bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of NRG1 gene fusion events in solid tumors.
Authors: Jonna Sushma , Feldman Rebecca , Ou Sai-Hong Ignatius , Nagasaka Misako , Swensen Jeffrey , Korn Wolfgang Michael , Borghaei Hossein , Vanderwalde Ari M. , Lopes Gilberto , Nieva Jorge J. , Spira Alexander I. , Kim Edward S. , Liu Stephen V. 
Published: May 2020

3113 Background: NRG1 fusions are actionable genomic alterations detected across tumor types. The NRG1 gene encode for neuregulin, which serves as a ligand for ERBB3 and ERBB4 receptors and activates downstream signaling through the MAPK and PI3K pathways. Here, we update the detection of NRG1 gene fusions across tumor types and further describe fusion characteristics. Methods: Samples submitted for clinical molecular profiling that included RNA-sequencing (Archer Dx or Caris MI transcriptome) were retrospectively analyzed for NRG1 fusion events. All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. Results: A total of 82 NRG1 fusion events (0.2% of 44,570) were identified. Among the fusions identified, the distribution across tumor types was as follows: non-small cell lung cancer (NSCLC, 54%), breast cancer (11%), ovarian cancer (7%), pancreatic cancer (7%), cholangiocarcinoma (6%), colorectal cancer (5%), and other (10%). Forty-two unique fusion partners were identified, the most common being CD74 (23%), ATP1B1 (9%), SLC3A2 (7%), RBPMS (6%) and SDC4 (4%). Almost half (47%) of all fusion events are expected to include the transmembrane domain contributed by the NRG1 fusion partner. Lung and pancreatobilliary cancers had the highest rates of transmembrane domain retention from their fusion partners (63.6% and 54.5%, respectively). In all other tumor groups, most fusion partners lacked transmembrane domains. In 15% of cases, the chimeric transcripts are predicted to lead to increased expression of NRG1. The most commonly reported breakpoints in NRG1 occur in exon 6 and exon 2. While fusions with the NRG1 breakpoint at exon 2 retain the immunoglobulin (Ig) domain and all downstream portions (including EGF-like domain), those at exon 6 do not contain the Ig portion and result in shorter chimeric proteins. The breakpoints in all CD74:NRG1 fusions, the most common fusions in NSCLC, occur at exon 5 or 6 and cause truncation of domains upstream of the EGF-like domain. In ATP1B1:NRG1 fusions, the most common fusions in pancreatobilliary cancers, the breakpoints are at exon 1 or 2 and retain the Ig domain. Conclusions: NRG1 fusion products are diverse across tumor types, but the significance of these variations is not clear. The biological and clinical implications of retaining certain domains of NRG1 (such as the Ig domain) and of fusion partners warrants further investigation.
Deep learning-based immune phenotype analysis reveals distinct resistance pattern of immune checkpoint inhibitor in non-small cell lung cancer.
Authors: Ock Chan-Young , Park Sehhoon , Yoo Inwan , Shin Jisoo , Lee Seungje , Lee Sarah , Paeng Kyunghyun , Choi Yoon La , Mok Tony S. K. , Lee Se-Hoon 
Published: May 2020

3119 Background: Resistance pattern and biological mechanism of immune checkpoint inhibitor (ICI) has been poorly understood. Sine suggested resistance mechanisms would be either innate resistance caused by lack of immune recruitment or acquired immune evasion after durable response of ICI treatment, we hypothesized that resistance pattern of tumor microenvironment would be distinct according to duration of ICI response in non-small cell lung carcinoma (NSCLC). In the current study, we applied deep-learning-based classification of three immune phenotypes (3IP): inflamed, excluded, and desert, to objectively assess the immunologic status of tumor microenvironment. Methods: Deep-learning algorithm of H&E Whole-Slide Images (WSI), called Lunit-SCOPE, was trained with 1,824 H&E WSI of NSCLC from Samsung Medical Center (SMC). WSI was divided into patches and each patch (~10 high-power fields) was classified as inflamed, excluded and desert, based on both quantity and localization of immune cells. Among NSCLC patients treated with ICI in SMC, 87 paired treatment-naïve (Pre, patch N = 15,415) and post-progression (Post, patch N = 18,197) tumor tissues were analyzed for Lunit-SCOPE. Results: In 87-paired samples, proportions of excluded and desert phenotypes were increased in post-progression tumor tissues (excluded; Pre 26.8% versus Post 32.5%, desert; Pre 19.5% versus Post 25.3%). Focused on 29 patients classified as inflamed in treatment-naïve, proportion of immune phenotypes of post-progression were clearly different according to duration of response, divided by median progression-free survival (PFS) of 3.7 m. Patients with rapid progression without ICI response (PFS < 3.7 m) turned into desert type (46.2%), whereas durable responder (PFS ≥ 3.7 m) either still remained on inflamed phenotype (42.9%) or turned into excluded phenotype (21.4%). Patients who remained on inflamed phenotype had favorable overall survival after progression on ICI, compared to turned into desert type (median survival not reached versus 6.6 m, P= 0.0296). Conclusions: Resistance patterns of ICI are distinct according to duration of response in patients with inflamed phenotype. Rapid progressor turns off immune into desert phenotype whereas most durable responder keeps immune recruitment into tumor microenvironment, which needs tailored strategy to overcome ICI resistance.
Extrachromosomal DNA (ecDNA) carrying amplified oncogenes as a biomarker for insensitivity to pembrolizumab treatment in gastric cancer patients.
Authors: Christiansen Jason H. , Nguyen Nam-phuong , Verhaak Roel , Kim Hoon , Bafna Vineet , Mischel Paul , Hassig Christian 
Published: May 2020

