tbuckley/cabot-search huggingface dataset:
Treatment response and survival in patients with pancreatic adenocarcinoma receiving neoadjuvant chemotherapy or chemoradiation.
Authors: Ahmed Khattab, Sunita Patruni, Stephen Abel, Shaakir Hasan, Gene Grant Finley, Dulabh K. Monga, Rodney E Wegner, Vivek Verma
Journal: Journal of Clinical Oncology (2019)

e15715 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis. Neoadjuvant chemotherapy (NeoChT) and chemoradiation (NeoCRT) have emerged as strategies to optimize resection, but data investigating predictors of treatment response and the overall survival (OS) impact are not well characterized. To investigate the effects of NeoChT/NeoCRT on primary tumor/nodal downstaging and OS, we analyzed the national cancer database (NCDB). Methods: We queried the NCDB for patients with PDAC receiving NeoChT/NeoCRT. Patients were classified as responders (T and/or N downstage), nonresponders (mixed/no response) and progressors (T and/or N upstage). Multivariable logistic regression identified predictors of response. Univariable and multivariable analyses identified characteristics predictive of OS. Results: 2,028 patients with PDAC receiving NeoChT/NeoCRT were analyzed. Univariable analysis of responders (n = 790) vs. nonresponders/progressors (n = 1,238) demonstrated a significant difference in median OS at 29.1 months vs. 25.3 months and 3-year overall survival of 40% vs. 34% [p = 0.006; HR: 0.95 (95% CI: 0.84-1.08)] respectively. When compared independently to both responders and nonresponders, progressors had a significantly decreased 3-year OS at 31% vs 40% and 37% respectively [p = 0.003; HR: 0.82 (95% CI: 0.70-0.96)]. Predictors of response on multivariable logistic regression included receipt of multiagent chemotherapy and receipt of NeoCRT. Only NeoCRT predicted for pathologic complete response (pCR). Multivariable analysis of patients with pCR demonstrated a trend towards increased OS (p = .08). Conclusions: Our results suggest that both response and progression following neoadjuvant therapy may predict for longer and shorter OS respectively. Randomized, prospective studies are needed to further validate these findings. [Table: see text]
Mutational signatures of early-onset colorectal cancer.
Authors: Silvia Marsoni, Federica Zanardi, Fabio Iannelli, Elisa Salviato, Francesco Ferrari, Paolo Luraghi, Luca Lazzari, Andrea Sartore-Bianchi, Salvatore Siena, Sergio Abrignani, Beatrice Bodega, Antonio Russo, Nabil Amirouchene-Angelozzi
Journal: Journal of Clinical Oncology (2019)

e15113 Background: Despite a reduction of Colorectal Cancer (CRC) incidence in western countries in the past decades, Early-Onset CRCs (EO-CRC, patients diagnosed with CRC ≤ 40 years old) incidence has increased. Although frequently occurring in the context of familial syndromes, EO-CRCs are mainly sporadic cases and phenotipically enriched for distal localisation and advanced stage at diagnosis. Whether EO-sporadic CRCs pathogenesis differs from that of normal-onset (NO) CRC and how this might impact incidence rates is currently unknown. This had prompted us to ask if, at the genetic level, “traces” of peculiar pathogenic processes could be identified in EO-specific (or -enriched) genetic signatures (GS). Methods: The mutational signatures of 424 TCGA CRC patient samples (19 EO and 405 ≥ 50 years at diagnosis) were analyzed and the similarity between each mutational profile and COSMIC GS was calculated using Bioconductor R package Mutational Patterns (doi: 10.1186/s13073-018-0539-0). Unsupervised hierarchical clustering of the samples according to similarity to GS was performed in single cohort and pooled analysis. Association between age and individual GS was assessed through grouped and linear correlation analysis. Results: EO-CRC patients were grouped in three main clusters: Cluster1 exposing a major similarity with GS10 (associated with defects in polymerase proofreading activity), Cluster2 showing stronger similarities with GS6 (associated with mismatch repair deficiency), and GS1 (associated with 5-MeC deamination) and Cluster3 presenting similarity with multiple GSs, such as 3 (associated with homologous recombination deficiency) and 5 (pathogenesis unknown). Overall this clustering was maintained when EO-CRC samples were pooled with NO CRC. Grouped and correlation analysis revealed no significant association between age and individual GSs, including GS1 (associated with age). Conclusions: These preliminary analyses show that the relative contribution of known GS is similar in EO and NO cohorts of patients. Possible enrichment for EO-CRC in specific signature clusters will be analysed on a wider sample series.
A multicenter analysis of abemaciclib after progression on palbociclib in patients (pts) with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC).
Authors: Seth Andrew Wander, Mark Zangardi, Andrzej Niemierko, Avinash Kambadakone, Leslie SL Kim, Jing Xi, Apurva Kumari Pandey, Laura Spring, Casey Stein, Dejan Juric, Irene Kuter, Beverly Moy, Therese Marie Mulvey, Neelima Vidula, Steven J. Isakoff, Megan Yuen, Adam Brufsky, Cynthia X. Ma, Joyce O'Shaughnessy, Aditya Bardia
Journal: Journal of Clinical Oncology (2019)

