tbuckley/cabot-search huggingface dataset:
A multi-histology basket trial of ado-trastuzumab emtansine in patients with <i>HER2</i> amplified cancers.
Authors: Bob T. Li, Vicky Makker, Darren J. Buonocore, Michael David Offin, Zachary T. Olah, Elizabeth Panora, Ronglai Shen, Alan Loh Ho, Rona Yaeger, Gopa Iyer, Michelle S. Ginsberg, Gary Ulaner, David B. Solit, David Michael Hyman, Charles M. Rudin, Michael F. Berger, Jose Baselga, Maurizio Scaltriti, Maria E. Arcila, Mark G. Kris
Journal: Journal of Clinical Oncology (2018)

2502 Background: Human epidermal growth factor receptor 2 (HER2, ERBB2) amplification occurs in 2-5% of non-breast non-gastric cancers. Ado-trastuzumab emtansine is a HER2 targeted antibody drug conjugate that may have activity against a variety of cancers driven by HER2 amplification. Methods: Patients with HER2 amplified cancers were enrolled into a multi-histology basket trial of ado-trastuzumab emtansine, treated at 3.6mg/kg IV every 3 weeks. The primary endpoint was overall response rate (ORR) using RECIST v1.1 or PERCIST. A Simon two stage optimal design was applied to each histology cohort with type I error rate under 2.7%, power of 89%, H0 10%, H1 40%. Other endpoints include duration of response (DOR), progression-free survival (PFS) and toxicity. HER2 amplification was identified by next generation sequencing (NGS), and tumors with adequate tissue were subsequently tested by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Results: 58 patients were treated across 8 cohorts of advanced lung, endometrial, salivary gland, biliary tract, ovarian, bladder, colorectal and other cancers. The median age was 63 (range 34-90 years), 72% were female. The median lines of prior systemic therapy was 2 (range 1-7). ORR was 26% (14/53 confirmed, 95% CI 15-40%), including 50% (3/6) for lung cancers, 22% (4/18, 2 CR) for endometrial cancers, 100% (5/5, 3 CR) for salivary cancers, 17% (1/6) for biliary cancers, 17% (1/6) for ovarian cancers, not including partial responses awaiting confirmation. Median DOR was 6 months (range 2-22+), median PFS was 3 months (95% CI 2-6). There was 1 (2%) grade 3 febrile neutropenia, but no treatment related deaths. The degree of HER2 amplification (NGS fold change 1.7 to 27.9) did not predict response. HER2 amplification by NGS correlated well with HER2/CEP17≥2 by FISH (40/41 tested) or IHC3+ (31/40 tested), and tumor shrinkage was seen in 2 patients who were tested IHC negative. Conclusions: Ado-trastuzumab emtansine showed efficacy in patients with HER2 amplified lung, endometrial, salivary gland, biliary tract and ovarian cancers as identified by NGS. This study has met its primary endpoint. Further development is warranted. Clinical trial information: NCT02675829.
Molecular classification of neuroendocrine tumors: Clinical experience with the 92-gene assay in &gt;24,000 cases.
