bluuebunny/crossref_metadata_2025_split huggingface dataset:
A genome-wide association study (GWAS) of docetaxel-induced peripheral neuropathy in CALGB 90401 (Alliance).
Authors: Hertz Daniel Louis , Owzar Kouros , Halabi Susan , Kelly William Kevin , Zembutsu Hitoshi , Jiang Chen , Patel Jai Narendra , Watson Dorothy , Shterev Ivo , Kroetz Deanna L. , Friedman Paula N. , Mahoney John Francis , Carducci Michael Anthony , Kelley Michael J. , Small Eric Jay , Febbo Phillip G. , Nakamura Yusuke , Kubo Michiaki , Ratain Mark J. , McLeod Howard L. 
Published: March 2020

11053 Background: There are currently no effective methods for predicting, preventing, or treating chemotherapy-induced peripheral neuropathy. We performed a genome-wide association study in a clinical trial of castration-resistant prostate cancer (CRPC) to discover variants that may be useful for identifying patients at high risk of neuropathy during docetaxel treatment. Methods: Treatment and toxicity data were collected prospectively on the Cancer and Leukemia Group B (CALGB) 90401 trial of chemotherapy naïve CRPC patients treated with docetaxel and prednisone ± bevacizumab. Genotyping was performed by the RIKEN Institute using the Illumina HumanHap610-Quad platform. Genetically defined European subjects were included in the discovery analysis of all single nucleotide polymorphisms (SNPs) that passed quality control. The primary endpoint was the cumulative dose level triggering a grade 3+ sensory neuropathy. The inference was conducted within the framework of a competing risk model accounting for early treatment termination induced by death or progression, or other toxicities. SNPs that were highly associated with neuropathy were assessed for a broader taxane effect in a cohort of paclitaxel-treated patients from a breast cancer clinical trial, CALGB 40101. Results: 623 Caucasian patients and 498,022 SNPs were included in the discovery analysis. The incidence of grade 3 neuropathy was 8%. One intergenic SNP (rs11017056) was associated with increased risk of neuropathy (HR=2.83, p=4.7x10-7). This association surpassed the genome-wide significance threshold after covariate adjustment (p=7.2x10-8). However, none of the 7 SNPs selected for replication were associated with neuropathy in the paclitaxel-treated breast cancer cohort. Conclusions: Using a prospectively enrolled prostate cancer patient cohort we identified multiple SNPs that may identify risk of docetaxel-induced peripheral neuropathy, but not paclitaxel-induced neuropathy. However, since it is unknown whether the genetic factors that affect taxane neuropathy are drug-specific, further replication studies in docetaxel-treated cohorts are of great interest.
Modulation of breast cancer cell-free DNA with surgical resection.
Authors: Urnovitz Howard B. , Beck Julia , Schütz Ekkehard , Singh Gopal , Mitchell William M. , Black Dalliah M. , Babiera Gildy , Bedrosian Isabelle , Kuerer Henry Mark , Mills Gordon B. , Meric-Bernstam Funda 
Published: March 2020

11060 Background: Recently we demonstrated the ability to detect the presence of invasive breast cancer by next generation sequence (NGS) analysis of cell-free DNA (cfDNA) in serum without prior knowledge of the specific gene perturbations of the neoplasm (J. Clin. Oncology 2010; 28 (15S):10505). We hypothesized that cfDNA levels would hold promise as a marker to monitor therapeutic efficacy in breast cancer. In this study, we sought to determine whether cfDNA decreases after surgery in patients with operable invasive breast cancer. Methods: Serum was collected before and 1-4 weeks after surgery from 16 breast cancer patients and also from 24 age and gender matched controls. cfDNA was isolated from the serum, amplified by Chronix proprietary method and sequenced on an Illumina HiSeq platform. The breast cancer derived cfDNA sequences from each patient were compartmentalized in 250kbp bins, normalized, and compared to the mean (+/- 3SD) of the controls to identify regions of chromosomal number imbalance (CNI). Genomic DNA was isolated from the primary tumor and blood WBC buffy coat, pre-amplified, sequenced and subjected to comparative analysis with cfDNA. Results: Analysis of pre- and post surgery serum demonstrate that CNIs are present in the pre-surgery serum cfDNA that correlated with the associated tumor CNI and was not observed in WBC genomic DNA. The number of tumor associated CNI DNA biomarkers ranged from as low as 3 to as high as 865. In 13 of 16 patients (81%) analyzed, the post-surgery cfDNA was free of detectable tumor related-CNI DNA. In the remaining 3 patients, only a partial reduction in tumor specific CNI DNA serum biomarkers was observed, since some markers were still detectable after surgery. Conclusions: cfDNA from primary breast carcinomas accurately reflects tumor CNI. Removal of the primary tumor results in the elimination of tumor cfDNA in the majority of patients. Thus cfDNA may be of clinical value in evaluation of therapeutic efficacy on a real time basis. Further work is needed to determine if residual tumor CNI in cfDNA after surgery is a marker of minimal residual disease which can be pursued as a prognostic marker.
Micro-RNA signature differences in lung adenocarcinoma with specific driver alterations.
Authors: Landi Lorenza , Gasparini Pierluigi , Carasi Stefania , Tibaldi Carmelo , Cascione Luciano , Ali' Greta , D'Incecco Armida , Salvini Jessica , Minuti Gabriele , Chella Antonio , Fontanini Gabriella , Cappuzzo Federico , Croce Carlo M. 
Published: March 2020

