bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-treatment hematological markers as a predictive biomarker for survival in patients with non-small cell lung cancer treated with nivolumab.
Authors: Patil Pradnya Dinkar , Khunger Monica , Rakshit Sagar , Stevenson James , Pennell Nathan A. , Elson Paul , Velcheti Vamsidhar 
Published: September 2018

11547 Background: The absolute neutrophil count (ANC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, AMC and NLR are prognostic for overall survival (OS) and evaluated change in NLR as a predictive marker of response per RECIST in non -small cell lung cancer (NSCLC) patients treated with nivolumab. Methods: A total of 115 patients with NSCLC treated with nivolumab were included. ANC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, AMC and NLR on OS and changes in NLR ratio in responders was assessed using Cox regression model. Results: ANC > 6, AMC > 0.5 and NLR > 2.8 at baseline were independently associated with shorter OS (Hazard ratio (HR) 1.17 (1.08-1.27), p = .00001; HR 4.53 (1.99-10.31), p = 0.04 and HR 1.09 (1.04-1.13), p = 0.0002 . Responders had a decrease in NLR by (median (range) -0.93 (-14.7-52.95), p = 0.03) whereas non-responders had an increase in NLR by (median (range) 0.85 (-8.6-132.9), p = 0.03). Conclusions: ANC, AMC andNLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response with nivolumab in NSCLC patients. [Table: see text]
Cerebrospinal fluid circulating tumor cells (CSF CTC) for real-time patient monitoring and response to treatment.
Authors: Malani Rachna , Fleisher Martin , Lin Xuling , Omuro Antonio Marcilio Padula , Groves Morris D. , Lin Nancy U. , Melisko Michelle E. , Lassman Andrew B. , Jeyapalan Suriya A. , Briggs Samuel , DeAngelis Lisa Marie , Raizer Jeffrey J. , Pentsova Elena ,   ASCO Authors
Published: September 2018

11549 Background: The validated CellSearch system (Janssen Diagnostics, LLC), utilizing an immunomagnetic CTC selection method based on EPCAM antibody conjugated ferroparticles, is an FDA-approved methodology for enumerating CTC from blood in pts with breast, prostate and colon cancers. The CellSearch system has been used to evaluate CSF CTC of pts with leptomeningeal metastasis (LM) and has demonstrated potential as a diagnostic marker and response to cancer treatment. We explored the use of CSF CTC enumeration in the follow-up of pts with LM from HER2+ cancers receiving intrathecal (IT) therapy, aimed at characterizing changes over time as a potential biomarker of treatment response. Methods: CSF from pts participating in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was evaluated by CellSearch system. 3 ml CSF from a ventricular reservoir was collected for CSF CTC enumeration at pre-treatment Day 1 of each cycle and correlated with CSF cytology from the same sample, and with clinical and radiographic response. LM progression was defined as clinical, CSF cytologic or radiographic worsening. Results: 15 pts with HER2+ LM (14 breast, 1 colon) were enrolled; 13 were women. At baseline 7 pts had positive CSF cytology, the other patients had a diagnosis by MRI. Of the 15 pts, 10 had greater than 1 cycle of treatment to be evaluable; 5 pts progressed during cycle 1 (Table). Mean CSF CTC at baseline was 82 per 3ml (range 0-200); 2 pts had no detectable CSF CTCs. A numerical decrease in CSF CTC was observed in 5 pts after cycle 1 and remained low (mean =9.5, range 0-92) while disease was stable. 3 pts (pts.3, 4 and 7) demonstrated a rise in CSF CTCs roughly 1 month prior to disease progression. Conclusions: Changes in CSF CTCs enumeration in response to treatment may allow quantitative surveillance of treatment response. CSF CTCs may serve as a platform to assess treatment response or as an early biomarker of LM progression and should be further investigated. Clinical trial information: NCT01325207. [Table: see text]
Tumor kinetic modeling and identification of predictive factors for tumor response to durvalumab in patients with non-small cell lung cancer (NSCLC).
Authors: Zheng Yanan , Narwal Rajesh , Jin Chaoyu , Wang Bing , Jin Xiaoping , Mukhopadhyay Pralay , Higgs Brandon W. , Gupta Ashok Kumar , Dennis Phillip A. , Roskos Lorin 
Published: September 2018