Authors: Andrew Eugene Hendifar, Harris S Soifer, Mason Israel, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2017)

e15700 Background: Histological diagnosis of metastatic neuroendocrine tumors (NET) can be straightforward, but identification of the specific NET tumor type/subtype is often challenging based on morphology alone. Accurate identification of tumor type/subtype in NETs of unknown primary has implications for grading, staging, and treatment decision-making as availability of targeted therapies increases. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor type/subtypes (including 7 NET subtypes) for patients with unknown/uncertain diagnoses. In this study, 92-gene assay results from cases submitted for clinical testing with molecular diagnoses of NET were evaluated. Methods: A de-identified database was created under an IRB approved protocol that contains clinical and molecular information from consecutive cases submitted for clinical testing with the 92-gene assay with sufficient tissue for testing. In this analysis, patient demographics and distribution of molecular diagnoses were analyzed based on biopsy site, age, and gender. Chi-squared tests were used to compare between subgroups. Results: Analysis included 24,484 patients. Median age was 65y (51% female). The 92-gene assay rendered a molecular diagnosis of NET in 6.3% of cases (n = 1551). Small/large cell lung carcinoma (50%) was the most common NET molecular diagnosis, followed by GI carcinoid (14%), islet cell (14%), Merkel cell (10%), and lung carcinoid (9%). In liver biopsies (39% of cases), all 7 NET subtypes were identified by the 92-gene assay. The proportion of molecular diagnoses classified as small/large cell lung NET increased with age, from 25% in &lt; 40y to 45% in 40-65y and 55% in &gt; 65y, and the proportion of islet cell NET decreased with age (p &lt; 0.0001). Men had a higher proportion of molecular diagnoses that were small/large cell lung NET (53%) vs women (46%; p &lt; 0.0001). Conclusions: These findings highlight the utility of molecular classification to identify distinct NET tumor types/subtypes to improve diagnostic precision and treatment decision-making. In addition, significant differences in the distribution of molecular diagnoses of NET subtype by age and gender were identified.
Association of activation levels of TIE2 with response to the angiogenesis inhibitor trebananib in HER2+ patients in the I-SPY 2 trial.
Authors: Rosa Isela Gallagher, Julia Dianne Wulfkuhle, Christina Yau, Denise M Wolf, Lamorna Brown Swigart, Gillian L. Hirst, Laura Esserman, Donald A. Berry, Laura van 't Veer, Emanuel Petricoin
Journal: Journal of Clinical Oncology (2018)

12103 Background: Trebananib (T), an angiopoietin 1/2 neutralizing peptibody that inhibits interaction with TIE2 receptors, was available to all HR/HER2 subtypes in the I-SPY2 TRIAL. The agent did not achieve the prescribed graduation threshold for any eligible signatures prior to accrual of maximum sample size. We postulated that response to a drug that blocks TIE2 receptor-ligand interaction could be predicted by the measurement of basal TIE2 phosphorylation and downstream signaling in the pre-treatment biopsies. Methods: Of 267 patients in the T and control arms, 203 patients (T: 128, controls: 73) had reverse phase protein microarray (RPPA) and pCR data available. RPPA data for 33 (phospho- and total) proteins involved in TIE2 signaling were evaluated for association between biomarker and response in the T and control arms alone (likelihood ratio test), and relative performance between arms (biomarker x treatment interaction) using a logistic model (LM). Analysis was also performed adjusting for HR/HER2 status. Markers were analyzed individually; p-values are descriptive and were not corrected for multiple comparisons. Results: In the TN subpopulation, TIE2 receptor levels (p = 0.037), ERBB3 (p = 0.048), total ERα (p = 0.05) and ERα S118 (p = 0.016) were negatively associated with response to T. In HER2+ patients, phospho-TIE2 Y1119 (p = 0.001) and Y992 (p = 0.0007) were positively associated with T response, as were downstream AKT-mTOR signaling activation proteins such as eIF4G S1108 (p = 0.005), p70S6K T389 (p = 0.011) and T412 (p = 0.038) and FOXO3a S253 (p = 0.041). ERBB2 Y877 (p = 0.028) was negatively associated with response in these patients. TIE2 Y1119, TIE2 Y992, eIF4G S1108, ERBB2 Y877, and FOXO3a S253 all demonstrated a significant treatment interaction by LM. Conclusions: While small sample sizes preclude drawing definitive conclusions, our results suggest that activation levels of the TIE2 receptor may be predictive of T efficacy in HER2+ patients and signaling activation downstream of TIE2 such as AKT-mTOR signaling may correlate with response in the HER2+ and TN populations. These results need to be independently validated to determine the significance of these findings. Clinical trial information: NCT01042379.