11066 Background: Oncogenic driving alterations define types of lung adenocarcinoma with different prognosis and sensitivity to targeted agents. MicroRNAs (miRNAs) are a new class of non-coding RNAs involved in gene expression regulation. How miRNAs are dysregulated in lung cancer with ALK translocation, EGFR or KRAS mutation is unknown. In this study we aimed to identify miRNA signatures according to the presence of specific driver and to correlate miRNAs deregulation with patient outcome. Methods: The study was conducted in a cohort of 70 lung cancer patients (pts) including 18 ALK+ tumors, 11 ALK-/EGFR mutation+, 15 ALK-/KRAS mutation+, 26 ALK-/EGFR and KRAS wild-type and defined as triple negative. Matched normal lung tissue from 18 cases representative of the entire cohort were also included onto the analysis. RNA was isolated from formalin-fixed paraffin-embedded tissue (FFPE), using the Recover ALL kit (Ambion). NanoString nCounter system platform was used to generate the miRNA profile. We used Limma to test for differential expression analysis of data. The miR-515 family expression between tissues was validated by RT-qPCRs, analyzed using the parametric t-test (unpaired, 2-tailed for validation). Results: miRNA expression profile clusters distinctly ALK+ pts from ALK- and normal lung tissue. Within the ALK- group we found specific miRNAs subsets able to sub-stratify KRAS versus EGFR careers clustering sharply triple negative versus EGFR mutation+ and triple negative versus KRAS mutation+. miRNAs belonging to the miR-515 family seems to be the most deregulated in the ALK+ versus ALK-. Although their expression is stably high in normal tissues and ALK+ class, they are highly downregulated in KRAS mutated versus EGFR mutated and versus triple negative (p-value <0.001 for all comparisons). Conclusions: miRNAs profile significantly differs in pts with ALK translocation, EGFR mutations and KRAS mutations. Analysis of miR-515 family members is ongoing in order to correlate their expression levels with pts’ outcome. In vitro modulation of miR-515 family expression levels, together with drugs treatment are ongoing in order to find possible chemo-resistance/chemo-sensitivity miRNA dependent, in ALK+ and ALK- model.
A mouse model for cancer immunoediting with renal cell carcinoma to explore mechanisms of immune escape.
Authors: Bigger Elizabeth , Quigley Michael , Yang Yiping 
Published: March 2020

