tbuckley/cabot-search huggingface dataset:
P04.62 The oncometabolite R-2-Hydroxyglutarate suppresses the innate immune microenvironment of IDH1-mutated gliomas via aryl hydrocarbon receptor signaling
Authors: M Friedrich, L Bunse, T Bunse, E Green, T Kessler, S Pusch, K Sanghvi, R Carretero, I Gutcher, A von Deimling, W Wick, M Platten
Journal: Neuro-Oncology (2018)

IDH1-mutated gliomas are associated with less abundant and phenotypically skewed innate and adaptive immune cell infiltrates compared to IDH1 wild-type tumors. Despite this, the most frequent mutation - IDH1R132H - represents a clonal shared neoantigen and mutations in IDH are associated with a more favorable prognosis. While the tumor cell-intrinsic consequences of the oncometabolite R-2-hydroxyglutarate (R-2-HG) accumulating in IDH1-mutated gliomas as a result of a neomorphic enzymatic function, are well-characterized, potential direct paracrine effects of R-2-HG influencing the glioma immune microenvironment remain incompletely understood. This study aimed at characterizing the impact of the oncometabolite R-2-HG on the innate immune microenvironment of IDH1-mutated gliomas. By means of comprehensive analyses of expression datasets from human gliomas and syngeneic murine tumor models as well as transporter studies we demonstrate that R-2-HG is imported by both microglia and macrophages via SLC family transporters and suppresses their function in a paracrine manner. Functional analyses of microglia and macrophages indicate an R-2-HG-driven induction of tolerogenicity as evidenced by accumulation of IL10 and TGFβ and suppression of MHC-II expression, which results in impaired activation of antigen-specific T cells and activation of immune checkpoint molecules. Multi-level signature profiling of human tumor-infiltrating as well as primary immune cells was complemented by reporter gene assays and pathway analyses and revealed that R-2-HG activates the cytosolic transcription factor aryl hydrocarbon receptor (AHR), a key immunomodulatory target of immunosuppressive tryptophan metabolism. By means of knockout models, the observed immunosuppressive phenotype was shown to be AHR-dependent. Functional relevance of R-2-HG-mediated, AHR-driven impairment of myeloid cell immunity was demonstrated in vivo by pharmacological AHR inhibition, increasing the efficacy of checkpoint blockade. R-2-HG impairs antitumor immunity in IDH1-mutated gliomas by activating the AHR in innate immune cells, thus suppressing the innate immune microenvironment by compromising antigen presentation and activation of antigen-specific T cells. This, together with recent findings on inhibitory effects on T cell immunity, represents a novel mechanism of immune evasion of an immunogenic driver mutation and opens a novel therapeutic approach to IDH1-mutated gliomas.
Topotecan (T) ± sorafenib (S) in platinum-resistant ovarian cancer (PROC): A double-blind placebo-controlled randomized NOGGO–AGO intergroup Trial—TRIAS.
Authors: Jalid Sehouli, Felix Hilpert, Sven Mahner, Tanja Neunhoeffer, Philipp Harter, Nikolaus de Gregorio, Claudius Fridrich, Susanne Markmann, Rolf Richter, Jochem Potenberg, Ralf Lorenz, Peter Klare, Marcus Schmidt, Petra Krabisch, Isolde Groell, Gabriele Doering, Antje Belau, Hans-Joachim Lueck, Andreas Du Bois, Radoslav Chekerov
Journal: Journal of Clinical Oncology (2016)

