tbuckley/cabot-search huggingface dataset:
Clinical validation and utility of a liquid biopsy for non-small cell lung carcinoma utilizing CTCs and ctDNA to analyze ALK, ROS and EGFR status.
Authors: Veena M. Singh, Vassilios Alexiadis, Tim Watanaskul, Edgar Salas, Lan Huynh, Christine Mitchell, Romeo Fauni, Lyudmila Bazhenova, Lyle Arnold
Journal: Journal of Clinical Oncology (2015)

e19086 Background: A liquid biopsy in addition to clinical utility in a setting of insufficient tissue biopsy and offering better representation of all regions of a tumor to offset tumoral heterogeneity seen in a tissue biopsy, affords a real-time monitoring option to assess biomarker status in patients with non-small cell lung carcinoma. Methods: Biocept, Inc has two key technologies that harness the maximum benefit of a liquid biopsy utilizing both CTCs and ctDNA for biomarker analysis in NSCLC patients in a CLIA laboratory setting. Using a unique microchannel device, CTCs are enriched more than 20,000 fold, stained, enumerated and analyzed for biomarkers using Immunocytochemistry and FISH. After the capture and enumeration of CTCs , ALK and ROS1 gene rearrangements in tumor cells are analyzed using FISH. Additionally, a highly sensitive ctDNA assay, Target-Selector is employed, capable of detecting as low as a single mutant copy in a vast excess of normal sequences. The analytical performance of a T790M Target-Selector assay, has been demonstrated to detect mutant level as low as 1:40,000 relative to normal wild-type copies. Results: Concordance rates of 80-100 % were observed between the tissue and liquid biopsy. In one clinical case, a lung tumor tissue biopsy at presentation was T790M negative, and subsequent testing of the patient’s plasma after clinical progression detected an emergent T790M mutation by utilization of the Target-Selector assay analyzing ctDNA. A significant percentage of T790M mutated sequences were found. After a re-biopsy, the patient was confirmed to be T790M positive and has been entered into the Clovis CO1686 trial. Conclusions: Liquid Biopsy holds great potential and value to supplement standard solid tumor biopsies and for subsequent serial monitoring of biomarker status after therapy and/or clinical progression.
Survival analysis of yttrium-90 radioembolization for unresectable intrahepatic cholangiocarcinoma.
Authors: Alexandra Gangi, Jehan Shah, Ravi Shridhar, Ambuj Kumar, Sarah E. Hoffe, Junsung Choi, Jessica M. Frakes, Gregory M. Springett, Ghassan El-Haddad, Daniel A. Anaya, Jennifer Sweeney, Benjamin Biebel, Mokenge Peter Malafa, Richard D. Kim, Bela Kis
Journal: Journal of Clinical Oncology (2017)

383 Background: Intrahepatic cholangiocarcinoma (ICC) is a rapidly progressing malignancy that frequently presents at an advanced stage and is often chemorefractory. The median overall survival (OS) with best medical treatment is approximately 12 months. The current study examines survival and characterizes predictors of mortality for ICC patients treated with transarterial yttrium-90 radioembolization (TARE). Methods: All patients with unresectable ICC who underwent TARE between May 2009 and May 2016 at a single institution were included and clinicopathologic variables reviewed. Primary endpoint was OS from time of TARE. Secondary endpoints included OS from time of diagnosis, post procedure toxicities and predictors of mortality. Results: A total of 134 TARE were performed on 85 patients. Average age at treatment was 73.4 ± 9.3 years and most patients were female (52%). More than one third of patients had an ECOG of 2 and had no significant post procedure sequalae. Thirty-six patients (42%) had extrahepatic disease at time of treatment and 61 patients (72%) were treated with systemic chemotherapy prior to TARE. A majority of patients (92.9%) received treatment to one lobe with an average radiation dose of 180.1±127.1 Gy. The median OS from time of the first TARE was 12 months (95% CI 7.8–16.1). The median OS from time of diagnosis was 21.4 months (95% CI 14.9-27.8). 51.8% and 26% of treated patients were still alive at 1 and 3 years, respectively. On univariate analysis, age at treatment, ECOG score, presence of extrahepatic disease, baseline albumin, alkaline phosphatase and AST correlated with OS. On multivariate analysis only low ECOG score and higher baseline albumin predicted improved OS (p &lt; 0.01). Conclusions: Y90 radioembolization demonstrates a survival benefit for patients with unresectable ICC compared to historic controls of best medical treatment and should be considered an effective therapy in select patients. A multi-institutional randomized control trial should be performed to evaluate efficacy of TARE in select patients as both 1 st line and salvage therapy.
Clinical presentation and outcomes in patients with advanced pheochromcytoma/paraganglioma: Evidence of temozolomide efficacy.
Authors: Daniel M. Halperin, Lauren Brais, Nikhil H. Ramaiya, Matthew Kulke
Journal: Journal of Clinical Oncology (2014)

