tbuckley/cabot-search huggingface dataset:
Interim analysis of a pilot study: Impact of high-dose, single fraction radiation on immunogenicity of sipuleucel-T in metastatic castration resistant prostate cancer patients.
Authors: Yuanquan Yang, Saby George, Ellis Glenn Levine, Thomas Schwaab, Jason Muhitch, Qiang Li, Kristopher Attwood, Adrienne Groman, Scott I Abrams, Pawel Kalinski, Anurag K Singh, Khurshid Guru, Gurkamal S. Chatta
Journal: Journal of Clinical Oncology (2019)

e16538 Background: Sipuleucel-T is known to have modest anti-tumor activity in pts with metastatic castration resistant prostate cancer (mCRPC). Synergy of radiotherapy and immunotherapy has been reported. We conducted a pilot study to assess the impact of radiation on immunogenicity of Sipuleucel-T. Methods: Pts with minimally symptomatic mCRPC and bone metastases were eligible. Pts received Sipuleucel-T every 2 wks x 3 infusions. 8 Gy RT to 1 bone lesion was given 2 days after the first infusion. Peripheral blood was collected at D0, 7d after each infusion, 3 and 6 m. Primary endpoint is the effect of RT on immunogenicity of Sipuleucel-T. Secondary endpoints were safety, PSA changes and survival. We will evaluate T cell proliferation and cytolytic response at baseline and post-treatment using thymidine incorporation assay, IFN-y ELISPOT and flow cytometry. Results: From 10/2013 to 7/2018, a total of 15 pts were enrolled. Median age was 69 years (59-77). 10 pts (67%) had GS &gt; = 8 disease. 7 pts (47%) failed prior abiraterone or enzalutamide. 13 pts completed treatment per protocol (2 withdrew). During a median follow-up of 48 mos, the 3-year overall survival was 48% (95% CI, 21-71); median survival was 30.7 mos (95% CI, 14.6-NR). No PSA responses were observed. 11 pts had post-treatment imaging (non-mandatory). 10 had PD and 1 had SD. 10 pts (67%) had Grade 1-2 drug-related AEs (most common: dizziness and hematoma 20%). No DLT or grade 3-5 drug-related AEs were observed. Conclusions: Sipuleucel-T plus RT is well tolerated. Median overall survival in this limited subset of pts was encouraging, when compared with historical data (25.8 mos in IMPACT trial). The evaluation of immune response is ongoing. (Funded by DENDREON; ClinicalTrials.gov ID: NCT01833208) Clinical trial information: NCT01833208.
Assessment of 2,000 patients presenting to a multidisciplinary prostate cancer clinic in the United Kingdom.
Authors: Pandora Rudd, John Hines, Eleanor Watkins, Thomas Powles, Karen Tipples
Journal: Journal of Clinical Oncology (2019)

5077 Background: Multidisciplinary clinics (MDCs) involving both oncologists and urologists are recommended for managing radical prostate cancer patients. The effectiveness of MDCs in arriving at best treatment decisions is unknown. We analysed patient characteristics and management decisions over 8 years in a MDC at Bart’s Hospital, London. Methods: Clinical data were collected in real time and analysed retrospectively, including demographics, tumour stage and grade, D’amico risk group, treatment choice and first clinician seen. We compared variables in 1000 consecutive patients presenting between 2011-2015 (cohort A) to 1000 patients presenting 2016-18 (cohort B) to investigate trends over time. Results: 2000 patients were included, age 65.2 ± 8.6 years and 65.9 ± 9.1 years (p=0.08), with presenting PSA 9.0 (6.3-14.4) and 9.2 (6.4-15.0) ng/ml (p=0.36), in cohort A and B respectively. Disease severity and initial treatment decision are shown in the table. In low risk disease, 126 (75%) patients had active surveillance in cohort A, and 158 (90%) in cohort B (p=0.0003). In high risk disease, 202 (59%) patients had radiotherapy compared to 194 (50%) in cohort B (p=0.011). In cohort B, 127 (39%) patients seeing oncology first had radiotherapy compared to 143 (25%) patients who saw urology first (p&lt;0.0001). 76 (23%) and 154 (27%) patients had surgery, that saw oncology and urology first, respectively (p=0.11). Conclusions: In 2000 patients presenting to a prostate MDC over 8 years, active surveillance in low risk disease increased, radiotherapy in high risk disease reduced, and the proportion undergoing surgery was unchanged. The initial clinician seen influenced treatment choice; having both specialists in the same consultation may improve consistency of treatment decisions. Disease severity and treatment choice before and after 2016. [Table: see text]
A Phase Ib/II Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer
Authors: James J. Harding, Andrew X. Zhu, Todd M. Bauer, Toni K. Choueiri, Alexander Drilon, Martin H. Voss, Charles S. Fuchs, Ghassan K. Abou-Alfa, Sameera R. Wijayawardana, Xuejing Aimee Wang, Brian A. Moser, Arantxa Uruñuela, Volker Wacheck, Johanna C. Bendell
Journal: Clinical Cancer Research (2019)

Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab.A 3+3 dose escalation of emibetuzumab plus ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC).A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non-small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug-drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64-8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression.Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.
Umbrella study of anticancer agents in Chinese patients with NSCLC.
Authors: Xin Zhao, Liyun Xiao, Yunpeng Yang, Guoyun Xie, Wenfeng Fang, Yuxiang Ma, Hongyun Zhao, Kui Wu, Li Zhang
Journal: Journal of Clinical Oncology (2019)

e20044 Background: As the rapidly increasing of potential anti-cancer agents, it has significantly improved clinical outcomes of non-small cell lung cancer (NSCLC). However, it has been challenged by the accurately characterize the genome changes which link to the response to specific targeted therapeutics. This umbrella study aimed to provide real-world data on the efficacy of targeted therapies by multiple gene sequencing in NSCLC of Chinese population and explore for the implementation of personalized lung cancer therapy in clinical practice. Methods: This study consists of five biomarker matched arms and one non-biomarker matched arm. Within biomarker matched arms, the different cohorts will test, 1) EGFR mutation for response to gefitinib, apatinib or osimertinib; 2) ALK fusion for response to crizotinib; 3) BRAF V600E mutation for response to trametinib; 4) MET amplification for response to CT053PTSA; 5) VEGFR mutation for response to apatinib or famitinib. Within the non-biomarker matched arm, cohort will test docetaxel or carboplatin. We will perform multiple gene testing on tumor tissue, pleural fluid, plasma and peripheral blood leucocyte of all patients. Results: A total of 336 patients were enrolled in this study, including 307 lung adenocarcinomas, 27 squamous cell carcinomas, and two adenosquamous carcinomas. Approximately 40% of patients carried at least one actionable mutation. The most frequently mutated genes were TP53 and EGFR, and the percentage of EGFR mutation subtypes 19Del, L858R and T790M were 25%, 19% and 16% respectively. In addition, the mutually exclusive mutations were significantly observed between EGFR and STK11 in TP53-mut patients. All patients will be allocated a corresponding arm according to their mutated genome profile and the clinical follow-up was still in progress. Conclusions: Multiple gene sequencing could be a useful selector for personalized lung cancer targeted therapy. Furthermore, mutation coexistence and mutual exclusion might be further predictors for the risk of drug resistant, recurrence at multivariate analyzes.
A randomized, phase II clinical trial of preoperative stereotactic body radiation therapy versus conventionally fractionated chemoradiation for resectable, borderline-resectable, or locally advanced type a pancreatic adenocarcinoma.
Authors: William Adrian Hall, Susan Tsai, Anjishnu Banerjee, Ben George, Paul S. Ritch, James P. Thomas, Eric Paulson, Kathleen K. Christians, Callisia Clarke, Kulwinder Dua, Abdul H Khan, Paul Knechtges, Catherine E Hagen, Douglas B. Evans, Beth Erickson
Journal: Journal of Clinical Oncology (2019)