5522 Background: Sorafenib (S), a multi TK-inhibitor in combination with topotecan (T), a topoisomerase inhibitor showed preclinical synergistic effects in ovarian cancer but critical toxicity. To avoid cumulative toxicity effects we selected the 5-day schedule of T and a sequential combination with S. Methods: Eligible pts with PROC (progression ≤ 6 mo after ≥ 4 platinum cycles) and ≤ 3 prior CT lines were randomized 1:1 to topotecan 1,25mg/m², d1-5, q21d with either placebo or sorafenib 2x400 mg/daily, d6-15 for 6 chemotherapy cycles, and maintenance sorafenib 2x400 mg/placebo daily for altogether 1 year. The number of treatment lines was stratified (2nd vs. 3rd/4th line). The primary objective was PFS. Secondary endpoints include OAS, objective response, safety and PRO measured by EORTC-QLQC30, OV28 and FOSI. Results: Overall, 172 pts were eligible for analysis. The median age was 59 (25-79 years) whereas 72 pts were in the second and 100 in the ≥ third line. 54.7% of the patients received 6 cycles chemotherapy. Addition of S to T induced no additional severe toxicity grade 3/4, but more hand-foot-skin reactions (13.3% vs. 0%; p<0.001) and alopecia grade 2 (28.9% vs. 13.5%; p=0.015) without significant clinical sequel. TS improved significantly PFS with 6.7 vs. 4.4 months (HR 0.6, 95%CI of 0.43-0.83, p=0.002) and OAS with 17.1 vs. 10.1 months (HR 0.65, 95%CI of 0.45-0.93, p=0.017). Both effects were robust as well in the 2nd and ≥3rd line subcohorts. Changes in PRO from baseline to end of therapy were not significantly different between groups, except of one symptom scale (attitude to disease and treatment with more improvement in TS, p=0.038). Conclusions: This is the first trial in PROC providing statistically significant and clinically meaningful improvement in PFS and OAS under implementation of oral multikinase inhibitor. Clinical trial information: NCT01047891.
Characterization of differential genetic expression profiles in mesenchymal and epithelial components of uterine and ovarian carcinosarcomas.
Authors: Abraham Hernandez Blanquisett, Raquel Lopez-Reig, Ignacio Romero, Jose Antonio Lopez-Guerrero, Isidro Machado, Carmen Illueca Ballester, Martin Ore, Andres Poveda
Journal: Journal of Clinical Oncology (2017)

e17104 Background: Gynecologic carcinosarcomas (GCS) are rare tumors with poor prognosis. Reasons include a high percentage of advanced stage at diagnosis and a low response to conventional treatments. GCS constitutes a model for research in both tumoral heterogeneity and the epithelial-mesenchymal transition (EMT) process. Our aim is to define molecular expression heterogeneity in GCS distinct morphologic components. Methods: A retrospective, single institution, IRB approved study of 13 patients diagnosed with GCS was undertaken. Total RNA was extracted from representative FFPE tissue blocks of both the epithelial and mesenchymal components. The expression profile for each component (n = 26) was determined using the GeneChip WT Pico Reagent Kit and the Clariom D Array (Affymetrix Inc., Santa Clara, CA, USA). Robust multi-array normalization (RMA) and t-statistics was used for detecting differentially expressed genes between the studied conditions. Genes with a p-value &lt; 0.05 and with an absolute fold change (FC) value &gt; 1.5 were selected as significant. Results: A total of 13 cases representing 26 distinct samples, 9 uterine (UCS) and 4 ovarian carcinosarcoma with a median age of 68 (range: 45-81), 38% presented FIGO IIIC-IV stage at diagnosis. Among UCS, 5 women had a previous personal history of breast cancer. A total of 101 genes appeared as differentially expressed between epithelial and mesenchymal components, highlighting 5 of them: HMGA2 (FC = 2.15, p = 0.04) and ERBB4 (FC = 2.14, p = 0.005) overexpressed in epithelial component and ANX2 (FC = 1.95, p = 0.0006), SPP1 (FC = 2.15, p = 0,005) and ERRFI1 (FC = 1.95, p = 0.001) overexpressed in mesenchymal component. Conclusions: This is the first expression profiling in GCS that helps identify candidate genes that show a distinct expression in mesenchymal and epithelial components that could have a potential prognostic and predictive role.
A drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies.
Authors: Jacqueline Ramirez, Larry House, Theodore G. Karrison, Linda A. Janisch, Michelle Turcich, Ravi Salgia, Mark J. Ratain, Manish Sharma
Journal: Journal of Clinical Oncology (2017)