e15157 Background: The clinical course and treatment options for patients with advanced pheochromocytoma (PCC) and paraganglioma (PGL) remain poorly defined. Few antitumor therapies have been developed for patients with this condition. Currently available regimens include radiolabeled metaiodobenzylguanidine (131I-MIBG), or treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Methods: We identified patients with locally unresectable or advanced PCC/PGL enrolled in a prospective clinical outcomes study of neuroendocrine tumor patients at Dana-Farber Cancer Institute between 2003 and 2010. We reviewed patient demographics, clinical symptoms, and treatment outcomes. Results: We identified 28 patients who presented to the institution with PCC/PGL, of whom 25 had recurrent or metastatic disease. Among these 25 patients, the most common signs and symptoms at presentation with metastatic disease were local pain, hypertension, and headache. Hypertension and headache were the dominant symptoms at time of recurrence. The median survival after the development of metastasis was 15 years. Eighteen patients received antitumor treatment, of whom 10 received treatment with the oral alkylating agent temozolomide. Among 8 patients evaluable for tumor response to temozolomide, six (75%) experienced some degree of tumor shrinkage, and 3/8 (37.5%) experienced RECIST 1.1-defined objective radiographic responses of 30% or more. All 8 evaluable patients experienced decreases in chromogranin A levels, and 4/8 had chromogranin A decreases of 50% or greater. Conclusions: While metastatic PCC/PGL often pursue a course that is more indolent than that of other malignancies, overall survival remains limited. Treatment with temozolomide was associated with both biochemical and tumor responses, and can be considered as a treatment option for this condition. Prospective studies further evaluating the activity of temozolomide in this setting are warranted.
Prognostic biomarkers in a series of stage II colon cancer.
Authors: Cristina Santos, Marta Terricabras, Adriana Lopez-Doriga, Sara Gonzalez, Anna Fernandez, Maria Martinez Iniesta, Xavier Sanjuan, David Garcia-Molleva, Alberto Villanueva, Victor Moreno, Sebastiano Biondo, Esther Kreisler, Gabriel Capella, Ramon Salazar
Journal: Journal of Clinical Oncology (2013)

3629 Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer (CC) that may benefit of adjuvant treatment. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as prognostic factors. Recently a high stroma component (EMT+ subtypes) has also been associated with poor outcome. The aim of the study is to analyze the prognostic value of MSI, BRAF and tumor-stroma ratio in a prospective series of stage II CC patients. Methods: FFPE tissue from 432 stage II CC patients operated at Hospital Universitari de Bellvitge (1996 - 2006) were included in the study. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X 2 ) tests. A Cox regression model was used to evaluate the Relapse Free (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined in 350 patients. 48 (14%) had MSI high (MSI-H) tumor. BRAF status could be assessed in 380 cases. 58 (15%) cases were BRAF mutated. Tumor-stroma ratio was analyzed in 407 tumor samples. 176 (43%) tumors had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in right colon (X 2 p-value = 1.03e-5), were poorly differentiated (X 2 p-value = 0.003) and had more than 12 lymph nodes resected (X 2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X 2 p-value = 0.02) and stroma-low (X 2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H /stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, microsatellite stable (MSS)/stroma-low and MSS/stroma-high patients (HR = 3.15; 95 CI, 0.76 – 13.1, p-value = 0.0602). Conclusions: MSI-H tumors have BRAF mutation as well as low intra-tumor stroma. Our results suggest that tumor-stroma ratio can explain differential prognosis in MSI-H stage II tumors.
MHC II antigen presentation pathway expression in triple-negative breast cancer.
Authors: Andres Forero-Torres, Katherine E Varley, Yufeng Li, Dongquan Chen, William E. Grizzle, Erinn Downs-Kelly, Todd C Burwell, Donald J. Buchsbaum, Richard M Myers, Albert F. LoBuglio
Journal: Journal of Clinical Oncology (2015)