1057 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used for pts with HR+/HER2- MBC. The MONARCH-1 trial of abemaciclib monotherapy in pre-treated pts demonstrated a median progression free survival (PFS) of 6.0 months, leading to approval as monotherapy in a CDK4/6i-naïve population. There are no data on abemaciclib in HR+/HER2- MBC after progressive disease (PD) with CDK4/6i. Methods: We evaluated clinical outcomes in pts with HR+/HER2- MBC who received abemaciclib following PD on prior palbociclib or ribociclib at 4 US academic centers. We conducted genomic analysis utilizing next-generation sequencing of tissue samples and blood (cell-free/cfDNA) when available. Results: From 2/2015 through 1/2019, 58 pts with HR+/HER2- MBC received abemaciclib following PD on prior palbociclib. 20 pts (34%) received sequential courses of therapy, while 38 pts (66%) had at least one intervening non-CDK4/6i regimen. 14 pts (24%) received abemaciclib monotherapy and 44 pts (76%) received it in combination with an antiestrogen, including fulvestrant (52%), an aromatase inhibitor (22%), and tamoxifen (2%). 22 pts (38%) required dose reduction, while 7 (12%) discontinued due to toxicity. At data cutoff (1/23/2019), 20 pts (34%) had early PD (duration &lt; 90 days), while 21 pts (36%) had treatment duration exceeding 6 months, including 10 who remain on treatment at interim analysis (range 181-413 days). The median PFS was 5.8 months (95%CI 3.4 – 8.0). Preliminary analysis of cfDNA revealed RB1 and FGFR1 alterations in pts with PD on abemaciclib. Additional analyses with mature clinical data and genomic sequencing will be provided at the meeting. Conclusions: This is the first multi-center experience to demonstrate that a substantial proportion of pts continue to derive clinical benefit with abemaciclib after prior CDK4/6i, highlighting the potential for its use following CDK4/6 blockade. A second subset had early progression, suggesting cross-resistance to CDK4/6i via common pathways. Future effort should be directed towards validating potential biomarkers to guide optimal utilization of continued CDK4/6 blockade in HR+/HER2- MBC.
Quantitative image profiling of the tumor microenvironment on double stained immunohistochemistry images using deep learning.
Authors: Mate Levente Nagy, Anna Juncker-Jensen, Ben Ovadia, Robert Smale, Karen Yamamoto, Josette William, Nicholas Hoe, Raghav Padmanabhan
Journal: Journal of Clinical Oncology (2019)

e14619 Background: Spatial locations of immune cells in the tumor microenvironment (TME) correlate with clinical outcome in cancers. A worse patient outcome has been reported in oral squamous cancer for individuals with an increased number of regulatory T cells within 30µm of CD8+ cells [1]. The spatial relationship between CD8+ and PD-L1+ cells has become an area of interest for understanding PD-L1 inhibition. The combined assessment of CD8 and PD-L1 in NSCLC tumors was shown to outperform CD8 or PD-L1 alone as prognostic markers for predicting treatment with immune checkpoint inhibitors [2]. Methods: As reported in these cases, quantifying spatial relationships between two biomarkers is valuable in providing clinical insights. Spatial analytics of the TME requires accurate cell segmentation and classification. To that end, NeoGenomics has developed a deep learning pipeline to automatically segment and classify cells from whole slide double stained IHC images. Results: In this study, we performed IHC double staining and cell classification analysis on two sets of assays (CD8+ PD-L1+ and CD8+ FoxP3+) in NSCLC tumors by modifying our MultiOmyx analysis pipeline [3]. In addition to cell segmentation and classification image outputs, we also generate tables with cell morphological information, phenotype counts and densities, and biomarker intensities that can be used to define H-score-like measures. Advanced spatial analytics is performed to identify clustering patterns of various phenotypes. These analyses enable investigation of complex cell interactions in TMEs. Conclusions: NeoGenomics quantitative double stained IHC assay is compatible with any two biomarkers of interest even if they are expressed on the same cell as long as the sub-cellular localization of the markers is different (membrane CD8, nuclear FoxP3). The combination of double staining for CD8+ PD-L1+ or CD8+ FoxP3+ and quantifying spatial relationships between the two biomarkers is capable of providing the needed context to guide treatment decisions. References: Feng Z et al., JCI Insight. 2017 Jul 20:e93652 Steele KE et al., J Immunother Cancer 2018;6:20 Nagy ML et al., AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL
Government is urged to set realistic digital targets for NHS
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Policy makers must take a realistic view when setting targets for NHS hospitals to digitise and should strike the right balance between “national standardisation and local flexibility,” experts have advised.