TPS4167 Background: There is growing consensus for the use of neoadjuvant therapy in patients with potentially operable pancreatic adenocarcinoma (PC). However, there is not consensus on the type and duration of chemotherapy or radiation therapy (RT) dose. Stereotactic body radiation therapy (SBRT) has gained popularity despite the absence of prospective data for its use in the preoperative setting. Furthermore, SBRT preoperatively has not been standardized. At present, there exists no randomized data comparing preoperative SBRT with conventionally fractionated concurrent chemo-RT. We designed this trial to examine differences between pre-op RT dose and fractionation schedules. Methods: This study is a prospective, randomized, two-arm, phase II clinical trial. Eligible patients must have cytologically confirmed PC and be deemed suitable for surgical resection with resectable, borderline resectable, or locally advanced type A disease, based on cross-sectional imaging. Before randomization patients are stratified by clinical node positivity, neoadjuvant chemotherapy, and stage of disease. Patients are then randomized to either 50.4 Gy over 28 fractions with concurrent weekly Gemcitabine vs SBRT to a total dose of 25-35 Gy over 5 fractions. The primary endpoint of the study is pathologic node positivity. We hypothesize that patients treated with neoadjuvant chemotherapy followed by conventionally fractionated chemo-RT will have a lower rate of pathologic node positivity as compared to those patients treated with neoadjuvant chemotherapy followed by SBRT. Secondary endpoints include patient reported quality of life, local recurrence, primary tumor pathologic response, margin status, surgical complications, MR based treatment response, and overall survival. We anticipate a node positivity rate of 37% when using preoperative chemotherapy followed by SBRT. We hypothesize that treatment with chemotherapy followed by conventionally fractionated chemo-RT will reduce the rate of node positivity to 17%. Using a one-sided Type I error rate of 0.1, approximately 88 total patients (44 per arm) provide an 80% power to detect the hypothesized difference in pathologic node positivity between the two arms. To address patient dropout, an additional 14 patients (about 15%) will be enrolled for a total target accrual of 102 patients. The trial opened in November 2018 and 8 of the planned 102 patients have been enrolled. Clinical trial information: NCT03704662.
Incidence and characteristics of cancer-associated thrombosis in a racially diverse population: A population-based study.
Authors: Gary E. Raskob, Aaron M. Wendelboe, John Grady Heller, Kai Ding, Nimia L. Reyes, Karon Abe, Alys Adamski, Michele G. Beckman, Lisa Carolyn Richardson
Journal: Journal of Clinical Oncology (2019)

e13088 Background: Venous thromboembolism (VTE) is a common complication in cancer patients, but contemporary data on the incidence and characteristics of cancer-associated VTE in different racial populations is limited. We sought to measure the incidence rate and characteristics of cancer-associated VTE in a racially diverse population. Methods: We performed a prospective, population–based cohort study of VTE in Oklahoma County, OK during April 1, 2012–March 31, 2014. Surveillance staff regularly visited all tertiary care and relevant outpatient facilities in the county and reviewed the text from all imaging results of chest computed tomography or magnetic resonance imaging, lung perfusion scans, and ultrasound of the extremities to identify cases of VTE. Data on patient characteristics were collected from the electronic medical record. VTE was considered cancer-associated if the patient had a history of cancer other than basal or squamous cell skin cancer. Cancer was defined as “active” if metastatic or diagnosed within 6 months prior to VTE. Associations and incidence were calculated using the chi-square test and Poisson regression, respectively. Results: Of 3,255 patients with ≥1 VTE event (deep-vein thrombosis and/or pulmonary embolism), 732 (23%) had a history of cancer, of whom 309 had active cancer. The types of cancer varied widely. The age-adjusted incidence of cancer-associated VTE was 648 per 100,000 adult population (age ≥ 18). Incidence increased with each decade of age. The racial/ethnic-specific incidence rates were as follows (each per 100,000): Whites non-hispanic (607), Blacks non-Hispanic (557), Native Americans (128), Asian/Pacific Islanders (113) and Hispanics (70). Risk factors for VTE among the 732 with cancer-associated VTE included previous VTE (19%), hospitalization (37%), surgery (33%), and central venous catheter (22%). Of those with a history of cancer ≥ 6 months previously, 32% had no other identifiable VTE risk factor. Conclusions: Cancer-associated VTE comprised about 20-25% of the total population burden of VTE. The incidence varied substantially by race/ethnicity. An appreciable proportion of those with a history of cancer ≥ 6 months previously subsequently developed VTE in the absence of other risk factors.
High-grade gliomas (HGGs) and immunotherapeutic early-phase clinical trials (ieCTs): A single-center experience.
Authors: Matteo Simonelli, Pasquale Persico, Angelo Dipasquale, Elena Lorenzi, Laura Giordano, Federico Pessina, Pierina Navarria, Marta Scorsetti, Lorenzo Bello, Armando Santoro
Journal: Journal of Clinical Oncology (2019)

