tbuckley/cabot-search huggingface dataset:
BTC1.02 New approach to classification of primary Central Nervous System (CNS) Tumors
Authors: G L Kobyakov, O Absalyamova, A Poddubsky, C Lodygina, E Kobyakova, N Kobiakov
Journal: Neuro-Oncology (2018)

The only classification that exists in neurooncology is the World Health Organization Classification Update of Central Nervous System (CNS) Tumors 2016. However, it only takes morphological and molecular genetic aspects of CNS tumors into consideration. The TNM classification that is important for other tumor types is not useful for CNS tumors. Meanwhile, when we detect signs of CNS tumor on MRI (and other neuroimaging modalities), we focus on the location of the tumor, its spread, signs of dissemination, etc., to decide if tumor removal or biopsy is needed in the given case and to suggest following combination of treatment options. We propose to systematize these data to form a multi-level diagnosis that would base on clinical, anatomical, neuroimaging and morphogenetic findings. The diagnosis of a primary CNS tumor should be the following: 1) Primary tumor (first signs) or disease progression. In case of tumor progression type of progression should be specified: local growth (at the site of primary lesion), growth into a new anatomical region (independent of the primary lesion), or dissemination (by brain and/or spinal subarachnoid spread, less often - outside the CNS). 2) Location of the tumor, L (we need to precise structured anatomical regions based on imaging data). Major structure affected: Lb (brain tumor), Ls (spinal tumor).Grading: (a) number of lesions (1 - solitary lesion, 2 - multiple (2 or more) lesions); (b) side affected (left or right). So, we can return the concept of brain gliomatosis that has been excluded from last redaction of the WHO classification of the CNS tumors. 3) Advanced neuroimaging data (T1, T2, T2 FLAIR and so on - so called “radiomics”) including PET / CT with amino acids tracers. 4) Pathological diagnosis based on the World Health Organization Classification Update of Central Nervous System 2016. Thus, for each case of CNS tumor multi-level diagnosis is formulated, which can be used to determine diagnostic algorithms and therapeutic strategies. Moreover, structured data allows easier understanding of patients’ disease stage for a physician. Possibly, precise classification of tumor clinical and anatomical properties would allow forming more uniform groups for clinical trials. Currently we apply this approach on our database of retrospective and prospective data of glioma patients to evaluate the prognostic significance of suggested clinical, anatomical and neuroimaging modalities in comparison with the prognostic significance of established morphogenetic parameters.
Gene expression and cytokine modulation in a first in human (FIH) study of a pan BET inhibitor ABBV-075 in solid tumors.
Authors: Bert H. O'Neil, Dimple Modi, Patricia LoRusso, Shekman Wong, Monica Motwani, Jasgit C. Sachdev, Johannes E. Wolff, Sapna Pradyuman Patel, Beibei Hu, Russell Zelig Szmulewitz, Anjla Sood, Minal A. Barve, Mark D. McKee, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2018)

2570 Background: ABBV-075 is an oral small molecule inhibitor of the BET family of bromodomain-containing proteins that function as regulators controlling many transcriptional programs required for cancer pathogenesis. ABBV-075 is currently being evaluated in a FIH study in advanced solid tumors (M14-546). Using a 3+3 dose escalation design, a total of 72 solid tumor patients were treated across 3 dosing schedules. Dose-limiting toxicities were thrombocytopenia, fatigue, aspartate aminotransferase elevation, gastrointestinal bleed, and hypertension in the dose escalation phase. Methods: In this report, pharmacokinetic (PK) and pharmacodynamic (PD) data are presented for 40 subjects. PD effect was measured in surrogate tissue (whole blood and serum), which was collected prior to therapy and at various time points post-dosing. Gene expression was evaluated by branched DNA assay. Soluble cytokines were analyzed by immunoassay (Myriad RBM’s InflammationMAP®). Results: The observed Tmax occurred at 2-4 hours post dosing, Cmax and AUCinf increased dose-proportionally within the dose-range studies, mean t1/2 : 13 - 32 hours. Exposure (Cmax) at day 8 correlated with decrease in platelet count on day 15 compared to baseline counts (Pearson correlation: -0.46, p = 0.032). HEXIM1 and DCXR gene expression increased, CD93 gene expression decreased at 6 hours post treatment. CD93 and DCXR demonstrated dose-dependent modulation. Statistically significant correlation was observed between gene modulation at 6 hours and drug exposure at day 8 (Pearson correlation: HEXIM1 = 0.435, CD93 = 0.375, DCXR = 0.541). Soluble BDNF expression demonstrated a dose and time-dependent decrease at cycle 2 and 3 compared to baseline (p < 0.0001). Conclusions: We demonstrated target engagement in surrogate tissue via modulation of gene and soluble cytokine expression, both of which were dose dependent. Strong correlation was observed between drug exposure and gene expression modulation as well as thrombocytopenia, after ABBV-075 treatment. Correlation of these PD effects with adverse events and clinical response, are currently under investigation. Clinical trial information: NCT02391480.
