bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of ATP-binding cassette (ABC) and solute carrier (SLC) transporters in pancreatic ductal adenocarcinoma (PDAC).
Authors: Mohelnikova-Duchonova Beatrice , Brynychova Veronika , Oliverius Martin , Hlavsa Jan , Honsova Eva , Mazanec Jan , Melichar Bohuslav , Kala Zdenek , Soucek Pavel 
Published: March 2020

11051 Background: Resistance against anticancer drugs significantly limits the clinical use and efficacy. One of the most important mechanisms of the multidrug resistance is low accumulation of the drug in cancer cells caused by an increased efflux (mediated mainly by ABCs) or by a decreased uptake (mediated by some members of SLCs). The aim of the present study was to investigate prognostic importance of 13 anticancer drug-relevant SLCs and all 49 human ABCs in PDAC patients in association with clinical and pathological characteristics and the tumor KRAS mutation status. Methods: Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 50 patients with histologically verified PDAC. The transcript profile of ABCs and SLCs was assessed using quantitative real-time PCR. KRAS mutations in exon 2 were assessed by high-resolution melting analysis and sequencing. Associations of transcript levels with clinical parameters were assessed by non-parametric Mann-Whitney tests. The Kaplan-Meier method with the log-rank test and Cox regression were used for analysis of overall survival (OS). Results: Most transporters investigated were deregulated in PDAC and 14 ABCs or SLCs were associated with clinical characteristics. Up-regulation of 7 drug resistance-associated ABC efflux transporters and down-regulation of 5 drug uptake-relevant SLC transporters was observed in tumors vs. non-neoplastic tissues. Moreover, expression levels of SLC28A1 and SLC22A1 were associated with OS of all patients (P=0.001). High transcript levels of SLC29A3 and SLC22A3 significantly predicted longer OS in chemotherapy-treated patients (P=0.004 and P=0.038, respectively). No association of ABC and SLC expression with KRAS mutation status was observed. Conclusions: Up-regulation of numerous drug resistance-associated ABCs and down-regulation of SLCs implicated in drug uptake may explain the generally very poor response of PDAC to cytotoxic agents. This study also identified some ABCs and SLCs as potential prognostic and predictive factors in PDAC. Supported by the Czech Science Foundation grant P301/12/1734 and CZ.1.05/2.1.00/03.0076 European Regional Development Fund.
Genomic profiling of breast cancer in African-American women.
Authors: Nunes Raquel , Wray Lynette , Mete Mihriye , Godwin Thomas , Herbolsheimer Pia Maarit , Smith Karen L. , Bijelic Lana , Boisvert Marc E. , Swain Sandra M. 
Published: March 2020

11054 Background: Molecular profiling of breast cancer (BC) identifies intrinsic subtypes with distinct gene expression and clinical characteristics. In the US, BC is less frequent in African-American females (AAF); however mortality is higher, particularly among younger women. Unfavorable subtypes of BC seem to be more frequent in premenopausal AAF. Methods: Tumor gene expression in AAF presenting with early stage or locally advanced BC was performed using the Symphony platform on fresh and paraffin-embedded tissue (Agendia inc), a microarray-based method which classifies tumors according to prognosis (MammaPrint, MP), molecular subtype (BluePrint, BP) and estrogen receptor (ER), progesterone receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER2) mRNA levels (TargetPrint, TP). Genomic information is correlated with clinical and pathologic characteristics and Oncotype DX recurrence score (RS) when available. We plan to enroll 100 patients. Results: Results available in 46 patients. Median age 62 years (range 24-100), 20 stage I, 15 stage II, 11 stage III disease. There was no significant association between MP risk and stage, but MP risk was significantly associated with grade 3 disease (p=.006). 9 cancers were triple negative by IHC; using BP, 8 of these were Basal-type and 1 HER2-type. Basal-type was the most common subtype in patients ≤ 40 years old (p < .001). In the 6 cases ER positive by IHC but negative by TP, 3 were Basal-type and 3 were HER2-type.14 patients had Oncotype RS results available: 2 were High Risk by Oncotype and MP; 3 had intermediate RS, 2 of which were High Risk by MP; 9 had a low RS, 4 of which were High Risk by MP. Conclusions: African-American women with stage I to III BC often present with High-Risk disease irrespective of stage. BP classified all young patients (≤40) as Basal-type. Molecular subtyping confirmed the biologic heterogeneity in triple negative and hormone positive tumors. Oncotype RS and MP offered different prognostic information. Follow up will be needed to determine correlation with outcome. Funding: MP, BP and TP test provided by Agendia. Biostatistical support by GHUTTCS-CTSA. [Table: see text]
Induction of an aggressive phenotype and poor survival in early-stage lung adenocarcinoma and epigenetic inactivation of microRNA-34b/c.
Authors: Nadal Ernest , Gallegos Marc , Chen Guoan , Palmero Ramon , Capella Gabriel , Cardenal Felipe , Beer David G. 
Published: March 2020