11555 Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objectives of this analysis were to describe the longitudinal tumor size profiles and identify the key factors predicting tumor growth and regression following durvalumab. Methods: Longitudinal tumor size data obtained from NSCLC patients in study 1108 (all lines of therapy) and ATLANTIC (third line and beyond) following durvalumab treatment were modeled using nonlinear mixed effect modeling. Tumor kinetics were described by four key parameters: tumor growth and killing rate constants, fraction of durvalumab-sensitive tumor cells, and delay time for tumor killing. Potential predictive factors for tumor growth and regression were evaluated in a multi-variable covariate analysis. The model was used to simulate response rates at different tumor PD-L1 expression cutoffs. Results: Tumor kinetic modeling accurately described the longitudinal tumor response profiles from NSCLC patients in both studies. The factors associated with more rapid tumor growth were liver metastases, ECOG score > 0, high neutrophil-to-lymphocyte ratio and EGFR/ALK mutation. Tumor cell PD-L1 expression, baseline tumor size and smoking history were identified as significant predictive factors for tumor killing or the fraction of sensitive tumor cells. Simulations using the tumor kinetic model showed increased response rates in patients with higher tumor cell PD-L1 expression (increased by 9-11% and 10-14% with 25% and 50% cutoff, respectively), patients receiving durvalumab as first-line therapy (increased by 12% vs. 2nd line/above), and patients with smoking histories (increased by 4-5% vs. non-smokers). Conclusions: Tumor kinetic modeling identified factors that predict tumor progression and response following durvalumab in NSCLC patients. The multivariate analysis accounts for various predictive factors within predictive biomarker strata, allowing better interpretation of different biomarker cutoffs. The modeling technique can potentially guide patient selection/enrichment, clinical trial design strategies and tumor biology. Clinical trial information: NCT02087423 and NCT01693562.
Breast cancer-related paraneoplastic neurologic disease.
Authors: Murphy Brittany L. , Zalewski Nicholas L. , Degnim Amy C. , McKeon Andrew , Flanagan Eoin P , Pittock Sean J. , Habermann Elizabeth B. 
Published: September 2018

11559 Background: Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by occult malignancy. Given the rarity of this disease, a paucity of data exists describing breast cancer (BC)-related PND; thus, we sought to further examine this specific population of patients. Methods: Using an institution specific clinical search tool, we identified all patients at our institution from 1997-2016 with a diagnosis of BC-related PND, verified by an international expert. Retrospective review was used to record tumor and treatment factors associated with PND and BC. A descriptive analysis was performed of the characteristics associated with BC-related PND. Results: BC-related PND was diagnosed in 58 female patients. Average age at BC diagnosis was 54.0±10.3 years. Most had invasive cancer of Stage II or higher [Stage 0 (10.3%), I (10.3%), II (44.8%), III (13.8%), IV (6.9%), unknown (13.8%)]. Most patients were hormone receptor (HR)+ (63.8%), while 4 (6.9%) were HR-, and 17 (29.3%) were unknown. Of the 34 patients where Her2/neu (Her2) data was available, 7 (20.6%) were Her2+ and 27 (79.4%) were Her2-. The majority (62.1%) had neurological symptoms prior to BC, 5.2% were concurrent, and 32.7% developed PND after initial BC. The interquartile range for time from PND to BC diagnosis was -8.5 to 10.5 months. Of the 58 patients, 29 (50%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]) (10), amphiphysin-IgG (n = 9), Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]) (n = 5), and other (n = 5). The most common syndromes were cerebellar ataxia (n = 14), myelopathy (n = 11), and myopathy (n = 11). Immunotherapy was used for PND in 53 of 58 (91.4%) patients; benefit from immunotherapy was assessed as complete 0 (0%), robust 11 (20.8%), mild to moderate 28 (52.8%), none 9 (17%), and indeterminate 5 (9.4%). Conclusions: BC-related PND is rare, with only 58 cases over 20 years at a large academic institution. Paraneoplastic symptoms often present prior to BC diagnosis and BC characteristics are typical of the general population. Over 75% of patients benefit from immunotherapy. These data may provide helpful information to providers treating this population of patients.
Combining chemotherapy and programmed death 1 (PD-1) blockade to induce a T-cell response in patients with metastatic triple negative breast cancer (mTNBC).
Authors: Obeid Elias , Zhou Chun , Macfarlane Alexander , Alpaugh R. Katherine , McAleer Cecilia , Dulaimi Essel , Campbell Kerry , Goldstein Lori J. 
Published: September 2018