National policies should focus on the most pressing needs of NHS patients and staff and on equipping the clinical and non-clinical workforce with the “skills and confidence” to work with technology, a report by the Nuffield Trust recommends.1

Policies should not be too prescriptive, and “much better and more effective” two way communication is needed between national policy makers and local NHS organisations, the researchers added.

In an accompanying blog post Rachel Hutchings, the report’s coauthor, wrote, “Failing to understand …
SHR-1210 plus GEMOX as first line treatment in biliary tract cancer: Results from a single-arm exploratory study.
Authors: Xiaofeng Chen, Xiaofeng Wu, Hao Wu, Qianwen Shao, Feipeng Zhu, Xiaofeng Qian, Fengjiao Zhao, Jing Sun, Jian Wang, Gaohua Han, Dongqin Zhu, Liuqing Zhu, Yang Shao, Yanhong Gu, Xiangcheng Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2019)

4092 Background: SHR1210 is a humanized anti-programmed cell death receptor 1 (PD-1) antibody. We conducted a single arm exploratory study to evaluate the efficacy and safety of SHR-1210 plus gemcitabine and oxaliplatin (GEMOX) as first line treatment in patients (pts) with biliary tract cancer (BTC). Methods: Pts received SHR-1210 (3mg/kg, total dose ≤200mg, ivd, D1/2W) combined with gemcitabine (800 mg/m2, ivd, D1/2W) and oxaliplatin (85mg/m2, ivd, D2/2W). Combined chemotherapy lasted for no more than 8-12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take SHR-1210 as single agent until disease progression or intolerable toxicity. Response was assessed every 8 weeks. Results: From February 2018 to Dec 15, 2018, 32 eligible pts were recruited, and 27 pts who had been treated for more than 2 months were included in this analysis. Median age was 64 (range 47-75) years. 16 pts were bile duct cancer, while 11 pts were gallbladder cancer. 26 pts can be evaluated for efficacy. Twelve pts achieved partial response (46.15%), 12 pts stable disease (46.15%), and 2 pts progressive disease. Pts with gallbladder cancer had the trend of higher objective response (63.64% vs 33.33%, p = 0.23) than those with cholangiocarcinoma. 19 pts had tissue sample for next generation sequencing. Gallbladder cancer had the tendency of higher median tumor mutation burden (TMB) than cholangiocarcinoma (8.1mut/Mb vs 5.4mut/Mb, p=0.33). Pts with high TMB(&gt;8.6 mut/Mb, based on geenseeq BTC database) had significantly higher objective response than low TMB (100% vs 26%, p=0.0294). The most common grade ≥3 adverse events were nausea (18.52%),increased GGT (gammaglutamyltransferase,18.52%), hypokalemia(18.52%) and fatigue (18.52%). Conclusions: SHR-1210 plus GEMOX showed promising efficacy with tolerable adverse events for BTC pts. Gallbladder cancer pts seem to benefit more from this treatment. Tumor mutation burden may be a predictive factor for immunotherapy. Clinical trial information: NCT03486678.
Abiraterone acetate plus prednisone (AA+P) without continuing LHRH-therapy in patients with metastatic chemotherapy: Naive castrations-resistant prostate cancer—Results from the SPARE-trial (NCT02077634).
Authors: Carsten Henning Ohlmann, Christoph Ruessel, Roger Zillmann, Eva Hellmis, Henrik Suttmann, Martin Janssen, Jan Marin, Johannes Dahm, Andreas Hübner, Jochen Gleissner, Michael Scheffler, Susan Feyerabend, Jens Telle, Peter Jähnig, Michelle Jäschke, Joerg Klier
Journal: Journal of Clinical Oncology (2019)