3123 Background: In the KEYNOTE-059 study, the anti-PD-1 checkpoint inhibitor pembrolizumab was shown to have a modest overall response of 11.6%. Common predictors of response including, high microsatellite instability (MSI-H), PD-L1 expression, tumor mutational burden (TMB) and tumor inflammation signature (TIS), were not individually sufficient for patient selection. Recent pancancer studies have highlighted a unique population of cancer patients whose tumors appear to be driven by oncogene amplifications on extrachromosomal DNA (ecDNA). These ecDNA-driven tumors are aggressive and characterized by high levels of genomic instability. We sought to understand if tumors that possess ecDNA may represent a subset of the patient group that is non-responsive to anti-PD-1 therapy. Methods: We determined the ecDNA status of gastric cancer patients (N = 108) using whole genome sequencing (WGS) from the TCGA Pan-cancer dataset These patients had been previously subtyped for EBV status, genomic stability (GS), microsatellite instability (MSI), and chromosomal instability (CIN). Patients that were ecDNA+ were re-classified into a set regardless of gastric subtype. Additionally, TMB, TIS, and PD-L1 expression levels were collected. Results: 32% of gastric cancer patients were positive for ecDNA signatures and mutually exclusive from the 23% of MSI-H patients. We found that ecDNA positive tumors had statistically significantly lower TIS than all other groups (p-value < 0.05) except CIN tumors (p-value = 0.09). The ecDNA positive tumors also had lower PD-L1 expression than all but GS tumors. Only MSI-H showed statistically significantly higher TMB scores compared to every other group (p-value < 0.001), no difference in TMB scores were observed between every other pair of groups. Conclusions: Patients whose tumors are ecDNA positive represent a unique population that display signatures for non-response to checkpoint inhibitor therapy, including MSS, low TIS, and PD-L1 expression. Thus, the determination of tumor ecDNA status may have utility as an additional patient selection strategy for checkpoint inhibitor therapy. As ecDNA are not limited to gastric cancers, this study highlights the importance of the development of a clinical diagnostic test for ecDNA status and the need for further research on ecDNA biology, its impact on immunotherapy response, and potential ecDNA-directed therapeutics
CIMAC-CIDC tissue imaging harmonization.
Authors: Akturk Guray , Parra Cuentas Edwin Roger , Lako Ana , Gjini Evisa , Espiridion Beatriz Sanchez , Wistuba Ignacio Ivan , Thurin Magdalena , Hewitt Stephen M. , Rodig Scott , Zhang Jiexin , Neuberg Donna S. , Lee J. Jack , Gnjatic Sacha , Tetzlaff Michael T. ,   CIMAC-CIDC Network
Published: May 2020

