ by IHC. XMT-1522 will be administered intravenously every 3 weeks. DES uses a 3+3 design. Post-dose assessments include LVEF measurement at the end of cycles 1, 3, then every 3 cycles, ophthalmologic exams at the end of cycles 1, 2, then every 2 cycles, and re-staging CT scans every 2 cycles. Pharmacokinetics of antibody, AF-HPA payload and an AF-HPA metabolite will be measured. Two patients have completed dose level 1 without DLT. The EXP segment will open at the RP2D and will further assess safety and tolerability of XMT-1522 and assess efficacy in selected patient populations. EXP will enroll 4 cohorts (N = 20 each). Cohort 1: HER2 1+/2+ advanced breast cancer with 2-3 prior chemotherapy regimens Cohort 2: HER2-positive advanced breast cancer with prior pertuzumab and ado-trastuzumab emtansine (T-DM1) Cohort 3: HER2-positive advanced gastric cancer with prior trastuzumab Cohort 4: HER2 2+/3+ NSCLC with at least 1 prior platinum regimen The protocol requires archival tumor tissue for central confirmation of HER2 status, alternative HER2 measurements, and targeted gene expression and sequencing studies. Tumor biopsies will be requested at the time of progression from patients who responded to XMT-1522. Clinical trial information: NCT02952729.