11563 Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.
Targeted next-generation DNA sequencing of paired tumor and normal DNA to reveal frequent actionable germline alterations.
Authors: Korn Wolfgang Michael , Yey Iwei , Van Ziffle Jessica , Grenert James P , Joseph Nancy , Solomon David A. , Laurance Megan , Talevich Eric , Onodera Courtney , Krings Gregor , Stohr Bradley A. , Blanco Amie , Bastian Boris C. 
Published: September 2018

11575 Background: Targeted next-generation DNA sequencing of paired tumor and normal DNA samples allows for detection of biologically relevant variants in the tumor with significantly greater accuracy than tumor-only sequencing. In addition, this approach presents with the opportunity of unveiling previously unknown cancer predisposition traits in a patient’s germline DNA. Methods: We sought to determine the rate of pathogenic germline alterations in 546 consecutive pediatric and adult patients who underwent molecular profiling using the UCSF 500 assay, a hybrid capture-based DNA sequencing assay targeting the coding regions of ~500 cancer-related genes, TERT promoter, select introns from 40 genes (for detection of gene fusions and other structural variants), and intergenic regions at regular intervals along each chromosome (for chromosomal copy number and LOH assessment). Results: Pathogenic germline alterations were found in 89/546 patients (16.3%), including 25 pediatric and 64 adult cases. Germline variants were identified in 37 genes with MUTYH (n = 15, 17%), CHEK2 (n = 10, 11%), BRCA2 (n = 9, 10%), BRCA1 (n = 5, 6%), TP53 (n = 5, 5%), and APC (n = 4, 5%) being altered most frequently. Loss of heterozygosity of genes affected in the germline was seen in tumor DNA 37 (42%) cases, highlighting their likely role as drivers of tumorigenesis. Clinically relevant germline findings not associated with increased cancer risk were identified in 6 (7%) of the cases, for example a COL1A1 mutation associated with Ehlers-Danlos Syndrome. In In 73 (82%) of the cases, pathogenic germline alterations were new findings and genetic counseling was recommended. A possible, previously unknown, role of germline mutations was found in some instances, including a TSC2 germline mutation in a patient with hybrid oncocytoma/chromophobe tumor (HOCT) with loss of the normal TSC2 allele in the tumor. Conclusions: Our data suggest that paired tumor/normal DNA analysis uncovers actionable heritable traits in a substantial fraction of patients and represents the preferred approach to analyzing malignancies in children and adults.
Clinicopathologic features of non-small cell lung cancer (NSCLC) harboring an NTRK gene fusion.
Authors: Farago Anna F. , Taylor Martin S , Doebele Robert Charles , Spira Alexander I. , Boyle Theresa A , Haura Eric B. , Azimi Roxana S. , Shaw Alice Tsang , Mino-Kenudson Mari , Drilon Alexander E. 
Published: September 2018