1066 Background: The purpose of this study was to identify gene expression differences between triple negative breast cancer (TNBC) tumors from patients who did or did not have disease relapse. Methods: 47 snap frozen macro-dissected primary TNBC tumors from treatment-naïve patients, with an adequate follow up (greater than 24 months), were analyzed using RNA-seq to identify gene expression differences between patients with disease relapse and patients who did not relapse. In addition, archived de-identified primary TNBC tumors underwent standard immunohistochemical analysis with anti-CD74 and anti-HLA-DPB1 antibodies. Results: Database included 22 patients with disease relapse and 25 who did not relapse. 24 genes had significantly higher expression in tumor tissue from patients who did not relapse and 11 of these genes were integral members of the MHC II antigen presentation pathway. The 24 gene signature was significantly associated with progression free survival (PFS) (HR = 0.24; log rank p = 0.00016). Individually expression of CIITA and CD74, key components of the MHC II pathway, were significantly associated with PFS (HR values of 0.17 and 0.35; log rank p = 0.0002 and 0.0164. A large meta-analysis of microarray data from 199 patients with TNBC (Breast Cancer Res 2013; 140: 219) validated that 10 of the 24 genes (including 6 MHC II genes) were prognostic for PFS with a HR = 0.31; log rank p = 0.0000009 and CD74 alone was similarly prognostic with a HR = 0.31; log rank p = 0.0000019. Immunohistochemical analysis of patient primary tumors detected CD74 and HLA-DPB1 protein in TNBC tumor cells (greater than 20% of the cells), suggesting the MHC II pathway may be aberrantly expressed in tumor cells. The expression MHC II pathway genes correlated strongly with a tumor infiltrating lymphocyte gene signature. Conclusions: Tumor MHC II antigen presentation pathway is likely an important component of the anti-tumor immunity associated with good prognosis TNBC.
SORAVE: A phase I trial to evaluate safety and efficacy of combination therapy with everolimus and sorafenib.
Authors: Christian Mattonet, Lucia Nogova, Matthias Scheffler, Sebastian Yves Friedrich Michels, Deniz Kahraman, Carsten Kobe, Uwe Fuhr, Ahmed Abbas Suleiman, Yingying Tian, Fritz Soergel, Karin Toepelt, Roland Schnell, Max Schlaak, Kerstin Rhiem, Reinhard Buettner, Juergen Wolf
Journal: Journal of Clinical Oncology (2015)

2550 Background: Combined inhibition of signaling pathways interfering with angiogenesis and cell proliferation may overcome mechanisms of drug resistance in tumors. We evaluated the combination of the multikinase inhibitor sorafenib (S) and the mTOR inhibitor everolimus (E) and assessed pharmacodynamic (PD) activity of E by PET. Methods: Patients with relapsed solid tumors received escalating doses of E 2.5-10.0mg/d in a 14 days monotherapy run in phase followed by combination therapy with a fixed dose of S 800mg/d from day 15. Further patients were treated with the MTD in an extension phase. The primary aim was to define a safe and feasible combination treatment regimen. DLT was defined as any drug related toxicity of CTC IV° or requiring hospitalization or interruption of therapy for > 2 weeks within the first 29 days of treatment. Pharmacokinetic (PK) analyses were performed on days 5, 14 and 29 combined with explorative PD assessment of E by FDG-PET on days 1, 5 and 14 of treatment. Efficacy was assessed by CT (RECIST 1.1) every six weeks of combination treatment. Results: 31 patients (mean age 58.5 years) were enrolled and evaluable from October 2009 to December 2013, of which 16 (51.6%) had NSCLC. DLT was not observed according to protocol definition in the dose finding phase (18 patients), however the MTD for treatment of further patients was defined at 7.5mg/d E + 800mg/d S due to toxicities at 10mg E occurring after the DLT-defining interval (leucopenia / thrombocytopenia III° and pneumonia III°). The median PFS of all treated patients was 99 days (95% CI 85.7 - 112.3), the median OS was 178 days (95% CI 116.9 - 239.1). In 24 of 29 evaluable patients (82.8%) a decrease in SUVmax of the hottest lesion could be observed in PET, the best response as by PERCIST criteria was PR in 7 (21.4%) and SD in 21 (72.4%) patients. No patient reached PR in CT scan whereas 8 of 21 (38.1%) evaluable patients showed confirmed SD over at least 14 weeks. Conclusions: Treatment of patients with relapsed solid tumors with a combination of 7.5mg/d E and 800mg/d S is safe and feasible. Most tumors show a moderate metabolic decrease in PET, however this seems to reflect more a pharmacodynamic effect than long term disease control observed in this group of patients. Clinical trial information: NCT00933777.
A population-based study of biliary tract cancers (BTCs) in Alberta, Canada: How do our patients fare?
Authors: Arthur Gregory Ang Lui, Dimas Yusuf, Brock Randolph, Vincent C. Tam, Oliver F. Bathe, Sunita Ghosh, Jennifer L. Spratlin
Journal: Journal of Clinical Oncology (2017)