11056 Background: The microRNA-34b/c (miR-34b/c) is a transcriptional target of TP53 that is frequently mutated in primary lung adenocarcinoma (AC). We investigated the clinical implications of miR-34b/c methylation in early stage lung AC patients and the functional role of miR-34b/c re-expression in lung AC cell lines. Methods: DNA methylation of miR-34b/c promoter was assessed by real-time PCR temperature dissociation in 15 lung AC cell lines and 140 early stage lung AC resected at the Bellvitge Hospital (Barcelona) and at the University of Michigan (Ann Arbor). Patient characteristics: 65% males, 88% smokers, 68.5% stage I and 31.5% stage II. Expression of miR-34b/c was determined by TaqMan RT-PCR. Two lung AC cell lines (NCI-H1838 and SK-LU-1) were transfected with an expression vector containing both miRs and the effects upon cell proliferation, migration and invasion were determined. Results: MiR-34b/c was methylated in 40% of cell lines and in 46% of primary tumors with significant association with higher tumor stage (P=0.033), recurrence (P=0.017) and death (P=0.005). In the training set (n=58), patients with higher levels of miR-34b/c methylation had significantly shorter median DFS (28.5 months) compared to low to medium levels (not reached, log-rank P=0.016). In the test set (n=82), higher levels of miR-34b/c methylation were also associated to shorter median DFS (19 months) compared to patients with low to medium levels (not reached, log-rank P=0.005). MiR-34b/c methylation remained an independent prognostic marker for DFS after adjusting by age, gender and stage. Tumors harboring TP53 mutations and miR-34b/c methylation expressed significantly lower levels of miR-34b/c (P≤0.001). Stable cells expressing miR-34b/c had lower proliferation rate relative to cells transfected with empty vector (P≤0.001). Expressing miR-34b/c in SK-LU-1 cells reduced migration and invasion ability. Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation is an independent prognostic marker in early stage lung AC. Ectopic expression of miR-34b/c generated a less aggressive phenotype in lung AC cell lines suggesting a potential for therapeutic targeting.
Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients.
Authors: Bivona Trever Grant , Giannikopoulos Petros , Costa Carlota , Karachaliou Niki , Viteri Santiago , Garcia-Campelo M. Rosario , St. John John , Uzilov Andrew V. , Wellde Anne S. , Polkinghorn William Reilly , Majem Margarita , Felip Enriqueta , Carcereny Enric , Heidecke Cordula Nicole , Massuti Bartomeu , Wellde George W. , Weissman Jonathan S. , Rosell Rafael ,   Cancer Therapeutics Innovation Group
Published: March 2020