3125 Background: The Cancer Immune Monitoring and Analysis Centers Cancer Immunology Data Commons (CIMAC-CIDC) network is a NCI Cancer Moonshots initiative to provide state-of-the-art technology and expertise for immunotherapy clinical trials. Multiplex tissue immunostaining is an integral assay provided that examines density and spatial distribution of immune cells and markers in tissues, for their prognostic or predictive value. Two approaches were evaluated for sensitivity, specificity, and reproducibility and subsequently harmonized: chromogenic-based Multiplex Immunohistochemical Consecutive Staining on Single Slide (MICSSS) and Multiplex Immunofluorescence (mIF) based tyramide signal amplification system. Methods: Harmonization was performed across CIMACs (Mount Sinai, Dana Farber Cancer Institute, MD Anderson Cancer Center) in multiple steps to prove that comparable data can be generated independent of site and platform. Goals: 1) harmonize image analysis platforms alone using tissues pre-stained with single chromogenic IHC for CD3 (membrane), Ki67 (nuclear), and CD68 (cytoplasmic), 2) compare image acquisition platforms, 3) streamline Antibody (Ab) clones and assess PD-L1 detection in relation to CLIA- assays, 4) harmonize staining protocols, image acquisition, and analysis platforms on 2 test head and neck tumor samples using MICSSS and mIF, 5) validate harmonization results with a tissue microarray on 27 tissues representing multiple tumors. For last steps, each CIMAC used their platforms for PD-L1, PD-1, CD3, CD8, and pan-cytokeratin (PanCK) staining on one of three consecutive slides from serial sections and compared densities of each marker. Results: Variables as PD-1 Ab clone, positive control reference tissues, sigma value for nuclear segmentation, and use of machine-learning based cell classifier were found to be key to produce accurate, reliable, comparable data. After visual quality control assessment and comparisons of each Region Of Interest (ROI), an overall inter-site Spearman correlation coefficient of ≥0.85 was achieved per marker within each tissue and across tissue types (expect pan-Cytokeratin, ≥0.7), with average coefficient of variation ≤0.1. Conclusions: These results show for the first time that two platforms can deliver harmonized data, despite differences in protocols, platforms, reagents, and analysis tools. Data resulting from retrospective and prospective CIMAC-CIDC analyses may be used with confidence for statistical associations with clinical parameters and outcome.
Immune-mediated adverse events following concomitant radiotherapy and immunotherapy in patients with melanoma and Merkel cell carcinoma: A preliminary report from an evolving retrospective registry.
Authors: Andreatos Nikolaos , Roopkumar Joanna , Khorana Alok A. , Funchain Pauline 
Published: May 2020

3144 Background: Radiotherapy (RT) potentiates immune-mediated responses against tumor antigens, an effect that is enhanced by checkpoint inhibitors (CPIs) and may hold therapeutic promise. However, the mechanisms underlying this abscopal effect can theoretically increase the rate of immune-mediated adverse events (irAEs). We estimated the incidence of irAEs in a single-institution cohort treated with concomitant RT and immunotherapy. Methods: We retrospectively screened 731 patients that received RT and CPIs at our institution. Patients diagnosed with melanoma or Merkel cell carcinoma (MCC) who underwent RT concurrently or within 30 days of CPI administration were eligible. A radiation period (RP) comprised the interval between the first and last treatment days (≤90 days); a patient could contribute multiple RPs. Data on new irAEs diagnosed within 3 months after RT and relevant demographic and clinicopathologic variables were collected; univariate analysis was performed with the chi-squared test. Results: 35 patients (23 male, 12 female) contributed 43 RPs; mean age was 65.5 years (range: 39-90). Five had MCC, and 30 had melanoma (24 cutaneous, 1 uveal and 5 urogenital melanomas). PD-1 inhibitors were most commonly employed (22 RPs), followed by ipilimumab-nivolumab (14 RPs), ipilimumab (4 RPs), and avelumab (3 RPs). CPIs were administered concurrently with RT in 32 RPs and sequentially in 11 RPs. Fourteen RPs comprised intracranial radiation. Importantly, 45.7% of patients (16/35) experienced irAEs, which manifested within a month of RT in 25.7% (9/35). Four patients experienced grade ≥3 irAEs leading to hospitalization; one died of respiratory failure after developing pneumonitis. On univariate analysis, no significant association between tumor type, CPI regimen, concurrent RT, intracranial vs. extracranial RT, and irAE incidence was noted. A trend for increased irAEs within the ipilimumab-nivolumab group was observed (p = 0.27). Conclusions: Almost half of patients developed new irAEs following RT, with 25% (4/16) of cases warranting hospitalization; these incidence rates appear to exceed rates from historical data and raise concerns about the additive toxicity of CPIs and RT. Comparison to non-RT cohorts and survival analyses are ongoing.
First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI).
Authors: Petrylak Daniel Peter , Gao Xin , Vogelzang Nicholas J. , Garfield Mary Harlow , Taylor Ian , Dougan Moore Marcia , Peck Ronald Alan , Burris Howard A. 
Published: May 2020