AMC075: A randomized phase II trial of vorinostat with R-EPOCH in aggressive HIV-related NHL.
Authors: Juan Carlos Ramos, Joseph A. Sparano, Page C. Moore, Ethel Cesarman, Erin G. Reid, Paul G. Rubinstein, Robert D Harrington, Robert A. Baiocchi, David Michael Aboulafia, Lee Ratner, Kaplan Lawrence, Christine Durand, Richard Ambinder, Jeanette Y. Lee, Ronald T. Mitsuyasu, Ariela Noy
Journal: Journal of Clinical Oncology (2018)

7573 Background: HIV+ individuals are at increased risk for developing aggressive NHL that are often EBV+ or HHV-8+. We recently reported a phase I study using the HDAC inhibitor vorinostat (V) with R-DA-EPOCH for untreated high-risk HIV-NHL. We hypothesized that V would enhance the anti-tumor effects of R-EPOCH, and transiently activate latent EBV, HHV-8, and HIV, thus targeting virus-infected reservoirs. The recommended phase II dose of V administered on days 1-5 with R-EPOCH was 300 mg. In 12 evaluable patients (pts), the complete response (CR) rate was 83% with a 1-yr event-free survival (EFS) of 83%. Methods: Eligibility: HIV+ pts with untreated high-risk non-Burkitt NHL (aa-IPI 2-3, or Ki-67 ≥ 80%, or DLBCL-ABC subtype, or other aggressive non-DLBCL NHLs) with CD4 count ≥ 50 cells/mm3. Randomized phase II (45 pts on each arm): The primary objectives were to determine safety and efficacy of R-DA-EPOCH +/- V using CR rate as the primary endpoint. Correlative studies compared treatment effects on HIV viral loads, T-cell subsets, and immunoglobulin (Ig) levels. Latent HIV reservoir was investigated longitudinally using quantitative viral outgrowth assay. Results: A total of 90 pts (93% male, median age = 48, median CD4 = 190 cells/mm3) were treated; the most common NHLs were DLBCL (n = 31, 69%), plasmablastic lymphoma (PBL) (n = 8, 18%), primary effusion lymphoma (PEL) (n = 5, 11%) under VR-EPOCH arm vs. 35 (78%) DLBCL, 7 (16%) PBL, and 2 (4%) PEL under R-EPOCH. Grade 4 neutropenia and thrombocytopenia wer more common with VR-EPOCH (44% and 27%, respectively), vs R-EPOCH (16% and 2%, respectively). There were 2 treatment-related deaths (1 for each arm), and similar rates of febrile neutropenia (18% vs. 16%, respectively). CR rates were 65% for VR-EPOCH vs. 77% for R-EPOCH (1-sided P = 0.895). The 1-yr EFS rates (±standard errors) in evaluable pts for V-R-EPOCH (n = 43) vs. R-EPOCH (n = 45) were 75.6% (±6.4%) vs. 82.2% (±5.7%), with 1-yr overall survival of 77.6% (±6.3%) vs. 86.7% (±5.1%), respectively. V had no significant impact on HIV viral loads, latent reservoir, T-cell subsets, or Ig levels. Conclusions: This study demonstrated no clinical benefit of adding an HDAC inhibitor to concurrent curative chemotherapy in aggressive HIV-NHL upfront. Clinical trial information: NCT01193842.