Abstract 15522: New DEStiny Revealed: A Young Women Post Ablation for WPW Syndrome With Recurrent Syncope and Progressive Myopathy
Authors: Gregory Aubert, Senda Ajroud-Driss, Lisa M Castillo, Janice Caliendo, Bradley P Knight, Sanjiv J Shah, Elizabeth M McNally
Journal: Circulation (2017)

A 25-year-old woman was initially evaluated three months after catheter ablation for Wolf-Parkinson-White (WPW) syndrome at an outside hospital. During that procedure a right posteroseptal accessor...
TCT-735 Clinical Utility of Combined Optical Coherence Tomography and Near-Infrared Spectroscopy for Assessing the Mechanism of Very Late Stent Thrombosis
Authors: Yasushi Ino, Takashi Kubo, Kunihiro Shimamura, Masahiro Takahata, Yoshiki Matsuo, Hironori Kitabata, Yasutsugu Shiono, Kosei Terada, Atsushi Tanaka, Takeshi Hozumi, Takashi Akasaka
Journal: Journal of the American College of Cardiology (2018)
Abstract 13183: A Novel Model of in vivo Platelet Thrombus Imaging Using CD41-ZsGreen1 Transgenic Rats
Authors: Makoto Mizuno, Atsuyuki Tomizawa, Kousaku Ohno, Joseph A. Jakubowski, Atsuhiro Sugidachi
Journal: Circulation (2015)

Introduction: Platelets play important roles in both hemostasis and thrombotic diseases including myocardial and cerebral infarction, and stent thrombosis. While mice models of in vivo fluorescence imaging have been described, there are few suitable in vivo models for platelet imaging in rats which are commonly used as thrombosis models. The objective of this study was to generate fluorescent platelets and assess their dynamics in injured arteries in rats. Methods: We generated CD41-ZsGreen1 transgenic (TG) rats, in which the green fluorescence protein ZsGreen1 was expressed specifically in megakaryocytes and thus platelets, and evaluated platelet dynamics in in vivo thrombus imaging experiments. Hematological, including platelet aggregation and blood clotting time, and biochemical parameters were analysed. In the imaging experiments, saphenous arteries of TG rats were injured with 10% FeCl 3 , and thrombus formation was evaluated as fluorescence accumulation using confocal microscopy. The effect of prasugrel, a thienopyridine ADP receptor antagonist, on thrombus formation was also evaluated. Results: The CD41-ZsGreen1 TG rats exhibited normal hematological and biochemical values with the exception of body weight and erythroid parameters, which were significantly lower than those in wild type (WT) rats. Platelet aggregation, induced by 20 μM ADP or 10 μg/mL collagen, and blood clotting times (APTT and PT) were not significantly different between TG and WT rats. In thrombus formation experiments, FeCl 3 application caused a time-dependent increase in fluorescence intensity in the injured artery in vehicle-treated rats. Prasugrel at an oral dose of 3 mg/kg, treated 2 h before the FeCl 3 application, significantly inhibited fluorescence accumulation compared to the vehicle-treatment group (14.9±2.4 vs 5.4±0.4 arbitrary fluorescence unit at 30 min for vehicle and prasugrel groups, respectively, n=8, p=0.0037). Conclusions: CD41-ZsGreen1 TG rats represent a useful animal for the in vivo imaging of platelet participation in thrombus formation and the evaluation of antithrombotic agents.
Association of loss of adaptive PD-L1 expression with upregulation of PBRM1 chromatin regulator in melanoma.