11580 Background: Gene fusions involving NTRK1/2/3 can generate oncoproteins containing the kinase domains of TRKA/B/C, respectively. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. An estimated 0.1 – 1% of NSCLCs harbor NTRK fusions. To date, clinical and radiographic responses to TRK inhibitors have been reported for 2 NTRK fusion-positive NSCLCs (Farago et al., 2015; Hong et al., 2016). Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion NSCLCs are not well characterized. Methods: Physicians across multiple institutions contributed deidentified cases to an NTRK fusion NSCLC database. A central pathologist (M.M.) reviewed tumor histology in cases with available tissue. Results: 10 NSCLC cases with NTRK gene fusions were identified. Of these, TRK kinase domain-containing potentially activating fusions were verified by next-generation sequencing (NGS) in 7, forming the study cohort. Fusions involved NTRK1 (6) and NTRK3 (1) with 6 different partners. Four (57%) patients were male. Median age at diagnosis was 47.6 years (range 27.9 – 86.0). The average smoking pack year history was 8.9 (range 0 to 30). Five (71%) presented with metastatic disease. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases. On pathologic review of 4 cases, all were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features. Of the 3 remaining non-study cohort cases, 1 was a non-kinase domain-containing NTRK1 fusion with a concurrent KRAS G12C mutation, 1 was an NTRK2 intragenic deletion disrupting the exon 18 3’ splice site, and 1 was an NTRK1 alteration detected by FISH but not verified by NGS and with a concurrent HER2 L755P mutation. Conclusions: NTRK fusions occur in both men and women across wide ranges in age and smoking history. We therefore suggest that all NSCLC adenocarcinomas without other oncogenic driver alterations be screened for NTRK fusions. Notably, not all NTRK alterations are activating, requiring validation of the specific position of the fusion.
Survival profile in breast cancer molecular subtypes without systemic and locoregional treatment.
Authors: Yang Sherry X. , Polley Eric 
Published: September 2018

11599 Background: It is unclear whether survival varies among breast cancer molecular subtypes without systemic and locoregional therapy. This study aims to evaluate the survival profile by molecular subtypes after surgery. Methods: In total, we evaluated 301 women with invasive breast cancer with stage I, II or III disease. Patients were classified into four major breast cancer subtypes by immunohistochemistry/FISH classifiers: luminal-A (ER+ and/or PR+/HER2-), luminal-B (ER+ and/or PR+/HER2+), HER2-enriched (HER2+/ER-/PR-) or basal-like (ER-/PR-/HER2-; triple-negative). Overall survival (OS) was analyzed by Kaplan-Meier analysis, and log-rank test for differences. Association between clinical outcome and subtype adjusting for breast cancer prognostic factors was assessed by multivariable Cox proportional hazards model. Results: All patients did not receive systemic chemotherapy and hormone therapy as well as radiation therapy. Luminal A was the most common subtype (N = 224), followed by basal-like (N = 43), luminal B (N = 21) and HER2-enriched (N = 13). Median follow-up for OS was 197 months (range: 1 – 273 months). Age at diagnosis was statistically different among the subtypes, with basal-like and luminal B having high proportions less than 50 years (P = 0.047). Patients with basal-like and HER2-enriched had more high grade tumors (P < 0.001). Notably, there was no difference in OS among the four subtypes (log-rank P = 0.983). In multivariable analysis, the adjusted hazard ratio (HR) was 1.1 for luminal A vs. luminal B (P = 0.781), 0.62 in luminal A vs. HER2-enriched (P = 0.273), or 0.67 in luminal A vs. basal-like (P = 0.158). In contrast, the adjusted HR were 2.2 in age less than 50 years (P = 0.0017), and 1.1 for number of positive nodes (P = 0.00074). Conclusions: OS, through long-term clinical follow-up, is not significantly different among molecular subtypes if not controlling for other prognostic factors in patients who only received surgery. Age and number of positive nodes are independent prognostic factors in patients with no systemic and locoregional treatments.
Effect of Wnt5a on aggressiveness of ER-positive breast cancer and cancer cell migration through JNK-ALCAM pathway.
Authors: Kobayashi Yoshie , Kadoya Takayuki , Amioka Ai , Gohda Noriko , Kono Miho , Sasada Shinsuke , Kajitani Keiko , Masumoto Norio , Okada Morihito 
Published: September 2018