Clinical relevance of intratumoural immune cell composition in non-small cell lung cancer.
Authors: Xuetao Li, Jia-Tao Zhang, Jian Su, Jinji Yang, Wenzhao Zhong, Xuchao Zhang, Yi-Long Wu, Jun Hou
Journal: Journal of Clinical Oncology (2018)

8547 Background: While the understanding of immune landscape of NSCLC has been greatly improved, it is largely unknown how local repertoire of tumor infiltrating leukocytes differs in context of tumor genomics and impacts on prognosis and response to immunotherapy. The aim of this study was to deconvolve immune cell fractions from bulk tissue gene expression profiles (GEPs), and to determine the distinct immune cell composition in molecular subgroups of NSCLC. Methods: Bulk GEPs of 1692 tumor samples of NSCLC patients with known clinical information were obtained from GEO. CIBERSORT algorithm was used to infer the relative proportions of 22 human leukocyte subsets in each tumor. The common and specific immune infiltrating patterns were established for histological and genomic subgroups of NSCLC defined by driver gene mutations. The correlation between intratumoural immune profiles and overall survival (OS) was assessed using multivariable Cox regression model. Results: An increased fraction of regulatory T cells (p < 0.001) and a decreased fraction of plasma cells (PCs) (p < 0.003) were found in advanced NSCLC. With respect to histology, macrophages (Ms) were significant differential cellular component between adenocarcinoma and squamous cell carcinoma. Nevertheless, the high fraction of PCs had longer median OS (8.4 vs 4.4 years, HR 0.59, p = 1e-05) than the low fraction of PCs. The median OS for the low fraction of neutrophils was 7.9 years vs 5.6 years for the high fraction of neutrophils (HR 1.64, p = 0.00072). We found that EGFR-mutant NSCLC was characterized by enriched CD4+ memory resting (CD4mr) (p < 0.0001) and dendritic resting (p < 0.0001) cells, as well as lacking of Ms (p < 0.001). Strikingly, ALK-mutant NSCLC showed a similar intratumoural immune profile with KRAS-mutant NSCLC, illustrated by a low fraction of CD4mr cells and enriched Ms in both molecular subgroups. Conclusions: Our results pointed out the complex relationship between the heterogeneity of intratumoural immune infiltrates, tumor genomics, and patient prognosis across subtypes of NSCLC. Further research is warranted to validate the relation in independent patient cohorts and to explore the impact of immune landscape on immunotherapeutic response.
Role of CD4 cells in the complete anti-tumor response to PD1 blockade in a syngeneic murine melanoma model with activated WNT signaling.