11074 Background: Cancer immunosurveillance is the immune system's ability to recognize and destroy newly arising malignant cells. Recent data suggests that the immune system functions also to apply a selective pressure, leading to growth of less immunogenic tumors, a process termed cancer immunoediting. However, direct experimental evidence to support this hypothesis has been lacking. Methods: We examined the interaction between tumor and tumor-specific CD8 T cells in vivo with a model tumor antigen, influenza hemagglutinin (HA), in a renal cell carcinoma cell line (Renca-HA) and studied the HA-specific CD8 T cell response to Renca-HA in vivo. Naïve HA-specific CD8 T cells (Thy1.1+) purified from HA-TCR transgenic mice that recognize a Kd-restricted HA epitope were transferred into congenic Thy1.2+recipients inoculated the day prior with Renca-HA or wild type Renca (Renca-WT). At subsequent time points, recipient lymphocytes and pulmonary tumors were harvested and analyzed. Results: Four days after transfer, vigorous proliferation of HA-specific CD8 T cells was detected in Renca-HA inoculated mice, but not Renca-WT inoculated mice, leading to activation and effector differentiation of HA-specific T cells. HA-specific CD8 T cell activation resulted in destruction of Renca-HA in vivo, causing a significant (p <0.001) reduction of tumor burden and prolongation of survival. However, a small fraction of Renca-HA tumor cells survived immune-mediated killing and evaded immune surveillance. Microarray technology identified upregulation of transforming growth factor β-3 (TGF-β3) expression in edited Renca-HA, but not in unedited Renca-HA, compared with Renca-WT, confirmed by real-time quantitative PCR. Functional abrogation of TGF-β3 signaling on tumor-specific CD8 T cells delayed Renca HA tumor growth in vivo. Conclusions: These data provide direct evidence for the cancer immunosurveillance and immunoediting processes, and suggest that tumor induction of TGFβ-3 during the immunoediting process suppresses tumor-specific CD8 T cell function in vivo, allowing tumor immune escape. Our results provide mechanistic insights as well as potential strategies to block cancer immune evasion.
Recall rate in a semi-annual breast surveillance program for high-risk women.
Authors: Abe Hiroyuki , Guindalini Rodrigo Santa Cruz , Obeid Elias , Patrick-Miller Linda J. , Bradbury Angela R. , Verp Marion S. , Hong Susan , Wroblewski Kristen , Karczmar Greg S. , Newstead Gillian , Olopade Olufunmilayo I. 
Published: March 2020

11084 Background: High recall rate and unnecessary biopsies are a concern with screening mammogram (MMG) and magnetic resonance imaging (MRI) in young women at high risk for breast cancer. The aim of this study is to investigate the overall recall rate (ORR) and its consequences in a semi-annual MRI surveillance protocol. Methods: A multi-modality surveillance program for women at high-risk for breast cancer was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years of this protocol, an additional 5 years of follow-up with yearly MMG and MRI were offered only to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, ORR were analyzed and biopsies findings characterized. Fisher’s exact test was performed to evaluate association between the effect of MMG density, menopausal status, mutation status, age (<50y or > 50y), and previous breast cancer with recalls. Results: With a mean follow-up of 3.6 years, 226 patients (pts) underwent 1,467 MRI and 851 MMG. Among 56 abnormal MRI and 18 abnormal MMG, 62 pts (27%) were recalled for further tests (6 recalled at two screening episodes). The MRI and MMG ORR were 3.8% and 2.1%, respectively. Only six cases (8.8%) were abnormal for both tests. Overall, 50 additional breast ultrasound, 10 additional MMG, 8 additional MRI were performed. Of the 40 biopsies in 38 pts (2 pts were biopsied twice), 11 cancers were detected (ductal in situ: 3; invasive: 7 ductal and 1 lobular). Abnormal MRI findings led to 37 biopsies, of which 10 (27%) detected cancers. One high-grade ductal carcinoma in situ was exclusively detected by MMG. The first and second MRI screening rounds together showed 27/56 (66%) abnormal findings which led to 23/40 (58%) of the biopsies, and detected 5/11 (45%) of the tumors. No statistically significant predictors of recall were identified (p < 0.05). Conclusions: Semi-Annual MRI protocol did not show increased ORR when compared to annual MRI/MMG surveillance. Approximately two-thirds of all recalls were in the first two rounds of screening which is consistent with previous results. Ongoing work will evaluate clinical and MRI features associated with recall to improve practice. Clinical trial information: NCT00989638.
Tumoral MET/HGF expression and MET gene amplification in patients with ALK 2p23 fusion driven lung cancer.
Authors: Feng Yan , Minca Eugen C. , Zhang Wei , Yin Lihong , Pennell Nathan A. , Farver Carol , Liu Angen , Tubbs Raymond R. , Ma Patrick C. 
Published: March 2020