e13512 Background: Patients with HGGs have historically been excluded from ieCTs due to unavailability of serial bioptic sampling, frequent need of corticosteroids, concerns on activity of immunotherapy in central nervous system, and rapid clinical deterioration. Methods: We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2018. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for age, line of treatment, MGMT methylation and IDH mutational status, was selected for comparison. Clinical parameters including use of steroids, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein, were correlated with survival through an univariate analysis. Results: 5 among 21 ieCTs allowed inclusion of HGG patients. 20 patients were enrolled in our experimental cohort (EC); 17 (85%) glioblastoma, 3 (15%) anaplastic astrocytoma. Median age was 53 years (range 30-71); 12 patients (60%) were men, 8 (40%) women; 13 pts (65%) required steroid therapy, with a median dexamethasone dose of 2 mg (range 1-6). The median number of prior systemic therapies was 1 (range 1-2). 11 patients (55%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 9 (45%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 45% (1 CR + 2 PR + 6 SD) and 30% (1 RP +5 SD), in EC and CC, respectively. 4 patients (20%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 22 months PFS-6 and OS-6 were 53% and 11% (p &lt; .0001), 80% and 42% (p &lt; 0.0001) in EC and CC, respectively. In our small series, none of clinical factors resulted prognostic. Conclusions: Survival outcomes of our HGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical selection factors remains crucial.
Effect of HER2/neu 655 polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.
Authors: Isabel Blancas, Celia Martín, Marta Legerén, Michel Martos, Silvia Sequero, Nuria Mut-Salud, Emma Gallardo, Jose Manuel Garrido, Fernando Rodríguez-Serrano
Journal: Journal of Clinical Oncology (2019)

1025 Background: HER2 overexpression in breast cancer is associated with a poor outcome, high risk of metastasis and a reduced overall survival. The introduction of Trastuzumab in the treatment scheme improved the prognosis of these patients. Nevertheless, around 20% of patients develop cardiotoxicity. The purpose of this study is to analyze the association of the HER2 Ile655Val A &gt; G polymorphism with trastuzumab-induced cardiotoxicity and with survival. Methods: The study included 93 patients recruited from San Cecilio University Hospital in Granada (Spain) who were treated intravenously with Trastuzumab. The cardiotoxicity was diagnosed during the treatment follow-up considering a decrease of the left ventricular ejection fraction (LVEF) from baseline or clinical manifestation of congestive heart failure. HER2 655 A &gt; G was genotyping using TaqMan SNP technology. Results: Genotype frequencies of HER2/neu 655 met Hardy-Weinberg equilibrium ( p= 0.363). We did not find differences in baseline LVEF in patients who developed cardiotoxicity vs those who did not. However, in cardiotoxicity group, the symptomatic patients had a baseline LVEF significantly lower than non-symptomatic patients (57.7 vs 66.1, p &lt; 0.028). Logistic regression analysis adjusted by hormonal status and anthracycline treatment showed significant differences between AG and AA (OR = 3.00, CI95% 1.07-8.41, P= 0.037) or AG and AA+GG (OR = 3.21, CI95% 1.15-8.96, P= 0.026). However, we did not find association between Her2/neu Ile655Val polymorphism and disease-free survival or global survival. Conclusions: HER2 655 A &gt; G polymorphism is significantly associated with higher risk of trastuzumab-induced cardiotoxicity but is not associated to a differential survival rate.
Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.
Authors: Amin Nassar, Archana Agarwal, Rebecca Nagy, Catherine Curran, Sarah Abou Alaiwi, Bradley Alexander McGregor, AmirAli Talasaz, Richard B. Lanman, Guru Sonpavde
Journal: Journal of Clinical Oncology (2020)

6 Background: Penile cancer is a rare disease associated with HPV infection and harbors recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. Among the entire cohort, 51 ctDNA alterations were detected (median=2, range 0-6) in 15/16 patients (94%) across 21 genes (table). Of the 51 alterations, 24 (47%) were actionable and had approved targeted therapies in other cancers. Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), and TERT promoter (5/16, 31%) (table). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected and appeared similar to previously described tumor tissue analyses. New alterations found on serial ctDNA assays shed light on patterns of tumor evolution and may inform drug development for this challenging orphan malignancy.[Table: see text]
Tumor genomic alterations in severe-combined immunodeficiency bare-lymphocyte syndrome genes are associated with high mutational burden and disproportional neo-antigen rates
Authors: Yu Wang, Douglas B. Johnson, Steve Lu, Luis A. Diaz, Yaomin Xu, Justin M. Balko
Journal: Journal for ImmunoTherapy of Cancer (2019)

The progression of cancer requires mutational adaptation to permit unrestrained proliferation. A fraction of cancer mutations are oncogenic drivers, while others are putative 'passengers' that do not contribute to oncogenesis. However, altered peptides arising from passenger mutations may bind MHCs and activate non-self immunologic signals (i.e. neoantigens), thus requiring immunoediting for cancer persistence. Disruption of antigen processing machinery in tumor cells may diminish this requirement. Here, we show that rare mutations in antigen processing machinery are associated with high mutational burden and increased predicted neoantigen load, providing insights into the mechanisms of high mutation burden in some patients.