246 Background: BTCs are poorly studied due to their rarity and heterogeneity. We explored demographics and outcomes of BTC pts over a 15 year period. Methods: All patients (pts) with biopsy-proven BTC (intrahepatic [IC] and extrahepatic [EC] cholangiocarcinomas, gallbladder cancers [GB], and ampulla of vater cancers [AV]) in Alberta were reviewed from January 1, 2000, to December 31, 2015. Demographic, pathologic, and survival data were extracted from electronic charts. Descriptive statistics were utilized. Overall survival (OS) was defined as the time from pathologic diagnosis to death date. Results: A total of 1,718 pts with BTCs were identified. Median age was 68 with 52% being male. The Table demonstrates OS breakdown based on tumour location and stage. Regardless of location of primary tumour, grade impacted survival (median OS in with well differentiated tumours vs undifferentiated tumors 26.6 vs 3.9 months). Pts who received standard of care palliative cisplatin/gemcitabine (Cis/Gem) chemotherapy (n = 123) had a median OS of 15.4 months. Conclusions: Patients with AV and IC have the best and worst prognosis, respectively. Shorter survival is observed with higher stage, grade, and unresectable disease. Pts who received palliative Cis/Gem had better OS than reported in the pivotal phase III trial. Further analysis of prognostic factors will be presented. [Table: see text]
Baseline comprehensive geriatric assessment to predict for toxicity of single-agent chemotherapy in elderly metastatic breast cancer patients: Results from the OMEGA study of the Dutch Breast Cancer Trialists’ Group.
Authors: Marije Hamaker, Caroline M. Seynaeve, Machteld Wymenga, Harm van Tinteren, J. W. R. Nortier, Eduard Maartense, Steffen de Groot, Carolien H. Smorenburg
Journal: Journal of Clinical Oncology (2012)

1080 Background: A comprehensive geriatric assessment (CGA) systematically appraises the somatic, psychosocial and functional health status of elderly patients. If CGA can predict toxicity of chemotherapy in elderly cancer patients, this assessment could be useful in deciding on optimal treatment. In this analysis, we evaluated the association between frailty on CGA or Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast cancer (MBC) patients treated with first-line chemotherapy. Methods: In the OMEGA study, MBC patients (≥ 65 years) were randomized between PEGdoxo 45mg/m 2 every 4 weeks or capecitabine 2000 mg/m 2 on days 1-14 every 3 weeks. Baseline geriatric assessment included functional status (ECOG performance status (PS), IADL), cognition (MMSE), mood (GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) and GFI. Frailty on CGA was defined as one or more of the following: IADL≤13, MMSE ≤23, GDS ≥5, BMI ≤20, ≥5 medications or Charlson ≥2. GFI score for frailty was ≥4. Results: In total, 78 patients were randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 patients were evaluable for toxicity and baseline CGA. Overall, 50 patients (70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 toxicity related to chemotherapy was reported in 30 patients (42%) and 50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 20% of CGA-fit patients (p=0.02). Grade 3/4 toxicity was experienced by 44% of GFI-frail patients, compared to 38% of GFI-fit patients (p=0.39). After correcting for type of chemotherapy and age, toxicity was associated with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 1.77-13.59, p=0.03) while GFI-frailty was not associated with toxicity (OR 1.11, 95% CI 0.85-1.46, p=0.43). Conclusions: In this randomized study on first-line single-agent chemotherapy in elderly MBC patients, baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of chemotherapy but GFI did not.
Abstract 16667: Pro-Inflammatory Effects on Endothelium of High-Density Lipoprotein From Patients With Coronary Artery Disease: Role of Its Proteome Remodeling and PI3k Pathway
Authors: Zhao Hui, Liu Hong, Yan L Rong, Hua Lu, Li Y Shi
Journal: Circulation (2014)