5046 Background: The value of continuation of androgen deprivation therapy (ADT) in metastatic castration-resistant prostate cancer (CRPC) remains controversial and clear evidence is lacking. Especially upon treatment with the life-prolonging cytochrome P450 17-alpha-hydroxylase/C 17,20 lyase (Cyp17)-inhibitor, abiraterone acetate (AA), which in combination with prednisone (P), has the ability to further suppress serum testosterone levels over ADT alone, continuation of ADT seems to be negligible. Methods: The exploratory phase II trial randomized CRPC patients to receive continued ADT plus AA+P versus AA+P alone (NCT02077634), funded by Jansen-Cilag GmbH, Germany. The primary endpoint was rate of rPFS at month 12, not powered for a direct comparison between treatment arms. Secondary endpoints included PSA response rate, objective response, time to PSA progression and safety. Results: Altogether, 67 patients were randomized between 08/2014 to 04/2017. Median testosterone-levels (T) remained far below castrate-levels throughout treatment in all patients. However, in 6 patients (18%) from Arm B, T-levels increased above castrate levels within 28 days after cessation of AA+P treatment. Median treatment duration is shorter in Arm A. Safety analysis is underway and results will be presented. Conclusions: Results of this exploratory study suggest that treatment with AA+P without ADT may be effective in patients with mCRPC and that ADT may not be necessary in patients receiving AA+P. In some patients, serum-testosterone levels may rise rapidly upon treatment discontinuation so that the levels should be monitored closely. Clinical trial information: NCT02077634. [Table: see text]
Preclinical functional characterization of AGEN1181, a clinical stage Fc-engineered anti-CTLA-4 antibody for the treatment of patients with early and advanced malignancies.
Authors: Jeremy Waight, Mariana Manrique, Randi Gombos, Matthew Costa, Priyadarshini Iyer, Sylvia Vincent, Rebecca Ward, Elena Paltrinieri, Dhan Chand, Nicholas Wilson, Jennifer Buell, David Savitsky
Journal: Journal of Clinical Oncology (2019)

e14126 Background: Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor that modulates T cell priming and CD28-dependent T cell activation. Modulation of this pathway by CTLA-4 antibodies has demonstrated clinical responses in patients with advance disease, however the mechanism of action of these antibodies remains controversial. It is currently understood that anti-CTLA-4 antibodies mediate antitumor effects through receptor-ligand blockade, and, in preclinical models, through depletion of intratumoral regulatory T (Treg) cells via an Fc-dependent mechanism. Recently, we reported a novel Fc-mediated contribution to T cell priming underscored the importance of Fc selection for optimal CTLA-4 antibody activity. AGEN1181 is a clinical stage Fc-engineered IgG1 antibody that leverages this novel mechanism for enhanced functionality. Methods: Fab-mediated biology of AGEN1181 was confirmed by assessing binding affinity, specificity, and blockade of CTLA-4:CD80/86 interactions. Fc-mediated functions of AGEN1181 were evaluated by FcγR binding, reporter-based FcγR signaling, and antibody-mediated Treg cell cytotoxicity assays. In vitro and in vivo pharmacology of AGEN1181 (alone or in combination with anti-PD-1) were evaluated in superantigen (staphylococcal enterotoxin)-mediated T cell stimulation assays and in a non-human primate (NHP) model. Safety and tolerability of AGEN1181 were assessed in cynomolgus monkeys administered 5 once-weekly intravenous bolus infusions at doses of 5, 30, or 100 mg/kg. Results: AGEN1181 bound to CTLA-4 with high affinity and specificity and demonstrated a range of enhanced functional activities relative to first-generation CTLA-4 antibodies. This included superior CD16 (FcγRIIIA) binding, Treg depletion and T cell priming (as measured by ZAP70 phosphorylation and interleukin-2 secretion). In NHP studies, a single dose of AGEN1181, alone or in combination with anti-PD-1 antibody upregulated Ki67 and ICOS expression on peripheral T cells. Finally, AGEN1181 exhibited an acceptable toxicologic profile in multi-dose NHP studies. Conclusions: AGEN1181, an Fc-engineered anti-CTLA-4 antibody exhibits a range of enhanced functional attributes relative to first-generation anti-CTLA-4 antibodies in preclinical studies. Phase 1 clinical studies for AGEN1181 will be initiated imminently.
Distinct radiological patterns of drug-induced pneumonitis (R-DIP) in early-phase clinical trials and predictive factors affecting outcome: A 10-year systematic review from the Royal Marsden Hospital Phase I Drug Development Unit experience.
Authors: Angelika Terbuch, Irene Moreno Candilejo, Mariana Scaranti, Daniel Bar, Miriam Estevez Timon, Malaka Ameratunga, Joo Ern Ang, Jonathan Ratoff, Anna Minchom, Udai Banerji, Johann S. De Bono, Nina Tunariu, Juanita Suzanne Lopez
Journal: Journal of Clinical Oncology (2019)