Authors: Siwen Hu-Lieskovan, Davis Yuri Torrejon, Jesse Meir Zaretsky, Jennifer Tsoi, Gardenia Cheung-Lau, Agustin Vega-Crespo, Katrina Meeth, Robert Michael Prins, Thomas Graeber, Marcus Besenberg, Catherine Grasso, Begonya Comin-Anduix, Antoni Ribas
Journal: Journal of Clinical Oncology (2018)

12013 Background: Recent data suggested a correlation of active WNT signaling and tumor T cell exclusion. We developed a syngeneic BRAFV600E/PTEN-/-melanoma model YUMM2.1 (Y2.1) that has partial response (PR) to anti-PD1 (Homet, 2016), and an inducible cre/lox system to stabilize ß catenin. We hypothesized that WNT activation would alter the efficacy of anti-PD1 therapy in this model. Methods: Y2.1 cells were treated with tamoxifen (4HT) in vitro and ß catenin stabilization was confirmed (Y2.1 4HT1). C57BL/6 mice were implanted Y2.1 4HT1 tumors sc, followed by ip anti-PD1 (RMP1-14) or Isotype q3d for 3wks when tumors reach 5-8mm. For in vivo depletion, antibodies (a) against CD4, CD8, NK1.1, CD40L was given starting 1d prior to anti-PD1 x2d then WKly x 3. Tumors were harvested for flow, RNAseq. Results: WNT activation rendered a partial response to anti-PD1 w Y2.1 to complete regression of Y2.1 4HT1 tumors by wk 8 in majority of treated mice (median vol 180 vs 48 mm3 in WK6, p = 0.02). This enhanced anti-tumor effect is seen in additional 4HT treated Y2.1 (Y2.1 4HT2-6), but not YUMM1.1 (resistant to anti-PD1), but is lost in Y2.1 4HT1 BCKO (ß catenin gene knocked out by CRISPR, median vol ISO 587 vs aPD 560 mm3 in WK6, p = 0.65). Depletion studies showed complete abrogation of anti-tumor response with CD4 depletion but only partial with CD8 depletion, aCD40L or in IFNg-/- mice (Table 1), and no effect w NK depletion. Flow Cytometry and RNAseq showed increased T cells, IFNg, granzyme B with anti-PD1 in Y2.1 4HT1 tumor. CD4 depleted tumors also have increased CD8 but w/o effector functionality, and a global downregulation of immune related genes by hierarchical clustering. Conclusions: WNT signaling activation results in complete response to anti-PD1 therapy, w increased T cell infiltration and CD4 cells being essential for this anti-PD1 mediated anti-tumor response. Y2.1 4HT1 Tumors ISO aPD ISO+ aCD4 aPD+ aCD4 ISO+ aCD8 aPD+aCD8 aPD+aCD40L N. 6 5 5 5 5 5 5 Median (week 5) 226 86 900 950 285 264 488 95% CI Lower limit 111 56 429 857 162 48 182 Upper limit 416 136 1029 1150 725 416 850 ISO vs aPD aPD+aCD4 vs aPD aPD+aCD8 vs aPD aPD+aCD40L vs aPD Mann Whitney test p = 0.009 ** p = 0.008 ** p = 0.45 p = 0.008 **
Comprehensive molecular profiling of paired patient samples of primary and metastatic (met) pancreatic ductal adenocarcinoma (PDAC).
Authors: Neel Trivedi, Rebecca Feldman, Hongkun Wang, Nabin Raj Karki, John Marshall, Benjamin Adam Weinberg
Journal: Journal of Clinical Oncology (2018)

4114 Background: Pancreatic cancer is the third leading cause of cancer-related death in the U.S. The vast majority of pancreatic cancer is PDAC (90%). Most patients with PDAC die from complications from met disease, thus it is vital to better understand the molecular changes that promote met spread. Prior studies have shown few molecular changes between primary and met PDAC in unpaired analyses, but limited data exist on large-scale comparisons between paired samples from the same patient. Methods: We analyzed next-generation sequencing (NGS) and immunohistochemistry (IHC) data from 123 patients with multiple PDAC tumors profiled by Caris Life Sciences and compared paired primary and met samples from the same patient. After patients with unrelated second primary cancers were excluded, 113 pairs were used for analysis. McNemar's test was used to compare primary and met tumor pairs. Results: The most common sites of mets were liver (33%), lung (19%), and peritoneum (18%). The average time between samples was 21.3 months (range 1-92). KRAS status changed in 13.2% of pairs (5.7% gained, 7.5% lost, n = 53, P = 0.710), TP53 status changed in 16.1% (16.1% gained, 0% lost, n = 31, P = 0.025), and SMAD4 status changed in 14.8% (7.4% gained, 7.4% lost, n = 27, P = 1.000). Mets gained expression of TOPO1 (37.5%, n = 80, P = 0.003), TOP2A (42.6%, n = 47, P = 0.003), PTEN (27.3%, n = 66, P = 0.050), and PD-L1 (11.1%, n = 36, P = 0.180). Tumor mutational burden (TMB) increased in mets in 11 of 12 pairs with TMB data (mean 6.67 v. 4.42 mutations per megabase, P = 0.0015 by Wilcoxon signed-rank test). Conclusions: KRAS mutational status between primary and met PDAC pairs was usually concordant but changed more often than previously reported. TOPO1, TOP2A, and PTEN expression were significantly discordant. The rate of discordance and increase in TMB support profiling of PDAC mets. Continued research into which mutations play key roles in PDAC mets could yield new targets for future therapies.