Introduction:  High-density lipoprotein(HDL) from healthy individual exerts endothelial protection through anti-inflammation. Recent studies revealed that HDL function may shift towards pro-atherogenic when coronary artery disease(CAD) occured.   Hypothesis:  HDL from CAD patients promoted endothelium inflammation due to its proteomic remodeling.   Methods:  Isolated by ultracentrifugation, plasma HDL samples from CAD patients or healthy volunteers(HDLCAD and HDLhealthy) were each pooled as a different group. Cultured HUVECs were treated with equal amount of HDLCAD or HDLhealthy. Specific PI3K inhibitor Ly294002 was added prior to HDLCAD treatment to investigate pathway involved. MCP-1 and IL-6 levels in the supernatant were measured by ELISA. Differential protein and modification profiles between CAD patients and healthy controls were compared by Isobaric Tags For Relative And Absolute Quantitation(iTRAQ) technology combined with nanoLC-MS/MS method. Gene ontology(GO) category enrichments were applied to analyze the functions of these differential proteins.   Results:  HDLCAD stimulated more MCP-1(6.19±1.39 ng/ml vs.0.37±0.09ng/ml,P   Conclusions:  HDLCAD promoted endothelial inflammation through a PI3K-mediated pathway and was associated with the alterations in HDL compostions.
Tracking aCAD-ALK gene rearrangement in urine and blood of a colorectal cancer patient treated with an ALK inhibitor
Authors: G. Siravegna, A. Sartore-Bianchi, B. Mussolin, A. Cassingena, A. Amatu, L. Novara, M. Buscarino, G. Corti, G. Crisafulli, A. Bartolini, F. Tosi, M. Erlander, F. Di Nicolantonio, S. Siena, A. Bardelli
Journal: Annals of Oncology (2017)
Predictive ability of tumor growth modeling for overall survival in metastatic colorectal cancer.
Authors: Virginie Rondeau, Agnieszka Krol, Loic Ferrer, Jean-Pierre Pignon, Cecile Proust-Lima, Michel Ducreux, Olivier Bouche, Stefan Michiels
Journal: Journal of Clinical Oncology (2015)

e14619 Background: The WHO and RECIST criteria have allowed the standardization of tumor response evaluation to identify disease progression time. These semi-quantitative measurements are often used as endpoints in randomized trials to study the efficacy of new therapies. However, through categorization of continuous tumor size, information can be lost. Recent methods of longitudinal biomarkers modeling can be used. Methods: We compare the predictive ability of cancer progressions based on categorical criteria and quantitative measures of tumor size and/or appearance of new lesions on OS. A joint model for a simultaneous analysis of three types of data: longitudinal marker (sum of longest diameters, SLD), recurrent events (new lesions) and terminal event (death) was used on a randomized trial in metastatic colorectal cancer patients (French Federation of Digestive Oncology trial FFCD 2000-05). Dynamic statistical tools are provided to compare predictive accuracy. Results: In FFCD200-05, 407 patients were randomly assigned to 2 therapeutic strategies with multiple successive chemotherapy regimens, of which 321 patients died during follow-up. On average, each patient had 6.2 reported tumor measurements, 1.1 new lesions and 1.8 progressions according to WHO, with a total of 2,505 SLD measurements. The treatment arm was not significantly associated with tumor progressions, appearances of new lesion, nor with death. The evolution of the tumor size decreased more in the combination than in the sequential arm. Baseline WHO performance status (in particular status 3) indicated well the severity of further evolution of the disease. Smaller treatment center size had a significantly higher risk of death (HR = 1.93, p = 0.019). Using measures of predictive abilities, the proposed joint model outperformed other prognostic models using only the categorical criteria for OS. Conclusions: Modeling jointly the measures of tumor size and appearances of new lesions increased the accuracy of OS prediction in the FFCD200-05 trial, which necessitates validation in other trials. The proposed dynamic prognostic tools can offer a powerful alternative analysis of clinical trials. Clinical trial information: NCT001126256.