e14066 Background: Warfarin is an anticoagulant and CYP2C9 substrate commonly used in oncology patients. Several studies suggest a drug-drug interaction between capecitabine and warfarin that may be mediated by CYP2C9. Celecoxib is a CYP2C9 substrate that may also have anticancer activity. We aimed to characterize the magnitude and the time course of the capecitabine-celecoxib interaction in cancer patients in order to better understand the effect of capecitabine on CYP2C9. Methods: Patients received 200 mg celecoxib PO twice daily continuously, with capecitabine (1,000 mg/m 2 PO twice daily for 14 days every 21 days) starting 7 days later. Celecoxib and celecoxib-OH pharmacokinetics (PK) were collected on days 7, 14 and 21. Thirteen patients were evaluable for PK analysis. Results: Comparison of steady state PK parameters showed an average 31%, 17% and 34% increase in celecoxib’s Cmax (p = 0.036; paired t-test), Cmin (p = 0.043) and AUC (p = 0.006) between day 7 (celecoxib only) and day 14 (celecoxib + capecitabine), respectively. PK comparison of day 7 vs. day 21 (after one week washout of capecitabine) showed a further increase in Cmax (46%, p = 0.011), Cmin (92%, p = 0.002) and AUC (49%, p = 0.006). Conclusions: Coadministration of capecitabine results in higher exposure to celecoxib, and the interaction persists for at least 7 days after discontinuation of capecitabine. Clinical trial information: NCT01705106.
TCT-646 Platelet to red cell distribution width ratio predicts high on-clopidogrel platelet reactivity in patients with percutaneous coronary intervention
Authors: Mariusz Tomaniak, Lukasz Koltowski, Szymon Jonik, Janusz Kochman, Adam Rdzanek, Arkadiusz Pietrasik, Ewa Pędzich-Placha, Dorota Ochijewicz, Tomasz Mazurek, Aleksandra Gąsecka, Sylwia Gajda, Zenon Huczek, Grzegorz Opolski, Krzysztof Filipiak
Journal: Journal of the American College of Cardiology (2018)
Epithelial circulating tumor cells in portal vein are associated with number of liver metastatic nodules of colorectal cancer.
Authors: Na Huang, Siting Zheng, Yisheng Fang, Min Shi, Wangjun Liao
Journal: Journal of Clinical Oncology (2017)

e15026 Background: Colorectal cancer has been one of the most diagnosed cancers worldwide, and circulating tumor cells (CTCs), resulting in colorectal liver metastases (CLM), relate to its mortality. Although the mechanism and prognostication of metastasis has attracted a broad interest, the definite relationship between CLM and different phenotype of CTC is still not sufficient. Our objective is to investigate the clinical implication of different phenotype of CTCs. Methods: Twenty-one patients with CLM were enrolled in this study. Peripheral venous (PeV) and portal vein (PoV) blood specimens were collected from each patient. Through real-time ultrasound-guided percutaneous portal vein access, Pov blood was collected. Then CTC detection technology was employed to isolate CTCs for categorization. Results: No difference in the number of total CTCs between PoV and PeV, while strikingly, the number of epithelial CTCs was higher in PoV. In patients with unresected primary lesions, epithelial CTCs in PoV were more than that in PeV, while there was no difference in resected ones. Furthermore, we demonstrate that the percentage of epithelial CTCs in PoV relate to the number of liver metastatic nodules. In addition, the increased percentage of epithelial CTCs in the PoV relates to low amounts of lymphocytes. Conclusions: Our study shows that high proportion of epithelial CTCs in Pov relates to increasing number of liver metastatic nodules in CLM.
Screening for Hepatitis B Infection in Pregnant Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force
Authors: Jillian T. Henderson, Elizabeth M. Webber, Sarah I. Bean
Journal: JAMA (2019)

This systematic review to support the 2019 US Preventive Services Task Force Recommendation Statement on screening for hepatitis B infection in pregnant women summarizes published evidence on the benefits and harms of hepatitis B infection screening and case management in pregnant women.
Prognostic value of testosterone levels during chemotherapy with carboplatin plus weekly docetaxel in metastatic castration- and docetaxel-resistant prostate cancer (mDRPC).
Authors: Christoph W. Reuter, Philipp Ivanyi, Viktor GrÃ¼nwald, Christoph AJ von Klot, Michael A. Morgan, Stefan Brunotte
Journal: Journal of Clinical Oncology (2018)