Fully automated PCR detection of KRAS mutations on pancreatic endoscopic ultrasound fine needle aspirates.
Authors: Dario De Biase, Caterina de Luca, Gianluca Gragnano, Umberto Malapelle, Giovanni Tallini, Giancarlo Troncone
Journal: Journal of Clinical Oncology (2016)

e15726 Background: In both cystic and solid pancreatic lesions, the assessment of KRAS mutational status can refine the diagnosis of uncertain endoscopic ultrasound (EUS) fine needle aspiration. However, this test should have a fast turnaround time, in line with the need of urgent clinical actions. Thus, rather than outsourcing suspicious EUS-FNA to a few referral molecular pathology laboratories, KRAS testing should be carried out in the same center where the patient is diagnosed, enabling the slide with the highest neoplastic cell content to be easily selected from in-house collected cytological material. The Idylla KRAS Mutation Test performed on a fully-automated platform, provides sample to result functionality, enabling method standardization even in those diagnostic units without molecular expertise and infrastructure. Methods: The Idylla KRAS Mutation Test was designed and intended for use with formalin-fixed paraffin-embedded (FFPE) sections. However, we directly pipetted 3 µl (corresponding to 1/5th of a DNA preparation from the FNA sample) in the cartridge which was automatically run as if a FFPE sample had been inserted. The clinical performance of the Idylla KRAS test was compared to Sanger sequencing, Allele Specific Locked Nucleic Acid PCR (ASLNAqPCR) and 454 Next Generation Sequencing (454-NGS) in light of clinico-pathological end-points Results: Idylla yielded valid results in 49/52 (94,2%) cases, in approximately two hours. A total of 18/49 cases showed a mutation either in KRAS exon 2 (14/18) or in exon 3 (4/18). Idylla KRAS Test had 100% specificity and a clinical sensitivity (55,1%) higher than Sanger sequencing (41,3%) and identical to that of ASLNAqPCR (55,1%). When the low-abundant mutant allele ( < 5%) cases were excluded from the analysis, the Idylla KRAS Mutation Test clinical sensitivity increased to 61,9% approaching that of 454 NGS (66,6%). Conclusions: This is the first study that applied the novel Idylla KRAS test to the clinical setting of pancreatic cancer. In particular, this system can be easily implemented in the routine assessment of pancreatic EUS-FNA-derived DNA samples to quickly provide information on KRAS mutational status to supplement cytological evaluation.
Chest x-ray (CXR) screening to improve outcomes in lung cancer: Reanalysis of the lung cancer component of the Prostate-Lung-Colorectal-Ovary (PLCO) randomized controlled trial.