11614 Background: Wnt5a is a representative ligand that activates β-catenin-independent pathways and involved in cell motility and cell polarity, and the like, being mediated by JNK. We elucidated the implication of Wnt5a expression in breast cancer. Methods: One hundred seventy eight breast cancer patients (mean age ± SD: 60.0 ± 13.2 years) with clinical Stage I-III between January 2011 and February 2014, were prospectively evaluated. We examined relationships between Wnt5a expression and clinicopathological factors by immunohistochemical analyses. 5-year relapse-free survival rates and sites of recurrence were analyzed. In addition, molecules induced by Wnt5a in cultured cells were identified by DNA microarray analysis. Results: Wnt5a expression was significantly more frequent when estrogen receptor (ER) was present, 68/153 (44%) than when ER was absent, 1/25 (4%) (P <0.001) (Table). In ER-positive breast cancer, a significant interaction between expression of Wnt5a with lymph node metastasis (P<0.001), high nuclear grade (P=0.004), and lymphatic invasion (P=0.001). 5-year relapse-free survival rates were 81.1% and 100% in Wnt5a-positive and Wnt5a-negative breast cancers, respectively (P = 0.024). All recurrent breast cancer patients in this study had bone metastasis. We established MCF7 stably expressing Wnt5a (Wnt5a/MCF7 cells) and microarray analyses identified several genes induced by Wnt5a (>3.0 fold), involving activated leukocyte cell adhesion molecule (ALCAM). ALCAM is known to be related with apoptosis, invasion and prognosis of breast cancer. We focused on ALCAM and investigated its protein expression by Western blotting, and found remarkable increase of ALCAM in Wnt5a/MCF7 cells. Conclusions: Wnt5a expresses in ER-positive breast cancer and is associated with high-grade malignancy and a poor prognosis through JNK-ALCAM pathway. Wnt5a could be a novel prognostic factor of ER-positive breast cancer. [Table: see text]
Microarray analysis to identifiy novel copy number alterations in acute myeloid leukemia.
Authors: Fontana Maria Chiara , Marconi Giovanni , Papayannidis Cristina , Fonzi Eugenio , Ottaviani Emanuela , Franchini Eugenia , Ferrari Anna , Simonetti Giorgia , Padella Antonella , Bruno Samantha , Testoni Nicoletta , Baldazzi Carmen , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Abbenante Maria Chiara , Paolini Stefania , Nanni Jacopo , Bertamini Luca , Martinelli Giovanni 
Published: September 2018

11622 Background: SNP microarray can detect Copy Number Alterations (CNAs) which could be predictive of response and can help define therapeutic strategies. Our aim is to improve conventional cytogenetic analysis and identify new genetic alterations relevant to leukemogenesis by a SNP array-based genotyping approach. Methods: We performed SNP 6.0/Cytoscan HD (Affymetrix) on 235 Acute Myeloid Leukemia (AML) patients at diagnosis. Seventy-eight/235 samples were also performed by Whole Exome Sequencing, WES (HiSeq,Illumina). SNP Array data were analyzed by Nexus Copy Number (BioDiscovery) and R Core Team. Results: We found several genes preferentially deleted, including MRPS5 (14.8%), PHF6 (9.3%), SCAPER (7.2%), CASK (5.9%), WNK (4.6%), STAG2 (4.2%), LRRK1 (3.4%), PALB2 (3.4%), genes preferentially amplified were RABL2B (16.1%), NF2 (10.2%), NBPF9 (7.6%), JAK2 (6.8%), RB1, NF1 and KMT2A (4.2%), PTEN (3.4%), TP73 and SMAD2 (2.5%). Single-copy losses and deletions were enriched (p < .001) for genes mapping in these pathways: aberrant PD-1 signaling, loss of function of SMAD4 in cancer and SMAD4 MH2 Domain mutants in cancer. The pathways significantly (p < .001) deregulated in our cohort with single copy gain and homozygous amplification were: regulation of transcription and nucleic acid, negative regulation of metabolic processes, constitutive signaling by aberrant PI3K in cancer and PI3K/AKT network. In order to define driver alterations, we correlate deletions and losses with mutational data. We found losses are also targeted by mutations ( BRCA2, LRRK1), while deleted genes, as CASK, CDK6 and MAPT, were involved in pathways affected by genomic mutations ( CASK deletion and MPP6 mutation, CDK6 deletion and PPM1D mutation, MAPT deletion and SPAG5mutation). Conclusions: We have identified new CNAs and pathways involving novel potential leukemia-related genes. The comparison between SNP and WES data could provide important findings on prognosis of AML patients. Minimal deleted regions of genes in deregulated pathways deserve further investigation in order to identify new genes which could be relevant AML biomarkers. Ackn: ELN, AIL, AIRC,prog. Regione-Università 2010-12 (L. Bolondi),FP7 NGS-PTL project,HARMONY.