11067 Background: Major obstacles limiting the clinical success of EGFR TKI therapy in non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy. Methods: We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA from the paired frozen biopsies and matched normal tissue was analyzed by whole exome sequencing and RNA from the biopsies was analyzed by whole transcriptome sequencing. High-resolution CT images were obtained at the time of each biopsy to compare the degree of molecular and radiographic response observed. Results: Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Selective depletion of each EGFR mutant allele, but not the EGFR wild type allele, was observed upon erlotinib treatment. Gene expression analysis of the paired transcriptomes revealed that erlotinib treatment resulted in significant upregulation of proapoptotic genes including BAD, BAX, BID, CASP3 and growth inhibitory genes including CDKN1A, GADD45B, GADD45G and downregulation of growth-promoting genes including CCNB1 and CCND3. Several unexpected and novel molecular biomarkers were identified by transcriptome analysis and the complete dataset will be presented. High-resolution CT scans revealed no interval radiographic changes in the target lesion and no clinical complications were encountered. Conclusions: This study is the first reported integrated genomic analysis of EGFR-mutant NSCLC immediately following EGFR TKI initiation. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response. Additional, serial integrated genomic analysis is ongoing in the index patient and others on therapy to enhance the management of NSCLC patients on targeted therapy.
Noninvasive measurement of prostate-specific membrane antigen (PSMA) expression with radiolabeled J591 imaging: A prognostic tool for metastatic castration-resistant prostate cancer (CRPC).
Authors: Tagawa Scott T. , Akhtar Naveed Hassan , Christos Paul J. , Osborne Joseph , Vallabhajosula Shankar , Freedy Shoaib , Goldsmith Stanley J. , Nanus David M. , Bander Neil Harrison 
Published: March 2020

11081 Background: PSMA is nearly universally expressed by PC, upregulated with increased grade and castration-resistance. Evidence points towards PSMA expression as a downstream cellular biomarker of androgen receptor (AR) activity and non-invasive measurement of PSMA expression has recently been demonstrated to be a novel biomarker of AR activity. Methods: Planar gamma camera images following radiolabeled J591 (111In-J591 or 177Lu-J591) were semi-quantitatively scored using 2 methods by 2 independent radiologists blinded to outcome.A 5-point visual score (VS) of 0 - 4+ was assigned. Tissue Targeting Index (TTI), a novel metric designed to semi-quantitatively score images was calculated using the ratio of lesion count density (corrected for background) to whole body count density, with maximum (TTImax) and mean (TTIave) scores recorded. Follow up tabulating subsequent therapies and overall survival (OS) was recorded and imaging scores were associated with OS using Cox regression analysis. Results: 130 men with metastatic CRPC underwent radiolabeled J591 imaging. 86.2% had bone metastases, 51.5% lymph node, 16.9% lung, 9.2% liver. 87.7% had accurate targeting of known sites of disease by planar imaging. CALGB (Halabi) nomogram scores were prognostic for the population. As continuous variables, TTImax (p=0.013) and TTIave (p=0.002) were associated with worse survival. VS demonstrated a trend for worse survival (p=0.09). In multivariate analysis, TTI maintained independent prognostic value when controlling for Halabi score: TTImax HR 1.05 [95% CI 1.01, 1.10; p=0.02], TTIaveHR 1.09 [1.03, 1.16; p=0.004]. Conclusions: Level of PSMA expression measured by planar gamma-camera imaging following radiolabeled J591 is associated with OS in men with metastatic CRPC. High PSMA expression may indicate more aggressive tumor biology with increased AR pathway dysfunction. Improvements in quantitative molecular imaging techniques such as PSMA PET/CT with 89Zr-J591 may prove to be a valuable prognostic and predictive biomarker, particularly in the setting of AR- and PSMA-targeted therapy. Clinical trial information: NCT00195039, NCT00538668.
Developing a molecular imaging agent for Met using onartuzumab (MetMAb).
Authors: Wright Cara Elizabeth , Jagoda Elaine , Cecchi Fabiola , Bhadrasetty Veerendra , Histed Stephanie , Williams Mark , Kramer-Marek Gabriela , Mena Esther , Rosenblum Lauren , Lang Lixin , Szajek Lawrence , Paik Chang , Choyke Peter L. , Marik Jan , Tinianow Jeffrey , Merchant Mark , Bottaro Donald P. 
Published: March 2020