Authors: John Paul Flores, Alejandro Moreno-Koehler, Matthew Finkelman, Jaime Caro, Gary M. Strauss
Journal: Journal of Clinical Oncology (2018)

1552 Background: CXR screening for lung cancer is considered ineffective because no randomized trial demonstrated a lung cancer mortality reduction. However, in the Mayo Lung Project, CXR screening has been reported to produce significant survival advantages not attributable to overdiagnosis or other screening biases (JCO: 20: 1973-83, 2002). PLCO compared CXR to no screening and reported no lung cancer mortality reduction after 13 years. Lung cancer survival was not reported. That analysis included all lung cancers diagnosed over 13 years, though active screening lasted only 3 years. Since screening is unlikely to benefit individuals diagnosed many years after screening is discontinued, we evaluated lung cancer outcomes among cases diagnosed only within 4 years of randomization. Methods: PLCO randomized 77,445 subjects to an experimental group (EG) undergoing a prevalence CXR and 3 annual incidence CXRs and 77,456 to an unscreened control group (CG). Lung cancer survival and mortality were calculated for all lung cancers diagnosed during the 13-year follow-up and those diagnosed only within 4 years of randomization. Results: After 13 years, 1,838 and 1,737 lung cancers were detected in EG and CG (RR = 1.06; 95%CI 0.99-1.13; p = 0.09). Five year survival was 24% vs. 19% in EG and CG (p < 0.001). There were 1,217 and 1,203 lung cancer deaths, indicating no mortality reduction (p = 0.77). Within 4 years of randomization, 658 and 582 lung cancers were detected in EG and CG (RR = 1.13; 95%CI 1.01-1.13; p = 0.030). Five-year survival was 27% vs. 18% in EG and CG (p < 0.001). Among these, there were 463 and 481 lung cancer deaths, a difference not statistically significant (p = 0.58). Conclusions: In PLCO, randomization to CXR screening produced a significant improvement in lung cancer survival, an advantage not attributable to any screening bias, including overdiagnosis as lung cancer incidence was not statistically different. The benefit is diminished when lung cancers diagnosed well beyond the active screening interval are included. This analysis supports that CXR screening did save lives in PLCO among patients diagnosed during the active screening period.
42-month follow-up of sonidegib efficacy and safety in advanced basal cell carcinoma: Final analysis from BOLT.
Authors: Michael Robert Migden, Karl D. Lewis
Journal: Journal of Clinical Oncology (2018)

9551 Background: Sonidegib is a hedgehog pathway inhibitor (HPI) approved in the United States for the treatment of adult patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy; and in Switzerland and Australia also for metastatic basal cell carcinoma (mBCC). Here we report the final analysis at 42 months from the phase 2 BOLT study, the longest follow-up data available from a clinical trial of an HPI. Methods: BOLT was a randomized, double-blind, multicenter, phase 2 study. HPI treatment–naïve patients (N = 230) with advanced BCC (laBCC, n = 194; mBCC, n = 36) not amenable to curative surgery/radiotherapy were randomized 1:2 to sonidegib 200 mg, or to 800 mg QD, respectively. Data analyses were performed at 6, 12, 18, 30, and 42 months. The primary endpoint was objective response rate (ORR) per central review. Secondary endpoints included rate of complete response, duration of response (DOR), time to tumor response (TTR), progression free survival (PFS), and safety. Results: Primary and secondary endpoint results were very similar to the 30-month data (Table). Tumor responses were durable in patients with either subtype of advanced BCC (≥23 months). The safety profile of sonidegib was manageable and consistent with prior analyses. Conclusions: Efficacy was maintained at the 42-month analysis, with no new safety signals identified. These data continue to support sonidegib’s durability of response in patients with advanced BCC. Proactive management of adverse effects may prolong treatment duration and improve outcomes.Clinical trial information: NCT01327053.Sonidegib efficacy at 6, 30 and 42 months in advanced bcc by central review. 6 months 30 months 42 months laBCC mBCC laBCC mBCC laBCC mBCC 200mg n = 66 800mg n = 128 200mg n = 13 800mg n = 23 200mg n = 66 800mg n = 128 200mg n = 13 800mg n = 23 200mg n = 66 800mg n = 128 200mg n = 13 800mg n = 23 ORR, % 47.0 35.2 15.4 17.4 56.1 45.3 7.7 17.4 56.1 46.1 7.7 17.4 DCR, % 90.8 78.2 92.3 82.6 90.8 82.1 92.3 91.3 90.9 82.0 92.3 91.3 DOR, mo NR NR NR 8.3 26.1 23.7 24.0 NR 26.1 23.3 24.0 NE PFS, mo NR NR 13.1 7.6 22.1 22.0 13.1 11.1 22.1 24.9 13.1 11.1 DCR: disease control rate; NE: not estimable; NR: not reached