e17069 Background: Recent data suggest that carboplatin plus weekly docetaxel (DC) may be effective in mDRPC. Platinum(II)-complexes interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3ß-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least two cycles of carboplatin AUC5 iv for 30 min on day 1 every 4 weeks (q4w), docetaxel at a dose of 35 mg/m2 iv for one hour on days 1, 8, (15) plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n = 82) and during carboplatin/docetaxel chemotherapy (n = 74). Results: Of the 105 pts. treated since February 2005, 96.2% had bone and 63.8 % soft tissue metastases (45.7 % lymph node, 26.7% liver and 20% lung involvement). At the time of the current analysis, the median follow-up time was 13.5 months, 101 pts. had died and 102 had progressive disease. The objective response rate was 35.8% and the disease control rate 56.8% in the 67 pts. with measureable disease. Response of prostate-specific antigen (≥50%) was observed in 50 patients (47.6%). Median progression-free survival (PFS) for all patients was 6.8 months (CI 95% 5.6, 8.0) and median OS was 14.1 months (CI 95% 11.0, 17.3). The most common reversible grade 3/4 toxicity was leukopenia/ neutropenia (40.9/32.4%). Median free and total testosterone levels were reduced below the detection limit during DC treatment (from 0.56 pg/ml to < 0.18 pg/ml and 0.085 to < 0.05 ng/ml, respectively). Median free testosterone < 0.3 pg/ml during DC treatment were associated with higher PSA response, longer PFS and post-hoc OS (p < 0.05). Conclusions: These data suggest that carboplatin plus weekly docetaxel may be an important second-line treatment option for DRPC patients by inhibition the testosterone biosynthesis.
Fusion detection and longitudinal circulating tumor DNA (ctDNA) profiling in ALK+ non-small cell lung cancer (NSCLC) patients.
Authors: Aurélie Swalduz, Sandra Ortiz-Cuaran, Virginie Avrillon, Solène Marteau, Séverine Martinez, Gilles Clapisson, Laure Montane, David Pérol, Emma Green, Karen Howarth, Frank De Kievit, Clive D. Morris, Maurice Perol, Pierre Saintigny
Journal: Journal of Clinical Oncology (2018)

e21031 Background: Therapeutic response in ALK+ NSCLC is driven by heterogeneous mechanisms of resistance. Liquid biopsy (LB) offers a non-invasive approach to study the tumor genomic landscape under therapy. However, the potential of LB for fusion detection and disease monitoring in ALK+ patients is poorly understood. Methods: LB was performed at diagnosis (n = 10), at each radiologic evaluation (n = 75) and at the time of progressive disease (PD) (n = 34) in 35 FISH/RNAseq confirmed ALK+ NSCLC patients, treated with ALK-TKI. EML4-ALK fusions (variants v1, v2, v3), and a 36–gene panel were investigated in LB using the Inivata InVisionFirst amplicon-based ctDNA NGS assay. Results: Preliminary results show that an EML4-ALK fusion was detected in 4/6 (67%) patients at diagnosis (2 v1, 1 v2 and 1 v3). The 2 patients for whom an ALK-fusion was not detected in LB had intrathoracic disease only. LB collected at the 1st radiographic evaluation under therapy revealed complete clearance of the fusion and associated TP53 mutations in all patients experiencing partial response. ALK resistance mutations were detected in samples collected at PD under crizotinib (L1196M+C1156Y), ceritinib (F1174L), brigatinib (F1174V, F1174L+G1202R, D1203N, R1192P) and lorlatinib (F1174L+G1202R). TP53 and CDKN2A mutations were detected in 41% of the samples. In patients with slow brain PD, fusion and resistance mutations were undetectable, possibly due to low ctDNA release. Among patients with PD, a striking difference in PFS was observed in patients harboring ALK secondary mutations (n = 6) versus those who did not (n = 13) with a median progression-free survival of 4.5 [95%CI: 3-12] vs. 22 [95%CI: 13-30] months respectively (log-rank p-value = 0.0002). Results for the remaining samples will be presented at the meeting. Conclusions: ctDNA profiling is a promising non-invasive alternative for the management of ALK+ NSCLC patients, from the identification of the fusion variant, to the monitoring of response to treatment and to the characterization of resistance mechanisms. Our results suggest heterogeneity in tumor biology regarding acquisition of resistance mechanisms.
Quantifying gender ascertainment bias in hereditary cancer testing.
Authors: Anthony Chen, Allison Anguiano, Ryan Bernhisel, Krystal Brown, Heidi Gorringe, Susan Manley
Journal: Journal of Clinical Oncology (2017)