Authors: Daniel Sanghoon Shin, Chen Cheng, Nhat Truong, Mykola Onyshchenko, Gabriel Abril-Rodriguez, Catherine Grasso, Begonya Comin-Anduix, Sk Kurdistani, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

12012 Background: Primary resistance to anti-PD-1 through genetic mechanisms is rare and may be mediated by loss-of-function (LoF) mutations in JAK1/2 or antigen presentation. 3 out of 48 human melanoma cell lines with complete loss of adaptive PD-L1 expression upon interferon (IFN)-γ exposure, two harbored LoF mutations in JAK1/2. The third had intact IFN-γ signaling pathway without LoF mutations. We therefore sought to determine whether an epigenetic mechanism that may result in loss of adaptive PD-L1 expression in this cell line might be an underlying cause of primary resistance in some patients. Methods: Human melanoma cell lines that represent good, poorly and non-responding to IFN-γ were analyzed by flow cytometry, gene expression, ChIP-seq and ATAC-seq upon IFN-γ exposure. Results: The M412b human melanoma cell line showed no PD-L1 expression in response to IFN-γ exposure despite increased expression of IRF-1, STAT1 and STAT-3. ChIP-seq analysis for IRF-1 in M412B cell line showed no significant enrichment at the PD-L1 promoter compared to three others. ATAC-seq in M412b showed little signal at the PD-L1 promoter, suggesting that M412b cell line lost adaptive PD-L1 expression due to a promoter inaccessible to transcription factors. Peng et al (Science, 2018) demonstrated that the PBAF form of the SWI/SNF chromatin remodeling complex is associated with resistance to checkpoint blockade immunotherapy in the B16 murine melanoma model. Miao et al (Science, 2018) reported increased response to checkpoint blockade immunotherapy when patients with advanced renal cell carcinoma harbored LoF mutations in the PBRM1 gene. Consistently, M412b cell line displayed the highest PBRM1 and ARID2 expression among 48 human melanoma cell lines, suggesting that constitutive high expression of this chromatin remodeling complex may prevent access to PD-L1 promoter by transcription factors that would otherwise activate the gene in response to IFN-γ signaling. We are now testing this model. Conclusions: Lack of adaptive PD-L1 expression upon IFN-γ is associated with increased expression of the PBAF chromatin remodeling complex, which may be an epigenetic mechanism of primary or acquired resistance to anti-PD-1 therapy.
Evaluation of feasibility of preoperative concurrent chemoradiotherapy in locally advanced operable oral cancer and resection and reconstruction of mandibular/maxillary segment with prefabricated free fibular graft.
Authors: Sanjay P Deshmukh
Journal: Journal of Clinical Oncology (2017)

e17558 Background: Every year more than 500,000 patients are diagnosed with oral cancer worldwide and majority require surgery and radiotherapy as a definitive curative treatment. Loss of bony segment of mandibular/maxillary bone with resultant loss of shape, function and ability to chew the food is known. Neoadjuvant chemoradiotherapy is known to have improved disease outcomes in many solid tumours. Methods: Total Seven patients underwent the planned protocol of 100 days. All patients were male and median age was 46 years. Six patients had disease involving lower alveolus and one had upper alveolus. All had no palpable nodes clinically. Step 1 a. Neoadjuvant treatment of Radiotherapy to Primary disease and draining lymph nodes dose of 45 to 50 Gy in 25 fractions over 5 weeks along with concurrent weekly Cisplatin 40mg/m2 for 5 cycles b. Mock surgery on 3D models with defining of insertion site of implants on fibular segment. Step 2 Insertion of dental implants in fibula and split skin graft in the desired fibular site in second week of radiotherapy. Step 3 Definitive surgery 6 weeks after completion of chemoradiotherapy and reconstruction by free fibular segment with primary dental prosthesis checking occlusion of oral bite. Results: Six patients(85.7%) are alive and free of disease at median follow up of 6.7 months. Three(42.8%) patients underwent prosthetic placement with acceptable outcome. Two patients had trismus and undergoing oral physiotherapy. Six patients had orocutaneous fistula. One had extrusion of fibular graft and one patient died. Five(71.4%) patients had complete response on final histopathology report and two had partial response. Conclusions: : A novel technique for better functional and aesthetic results with possible improved survival in operable oral cancer. Future randomized studies are needed for validation.
Weight change in postmenopausal breast cancer survivors: Independent effects of adjuvant tamoxifen and aromatase inhibitors.