11091 Background: MET receptor and its ligand HGF are both promising targets in non-small cell lung cancer (NSCLC) therapy. Crizotinib, a recently approved ALK inhibitor for NSCLC harboring oncogenic ALK 2p23 fusion (ALK+), was initially developed as a bona fide MET inhibitor. The role of MET/HGF pathway in ALK+ NSCLC is still unknown. Methods: The study included 73 NSCLC patients tested for ALK rearrangements at Cleveland Clinic (2000-2012), including 21 ALK+ and 52 ALK-. Immunohistochemistry (IHC) on FFPE tumor tissue was performed for c-MET using a monoclonal CONFIRM antibody (SP44, Ventana) with Ventana Benchmark XT automated immunostainer and for HGF using a polyclonal antibody (R&D) following a manual protocol. IHC scoring was interpreted on a 4-tier system (0, 1+, 2+, 3+). MET gene amplification by MET/Chromosome 7 dual probe in-situ hybridiazation (DISH) (Ventana) was also performed. Statistical analysis was performed using Fisher exact test in JMP. Results: Of the tested tumors, 61 were adenocarcinoma (21 ALK+ and 40 ALK-), 6 squamous cell, 4 large cell and 2 NSCLC-NOS. None received any MET inhibitor prior to tissue collection. MET expression by IHC score 0-3 was: 35%, 33%, 15% and 17% in ALK-, and 5%, 37%, 42% and 16% in ALK+ tumor group, respectively. HGF IHC score 0-3 was 34%, 55%, 11% and 0% in ALK-, and 0%, 63%, 32% and 5% in ALK+ tumor group, respectively. The percentages of high MET or HGF expression (2+ or 3+) were higher in ALK+ group compared to ALK- (58% vs 32%, p=0.06, and 37% vs 11%, p=0.03). The correlation coefficient between MET and HGF expression was 0.48. MET gene amplification by DISH was detected in 15% (7/47) ALK- tumors but 0% (0/15) ALK+ tumors (difference not statistically significant, p=0.18). The correlation coefficient between MET IHC and MET gene amplification was 0.33. Conclusions: MET and HGF expression is commonly seen in NSCLC, with more frequent high expression levels in ALK+ than ALK- tumors. Using a newly developed DISH method, we show that MET gene amplification tend to be less frequent in ALK+ tumor. A prospective study with larger sample size is warranted to further define the role of MET/HGF as biomarkers in the biology of NSCLC with ALK rearrangements and their targeted therapy.
Association of tumor perivascular desmin expression with survival in patients with sunitinib-treated renal carcinoma.
Authors: Bolling Magnus Frodin , Sandström Per , Mezheyeuski Artur , Egevad Lars , Ostman Arne 
Published: March 2020

11097 Background: The introduction of tyrosine kinase inhibitors has markedly improved the outcome for patients with metastatic renal carcinoma (mRCC), but lack of reliable response-predictive markers makes it difficult to individualize treatment. Pericytes surround endothelial cells of capillaries and regulate vessel function. Associations between pericyte marker expression and response to sunitinib have not been well characterized. Methods: A tissue micro array with samples from 67 mRCC patients ( 34 males, 33 females, age 42 – 84) treated at Dept. of Oncology, Karolinska University Hospital where constructed from primary tumors. All patients included had received at least one course with the tyrosine kinase receptor inhibitor sunitinib. Data of treatment, progression free survival and overall survival was collected in a clinical registry. Tissues were double-stained with the endothelial cell marker CD 34 and either of three pericyte markers desmin, PDGF beta receptor and alpha smoth muscle actin (ASMA). By semi-quantitative visual scoring, the perivascular staining of these markers was evaluated and cases dichotomized into negative/low- or positive/high-expressing groups. Results: For patients with desmin positive/high vessels ( n = 12), median PFS where 5.0 months (2.9 – 7.1, 95% CI) vs 7.0 months for patients with desmin negative/low vessels (n = 55, 3.8 – 10.2, 95% CI, Mantel Cox log rank test p<0.02). The median OS in the desmin-positive/high group was 24 months ( 7 – 41, 95% CI) vs 46 months in the negative/low group ( 34 – 58, 95 % CI, Mantel Cox log rank test p<0.014). No significant associations were seen between PFS or OS and the expression of perivascular PDGF beta receptor or ASMA. Conclusions: Metastatic RCC displays a clinically relevant variation in perivascular desmin expression which is associated with survival in sunitinib-treated patients. Future studies are warranted which further explores the prognostic and/or response-predicative capacity of this novel candidate renal cell cancer biomarker.
Comparison of [99mTc] tilmanocept and [99mTc] sulfur colloid for identification of sentinel lymph nodes in clinically node-negative breast cancer patients.
Authors: Baker Jennifer L. , Pu Minya , Tokin Christopher A. , Messer Karen , Hoh Carl , Vera David R. , Wallace Anne M. 
Published: March 2020