11083 Background: Developing an imaging agent to assess Met expression would aid in diagnosis and monitoring tumor response to Met-targeted therapies. Onartuzumab (MetMAb), a Met selective humanized one-armed monoclonal antibody, has been studied in Phase I-II clinical trials in which it was generally well tolerated and has shown the most benefit in patients with MET positive tumors. Methods: Studies to assess Met-binding were executed using the human gastric carcinoma cell line MKN-45 which exhibits a high level of Met expression. Murine PET studies and biodistribution assays were performed using MKN-45 xenografts. Results: Plasma shed Met concentration is directly related to total tumor burden (p < 0.001). The absence of a positive correlation between shed Met and %ID in blood indicates that binding of tracer to shed Met present in plasma is unlikely. There are positive correlations between tumor mass, Met abundance, and phosphoMet content and uptake of 89Zr-df-onartuzumab in MKN-45 mouse xenografts. Lastly, tumor mass, Met, pMet and 89Zr-df-onartuzumab uptake were all significantly decreased by drug treatment. Conclusions: MKN-45 tumor uptake of 89Zr-df-onartuzumab correlated significantly with tumor mass and Met abundance. Blood tracer uptake did not positively correlate with the presence of plasma shed Met. The amounts of Met, pMet, as well as 89Zr-df-onartuzumab image intensity correlated significantly with tumor size (all Spearman p values < 0.001).Tumor volumes and Met content were significantly decreased in TKI treated versus control mice, which correlated with imaging results.89Zr-df-onartuzumab has potential utility for imaging Met to identify patients for treatment with Met-targeted therapeutics and to identify the emergence of Met-driven acquired resistance to other molecularly targeted cancer therapies.
BRAF mutation testing with a novel, rapid, fully automated molecular diagnostics prototype platform.
Authors: Huang Helen J. , Devogelaere Benoit , Falchook Gerald Steven , Fu Siqing , Angelo Laura S. , Hong David S. , Piha-Paul Sarina Anne , Naing Aung , Holley Veronica R. , Tsimberidou Apostolia Maria , Stepanek Vanda M. T. , Kim Kevin , Subbiah Vivek , Wheler Jennifer J. , Zinner Ralph , Wolff Robert A. , Sablon Erwin , Maertens Geert , Kurzrock Razelle , Janku Filip 
Published: March 2020

11086 Background: Mutations in the BRAF gene provide actionable targets for cancer therapy in melanoma and other tumor types. Novel, fast, and accurate diagnostic systems are needed for further implementation of personalized therapy. Methods: The molecular diagnostics (MDx) prototype platform (Biocartis, Mechelen, Belgium) is a fully integrated real-time PCR-based system with high sensitivity (1% mutant in wild-type [wt] background) and fast turnaround time (< 90 minutes), which requires no sample preparation and <2 min hands-on time. Archival formalin-fixed paraffin-embedded tumor samples (1 to 5 shavings of 10 µm) from patients (pts) with advanced cancers previously tested for V600 BRAF mutations in a CLIA-certified Molecular Diagnostic Laboratory (PCR-based sequencing or Sequenom MassARRAY) were tested for BRAF V600 mutations using the MDx prototype platform. Concordance between methods and treatment outcomes with BRAF/MEK inhibitors were analyzed. Results: Forty-seven pts (melanoma, n=26; colorectal, n=8; papillary thyroid, n=3; other cancers, n=10) with available tissue and CLIA laboratory BRAF results were selected (BRAF V600 mutant, n=37; BRAF V600 wt, n=10). Of the 40 pts for whom the same tissue block was used for MDx and CLIA, BRAF status was concordant in 38 (95%; kappa 0.87; 95% CI 0.69-1.05) of them. BRAF status by MDx was discordant with CLIA in 3 of 47 cases (mutant by CLIA, but not MDx); one discrepant case contained a different mutation subtype (resp. V600E vs. V600K/R), and in another case different tissue blocks were used for MDx vs. CLIA testing. Of 34 pts with BRAF mutations detected by MDx, 28 were treated on protocols (on the basis of the CLIA results) with BRAF/MEK inhibitors and 8 (29%) had a partial (n=7) or complete response (n=1). Of interest, 1 pt with prostate cancer (V600E by CLIA, wt by MDx) received a BRAF/MEK inhibitor and did not respond. Detailed patient characteristics, mutation types and discrepancy analysis will be presented. Conclusions: The BRAF V600 mutation MDx prototype assay is a fast (turn-around time about 1.5 hours) and simple (<2 minutes hands-on time) test to determine BRAF mutation status with 95% concordance with CLIA laboratory if identical tissue blocks are used.
Molecular subtyping to predict better clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxel-capecitabine with or without trastuzumab.
Authors: Gluck Stefan , Royce Melanie , Stork-Sloots Lisette , De Snoo Femke 
Published: March 2020