Authors: Kirsten A. Nyrop, Allison Mary Deal, Hyman B. Muss, Jordan T Lee, Samara Ann Dixon, Shlomit Strulov Shachar
Journal: Journal of Clinical Oncology (2016)

e21581 Background: We investigated weight change in postmenopausal Stage I-III breast cancer (BC) survivors on adjuvant endocrine treatment (ET) -- tamoxifen or aromatase inhibitors (AI) [anastrozole, exemestane, letrozole]. Clinical focus on > 2kg (4.7lbs) weight change within first 2 years of ET. Methods: Retrospective chart review. Weight measures taken during routine clinic visits. Fisher’s exact tests and ANOVA were used to compare patient characteristics between weight change groups. Results: Sample N = 212; 75% Caucasian, mean age 66 (8.4). Stage I: 51%, Stage 2: 38%, Stage III: 11%. Body Mass Index (BMI) at diagnosis 29.6 (6.4). 42% chemotherapy, 64% radiation. ET: 10% tamoxifen only, 45% anastrozole only, 16% letrozole only, 2% exemestane only, 15% more than one AI; 12% both tamoxifen and AI. Comorbidities: 0-1 32%, 2-3 48%, > 4 20%. Weight gain > 2kg was associated with higher BC stage (p = 0.01) and chemotherapy (p = 0.006). Both > 2kg weight loss and > 2kg weight gain were associated with higher baseline BMI (p = 0.005) and greater number of baseline comorbidities (p = 0.02). No significant association between weight change and race, radiation, or ET type. (Table 1) Conclusions: In our sample, 27% had clinically significant weight loss and 37% weight gain within first 2 years of ET. We found no significant differences in weight change by type of ET. The first 2 years of ET present an opportunity to educate BC survivors about the importance of weight management for overall wellness, prognosis and survival. Sample N = 212. > 2kg weight loss Stable weight > 2kg weight gain Year 1 23% 49% 28% Year 2 27% 36 % 37% Age at start of ET 66.8 (8.7) 66.6 (8.5) 64.0 (7.8) Race – Caucasian 25% 37% 38% BMI at diagnosis ** 31.1 (7.1) 27.7 (6.5) 30.3 (5.3) Comorbidities * 2.6 (1.6) 1.9 (1.5) 2.5 (1.6) Stage ** Stage I 35% 30% 35% Stage II 22% 44% 35% Stage III 9% 27% 64% Chemotherapy ** No 33% 38% 29% Yes 18% 33% 49% Radiation No 28% 33% 39% Yes 26.5% 37.5% 36% Endocrine Treatment Tamoxifen 28% 48% 24% Anastrozole 34% 31% 35% Letrozole 14% 40% 46% Exemestane 20% 20% 60% More than one AI 16% 36% 48% Tamoxifen and AI 32% 40% 28% *p ≤ 0.05 **p ≤ 0.01
TCT-346 Primary PCI in STEMI with sirolimus eluting FANTOM bioresorbable vascular scaffold first guided with optical coherence tomography– acute results from a FANTOM STEMI pilot study.
Authors: Lukasz Koltowski, Mariusz Tomaniak, Jakub Maksym, Martyna Zaleska, None Zenon huczek, Arkadiusz Pietrasik, Adam Rdzanek, Tomasz Mazurek, Ewa Pędzich-Placha, Grzegorz Opolski, Janusz Kochman
Journal: Journal of the American College of Cardiology (2018)
Targeted gene sequencing panel for identifying actionable genomic alterations in Taiwanese lung cancer patients.