11098 Background: Receptor-targeted (CD206) [99mTc] tilmanocept is a radiopharmaceutical specifically engineered for sentinel lymph node (SLN) identification that has recently completed phase III clinical trials. The agent has been compared to vital blue dye in prior studies, but has not yet been compared to radio-labeled sulfur colloid. We compared the performance of [99mTc]tilmanocept vs. filtered [99mTc]sulfur colloid (fTcSC) in two cohorts of clinically node-negative breast cancer patients (BCP) who underwent SLN mapping at a single institution. Outcomes were degree of SLN localization and % positive nodes among those removed. Methods: The [99mTc]tilmanocept cohort was composed of UCSD-specific patients pooled from two phase III clinical trials (Jun 2008-Jun 2009, Jul 2010-Apr 2011); the fTcSC cohort was composed of consecutive BCP undergoing SLN mapping at UCSD (Mar 2011-Feb 2012). Demographic, lymph node-specific, and cancer characteristics were compared between groups. A zero-inflated binomial model compared %-positive nodes among nodes removed. Results: There were 85 vs.120 patients in the [99mTc]tilmanocept and fTcSC cohorts, respectively. The groups did not differ in demographic or clinicopathologic factors predictive of axillary metastatic disease (age, race, cancer stage, histologic subtype and grade, hormone and HER2-Neu status or presence of lymphovascular invasion). The [99mTc]tilmanocept group had significantly fewer SLNs removed (mean 1.9 vs. 3.9, p<0.001), achieved higher gamma counts/node (28 vs. 1.6 kcps, p<0.001), and detected a significantly higher percent of tumor-positive SLNs (73% vs. 49%, p=0.016) while identifying the same rate of node-positive patients (24% vs. 18%, p=0.4). Conclusions: [99mTc]Tilmanocept identified the same rate of node positive patients and removed fewer SLNs compared to fTcSC among BCP with similar risk of axillary metastatic disease. These data suggest that [99mTc]tilmanocept more precisely targets true SLNs and may minimize morbidity while maintaining or improving the accuracy of axillary staging in clinically node-negative breast cancer patients.
Cosmetic outcome after intraoperative radiotherapy or external beam radiotherapy for early breast cancer: An objective assessment of patients from a randomized controlled trial.
Authors: Keshtgar Mohammed R. , Williams Norman R. , Corica Tammy , Bulsara Max , Saunders Christobel , Flyger Henrik , Bentzon Neils , Cardoso Jaime S. , Michalopoulos Nikolaus , Joseph David John 
Published: March 2020

1110 Background: The international randomised contolled TARGeted Intraoperative radioTherapy (TARGIT) trial has demonstrated non-inferiority between the novel technique of TARGIT (intra-operative radiotherapy with Intrabeam) and conventional whole-breast external beam radiotherapy (EBRT) in women with early breast cancer, in terms of the primary outcome measure of risk of local relapse within the treated breast. With very low recurrence rates, cosmesis becomes an increasingly important outcome of breast conserving treatment with both surgery and radiotherapy. This study was performed to determine if the single high dose of TARGIT leads to impaired cosmesis. Methods: A validated, objective assessment tool for evaluation of cosmetic outcome was used. Frontal digital photographs were taken at baseline (before TARGIT or EBRT) and yearly thereafter for up to five years. The photographs were analysed by BCCT.core software which produces a composite score based on symmetry, colour and scar. Results: 342 patients were assessed, all over 50 years old with a median age at baseline of 64 years (IQR 59 to 68). The scores were dichotomised into Excellent and Good (EG), and Fair and Poor (FP). There were statistically significant increases in the odds of having an outcome of EG for patients in the TARGIT group relative to the EBRT group at year 1 (OR = 2.07, 95%CI 1.12 to 3.85, p = 0.021) and year 2 (OR = 2.11, 95%CI 1.0 to 4.45, p = 0.05). Conclusions: Following an objective assessment of aesthetic outcome in patients from a randomised setting, this study demonstrates that those treated with targeted intraoperative radiotherapy have a superior cosmetic result compared with those patients who received conventional whole-breast external beam radiotherapy.