11090 Background: Classification into molecular subtypes is important for the selection of therapy for patients with early breast cancer. Here we determine rates of pathological complete response (pCR) in early stage breast cancer to neoadjuvant capecitabine plus docetaxel, +/- trastuzumab, and investigate MammaPrint together with the molecular subtyping profile BluePrint as markers of pathological response in comparison to other biomarkers. Methods: This analysis was carried out on data from 122 patients enrolled in a multicenter study (XeNA) of neoadjuvant therapy for four 21-day cycles with capecitabine 825 mg/m2 plus docetaxel 75 mg/m2if HER2-, and a standard trastuzumab dose if HER2+ (Glück , BCRT 2011). Clinical and pathological features, TP53 mutation analysis and PAM50 results were collected through GEO at NCBI (GSE22358). MammaPrint and BluePrint outcomes were determined from the available gene expression data and resulted in 4 distinct molecular groups: Luminal A (MammaPrint Low Risk/Luminal-type), Luminal B (MammaPrint High Risk/ Luminal-type), Basal-type and HER2-type. Results: In patients who completed 4 cycles of chemotherapy and surgery the overall pCR rate was 16%. Stratified by BluePrint pCR was observed in 1/15 (7%) of the Luminal A and 2/44 (5%) of Luminal B, in 10/22 (45%) of the HER2-type and in 7/41 (17%) of the Basal-type. The response rate among TP53 mutated patients was 6/61 (26%), which was significantly higher than TP53 wild-type patients (3/54 4%; p=0.012). Concordance of BluePrint/MammaPrint with PAM50 molecular subtyping was 61%. Conclusions: Molecular Subtyping with BluePrint and MammaPrint can identify better outcomes of patients in the neo-adjuvant setting. Patients with Luminal A breast cancer have a good baseline prognosis with excellent survival and may not benefit from chemotherapy (Glück, SABCS 2013). MammaPrint and BluePrint provide predictive information for patients treated with treated with docetaxel-capecitabine +/- trastuzumab.
Utilizing a collaborative working model to optimize molecular analysis of solid tumors in the Cancer Research UK's Stratified Medicine Programme.
Authors: Walker Ian , MacDonald Fiona , Stuart Helen , Butler Rachel , Ellwood-Thompson Rhianedd , Brown Celia , Eden James , Gonzalez de Castro David , Thompson Lisa , Lillis Sue , Mair Debbie , Cloke Vicky , Rehal Pauline , Bell Jenny , Smith Matthew , O'Sullivan Brendan , Taniere Philippe , Griffiths Michael , Johnson Peter W. M. ,   Stratified Medicine Programme Team
Published: March 2020

11094 Background: The Stratified Medicine Programme is demonstrating large scale molecular testing of solid tumours in the UK using a range of technologies. The collaborative model has allowed three laboratories to share and compare data on mutation frequencies including mutation exclusivity, test turnaround times and failure rates, to inform a future routine service for clinical care. Methods: Phase One is a two-year pilot study of molecular analysis of surplus diagnostic FFPE tumour tissue obtained from patients with cancer of the breast, colorectum, lung, ovary, prostate or malignant melanoma. Samples are tested for specified genes of clinical and research interest (for example KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, TMPRSS2-ERG, EGFR, EML4-ALK and KIT). The labs have developed and validated protocols with comparable sensitivity for the simultaneous molecular analysis of multiple genes. Results: By 31 December 2012, 4,734 sets of molecular results were completed with 60% of tumour-site specific reports issued within the target 15 days (from sample receipt). Failure rates vary with both sample quality and the type of analysis performed. The Table illustrates the link between turnaround times and failure rates, showing that repeat testing for specimens which initially fail may reduce overall failure rates but consequently increase average turnaround times. Conclusions: We will report comparative data across the three testing labs and identify multiple factors that affect mutation detection rates, failure rates, turnaround times and reporting procedures. The Stratified Medicine Programme acknowledges funding from Cancer Research UK, AstraZeneca, and Pfizer. [Table: see text]