Authors: Yen-Jung Lu, Kien Thiam Tan, Chun-Jung Chen, Ren-Shiang Jhou, Yi-Ting Yang, Chien-Hung Chen, Hua-Chien Chen, Shu-Jen Chen, David T. Chung
Journal: Journal of Clinical Oncology (2017)

e20522 Background: Lung cancer boasts an arsenal of targeted therapies directed at various molecular aberrations such as EGFR mutations and fusion genes. Simultaneous assessment for genetic alterations provides biomarkers to assist clinicians in their treatment selections. Methods: A total of 43 FFPE (formalin-fixed, paraffin-embedded) samples obtained from lung cancer patients in Taiwan were subjected to next-generation sequencing (NGS), using a compact panel encompassing 17 potentially actionable, lung cancer-associated genes. NGS was performed on the Ion Torrent PGM or Proton System with a targeted average depth of &gt; 800x. Genomic alterations detected were categorized as single nucleotide variants (SNV) or chromosomal copy number alterations (CNA). Results: A total of 74 putatively actionable genomic alterations were detected across 38 patients (88.4%), which may predict sensitivity or resistance to established and/or therapies that are still in clinical development. 19 patients (44.2%) had tumors harboring activating EGFR mutations in the tyrosine kinase (TK) domain – L858R substitution or exon 19 deletion, which may suggest clinical benefit to first- and second-generation EGFR TK inhibitors (TKIs). Three patients (7.0%) whose tumor had acquired the EGFR T790M mutation were advised to switch to third-generation EGFR TKI. Possible resistance mechanisms to EGFR TKIs via increased copy number of EGFR (14.0%, n = 6) and MET (11.6%, n = 5) were observed. Deletion or loss of CDKN2A gene were detected in 14 patients (32.6%), which may confer sensitivity to CDK4/6 inhibitors. Inhibition of downstream effectors in the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways were suggested for patients whose tumor harbored PIK3CA and/or KRAS oncogenic mutations. Conclusions: Next-generation sequencing using a compact panel of genes may be sufficient to identify biomarkers for targeted therapies selection for most lung cancer patients in Taiwan.
Early detection of lung-cancer in a community screening program using low-dose computer tomographic scanning.
Authors: Wesley Garner, John Esther, J. Thaddeus Beck, Eric Scott Schaefer, Gregory James Oakhill, Daniel S. Bradford, Joanna Thompson
Journal: Journal of Clinical Oncology (2016)

8535 Background: Lung cancer’s high mortality rate and often advanced staging at diagnosis has motivated the field of medicine to devise an appropriate screening tool to help combat its aggressive nature. The landmark National Lung Screening Trial (NLST) found using Low-Dose CT (LDCT) as a screening tool reduces mortality in lung cancer patients (N Engl J Med 2011;365:395-409). Northwest Arkansas’s Lung Cancer Screening Program (LCSP) initiated LDCT screenings based on the findings of the NLST. Methods: From March of 2013 to January 2016, the LCSP screened 1,791 individuals. Their primary care physicians referred patients to the program. If they met certain high-risk criteria they underwent LDCT and multidisciplinary evaluation. High-risk category 1 (CAT1) were at least 55 years old, had at least a 30 pack-year smoking history. If they had quit smoking, it was within the last 15 years. High risk category 2 (CAT2) patients were greater than 50 years old with a more than 20 pack-year smoking history and one of the following risk factors: second hand smoke exposure, radon exposure, occupational exposure, cancer history, family history of lung cancer, or lung disease history, and not in CAT1. Results: The adherence rate of screening was above 99%. Of 1,791 participants screened, cancers were diagnosed in 46 patients, 2 of which had 2 cancers. There were 25 patients who had stage Ia non-small cell lung cancer (NSCLC). CAT1 patients comprised the majority of the cancer diagnoses finding 46 cancers in 44 patients while only 2 cancers were diagnosed in CAT2 patients. Of these 48 cancers, 11 were cancers other than NSCLCs. Overall, stage Ia cancers comprised 67.6% of the NSCLCs diagnosed (37 NSCLC total). The NSCLC incidence rate along with similar data from the NLST can be seen in table 1. Conclusions: Screening with LDCT resulted in earlier detection of lung cancer at diagnosis and the LCSP provides a template for screening in a community setting using a multidisciplinary approach. Incidence rates in the LCSP exceeded the NLST for CAT 1 patients. CAT2 had a low rate of positive screening. Incidence rate for lung cancer detection (per 100,000 person-years). LCSP NLST (using LDCT) Overall 730 645 CAT1 914 645 CAT2 89 N/A