3088 Background: We studied clinical and radiological parameters influencing DIP in patients (pts) participating in phase I clinical trials, aiming to investigate predictive factors affecting DIP, in particular those affecting outcome. Methods: 2439 consecutive stage IV cancer pts on phase I clinical trials from 2007 to 2017 were identified. Pts with respiratory symptoms or abnormal lung imaging were reviewed in detail, with longitudinal analysis of imaging by an experienced radiologist. R-DIP was categorized according to internationally recognized criteria. Results: 60 pts developed R-DIP (overall incidence 2.5%); most frequent in pts receiving drug conjugates (31.1%) followed by targeted therapies (8.3%). Hypersensitivity pneumonitis was most common (33.3%) followed by non-specific interstitial pneumonitis (30%) and cryptogenic organising pneumonitis (26.7%). 45% pts who developed R-DIP were clinically asymptomatic. The number of affected lobes (OR 1.47, 95% CI: 1.19-1.81, p &lt; 0.001) and the pattern of R-DIP (OR 5.83 for ARDS, 95% CI: 0.38-90.26, p = 0.002) were significantly associated with a higher CTCAE pneumonitis grading. 23% pts (14/60) had investigational medicinal product (IMP) temporarily discontinued or had a dose reduction while 42% pts (25/60) had IMP permanently discontinued. 48% pts were treated with steroids. The number of affected lobes, pattern of R-DIP and steroid therapy did not influence an improvement in R-DIP (p = 0.65, 0.27 and 0.23 respectively). Continuation of treatment resulted in worsening of DIP in 42.9% of cases. The only predictive factor for an improvement in DIP was an interruption of treatment (OR 0.05, 95% CI: 0.01-0.35, p = 0.01). 14 pts were retreated with a reoccurrence of R-DIP in 4 pts (28.6%). Conclusions: R-DIP from novel agents in early phase clinical trials presents in varied radiological patterns, with findings often preceding clinical symptoms. Treatment interruption leads to improvement of DIP and should be considered early. Close clinical and radiological surveillance is recommended should IMP be restarted.
Impact of the addition of bevacizumab (Bev) to chemotherapy on survival in metastatic colorectal cancer (MCRC): A real-world population-based analysis.
Authors: Sunand Nageswaran Kannappan, Rahul Krishan Arora, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2019)

e18215 Background: The addition of bev to IFL chemotherapy in MCRC was shown to improve survival in clinical trials, but its benefit in the real-world where it is frequently used with other systemic therapy regimens has not been fully evaluated. We aimed to assess the impact of bev on MCRC outcomes in a population-based setting. Methods: We examined all patients diagnosed with MCRC from a large Canadian province between 2004 and 2016. We categorized cases based on receipt of bev. Predictors of bev use were examined with multivariate logistic regression models. We also determined correlates of overall survival (OS) and disease specific survival (DSS) using Kaplan-Meier methods and Cox regression models, adjusting for measured confounders. Results: In total, 1,324 MCRC patients received systemic therapy. Median age was 68 years and 728 (55.0%) were men. Among them, 310 (23.4%) received bev. Younger age and better Charlson comorbidity score were associated with a higher likelihood of bev treatment (all p &lt; 0.05). In multivariate analysis, bevacizumab receipt did not correlate with OS or DSS for the entire cohort or for those who received bev with single agent chemotherapy (see Table). However, use of bev was correlated with improved outcomes for patients treated with oxaliplatin-based chemotherapy (HR for OS: 0.751 [0.571 – 0.987], p = 0.040; HR for DSS: 0.680 [0.502 – 0.920], p = 0.013), but worse outcomes for irinotecan-based chemotherapy (HR for OS: 1.327 [1.083 – 1.628], p = 0.006; HR for DSS: 1.309 [1.054 – 1.627], p = 0.015). Conclusions: Bev was only associated with improved survival when used with specific chemotherapy regimens. Table: Univariate and multivariate survival analysis for MCRC patients based on receipt of bevacizumab. m = median; (m) = months; HR = hazard ratio [Table: see text]