6516 Background: Historically, hereditary cancer genetic testing has been much more prevalent among women, in part due to gender-specific cancer risks associated with Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Despite expanded genetic testing that includes hereditary cancer syndromes that affect both men and women, the gender gap still persists. Here we report on gender ascertainment bias in hereditary cancer testing by evaluating the proportion of test cancellations in men and women who were not affected with cancer at the time of testing. Methods: A commercial testing cohort was queried to identify individuals for whom genetic testing with a multi-gene pan-cancer panel was ordered between September 2013 and December 2016. Individuals who were ascertained for testing based on a clinical suspicion of HBOC or Lynch syndrome (LS) and did not have cancer at the time of testing were included. Test cancellations (i.e. a test order that did not yield any reported result) due to lack of insurance coverage were assessed, as this is directly related to clinical testing criteria. Results: Genetic testing was ordered for 259,919 individuals who did not have cancer at the time of testing, which included 6007 men (2.3%) and 253,912 women (97.7%). Overall, 21.2% of tests ordered for men were cancelled due to lack of insurance coverage, which is significantly higher than the cancellation rate among women (14.4%, p &lt; 0.001). This trend was observed among individuals tested for suspicion of HBOC (18.7% for men vs. 13.2% for women; p &lt; 0.001), but not for those tested for LS (26.6% for men vs. 25.1% for women; p = 0.137). Among those whose tests were not cancelled, the positive mutation rate was twice as high for men compared to women (9.6% vs 4.6%, respectively; p &lt; 0.001). Conclusions: In this analysis, the proportion of genetic tests ordered was substantially biased towards women. Cancellation rates for men were significantly higher compared to women, while the mutation positive rate was twice as high. Although men and women who are unaffected with cancer have an equal probability of having a family cancer history that meets HBOC testing criteria, the data presented here suggests that there is a higher clinical standard for men to receive genetic testing.
Phase 1 study of the anti-HER3 antibody drug conjugate U3-1402 in metastatic or unresectable EGFR-mutant NSCLC.
Authors: Pasi A. Janne, Helena Alexandra Yu, Melissa Lynne Johnson, Michele Vigliotti, Nicole Shipitofsky, Ferdinand Morales Guevara, Shuquan Chen, Channing Yu
Journal: Journal of Clinical Oncology (2018)

TPS9110 Background: While outcomes for patients with EGFR-mutant NSCLC have significantly improved with the use of EGFR tyrosine kinase inhibitors, there remain limited treatment options for many patients once they develop resistance to these agents. The HER3/ERBB3 oncogene is overexpressed in many cancers, including NSCLC, and higher expression is correlated with poorer outcomes. U3-1402 is a HER3-targeting antibody-drug conjugate (ADC) of high drug-to-antibody-ratio (DAR = 7 to 8) with a novel linker and topoisomerase I inhibitor payload. Methods: This is a multicenter Phase 1, Dose Escalation, and Dose Expansion study of U3-1402 in metastatic or unresectable adenocarcinoma NSCLC subjects harboring EGFR-activating mutation who (a) are T790M mutation-negative after disease progression during treatment with erlotinib, gefitinib, or afatinib or (b) develop disease progression while on osimertinib. Eligible subjects are at least 18 years of age, have ECOG PS 0 or 1, have radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib, have at least one measurable lesion per RECIST v1.1, have adequate bone marrow and organ function, do not have mean QTc prolongation to > 470 ms for females and > 450 ms for males, and do not have spinal cord compression or clinically active brain metastases. In Dose Escalation, subjects receive U3-1402 via intravenous infusion in 21-day cycles. In Dose Escalation, escalation of U3-1402 dosing is based on dose-limiting toxicity data in subjects, guided by the modified Continuous Reassessment Method (mCRM). In Dose Expansion, subjects receive U3-1402 at the recommended dose for expansion (RDE) determined in Dose Escalation. Primary objectives are to determine the safety, tolerability, and RDE of U3-1402. Secondary objectives are to assess the pharmacokinetic parameters of U3-1402 and its components, and to assess antitumor activity of U3-1402 (RECIST v1.1). Enrollment to cohort 1 began in January 2018. Clinical trial information: NCT03260491.