3500 Background: Proteolysis Targeting Chimera (PROTAC) protein degraders induce selective degradation of targeted proteins by engaging the ubiquitin proteasome system. ARV-110 is an orally bioavailable PROTAC that specifically degrades AR ≥ 95% and achieves anti-tumor activity in ENZ-naïve and -resistant prostate cancer xenograft models. Methods: To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ARV-110, pts with ≥ 2 prior therapies for mCRPC, including ENZ and/or ABI, received ARV-110 orally once daily. Dose escalation is per 3+3 design. Endpoints include dose limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics (PK), biomarkers (e.g., AR mutation analysis), RECIST and PSA response. Results: By January 2020, 18 pts were dosed: 35 mg (N = 3), 70 mg (N = 4), 140 mg (N = 8), 280 mg (N = 3). 12 pts received both ENZ and ABI; 14 received prior chemotherapy. 1 of 18 pts experienced a DLT (280 mg) of Grade (Gr) 4 elevated AST/ALT followed by acute renal failure while taking rosuvastatin (ROS). A 2nd pt had Gr 3 AST/ALT with ROS that resolved off ROS, permitting ARV-110 retreatment. ROS plasma concentrations demonstrated significant increases concurrent with AST/ALT elevations in both pts. Subsequently, ROS was prohibited without further ≥Gr 2 AST/ALT AEs. No other related Gr 3/4 AEs were reported. ARV-110 PK was generally dose proportional and at 140 mg reached levels associated with preclinical anti-tumor activity. 15 pts were evaluable for PSA response (excludes 1 pt stopped after 1 dose for early progression and 2 pts initiated 2 weeks before cutoff, all at 140 mg). Of these, 8 pts initiated dosing at ≥140 mg. 2 pts achieved confirmed PSA declines of >50%, both at 140 mg. Prior therapy in both pts included ENZ and ABI, chemotherapy, bicalutamide and radium-223 plus other regimens. 1 pt had 2 AR mutations known to confer ENZ resistance. The 2nd pt also achieved an unconfirmed RECIST partial response (confirmatory scan pending). Both responses were ongoing at data cutoff (8+ and 21+ weeks of treatment). Conclusions: To date, ARV-110 has an acceptable safety profile. Concurrent ROS is now prohibited. MTD has not yet been established; determination of RP2D continues. ARV-110 demonstrates antitumor activity in mCRPC after ENZ/ABI with 2 ongoing confirmed PSA responses, one of which was associated with tumor reduction. Updated data for this first PROTAC in clinical testing will be presented. Clinical trial information: NCT03888612 .
Results from a phase I, open-label study of ceralasertib (AZD6738), a novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer (NCT02630199).
Authors: Lee Jeeyun , Tae Kim Seung , Smith Simon , Mortimer Peter G. , Loembé Bienvenu , Hong Jung , Kozarewa Iwanka , Pierce Andrew , Dean Emma 
Published: May 2020

3503 Background: Ataxia Telangiectasia and Rad3 Related (ATR) is an apical kinase with a critical role in the DNA-damage response. During normal DNA replication, ATR is recruited at stalled replication forks which can progress to double strand breaks if left unrepaired. AZD6738 is an oral inhibitor of the serine/threonine protein kinase ATR, a member of the phosphoinositide 3-kinase related kinase (PIKK) family. Methods: Eligible patients (pts) with advanced solid tumours were administered AZD6738 in combination with fixed dose paclitaxel 80 mg/m2 D1, D8, D15 in 28-day cycles. The dose of AZD6738 was escalated to reach a maximum tolerated dose (MTD) in a rolling 6 design. The trial evaluated safety, MTD, pharmacokinetics (PK) and pharmacodynamics (PD). Translational studies on plasma samples included cytokine analysis, panel sequencing of ctDNA, as well as IHC and immunofluorescence of immune cell markers. Results: 58 pts (34 melanoma, 15 gastric cancer (GC), 4 sarcoma, 3 colon cancer, 1 neuroendocrine and 1 hepatocellular cancer) were enrolled in 7 dose cohorts ranging 40mg OD to 240 mg BID. One dose-limiting toxicity (DLT) of neutropenic fever occurred in each cohort of n = 6 evaluable pts at AZD6738 160 mg BD and 240 mg BD days 1-14. Per protocol, the maximum tolerated dose of AZD6738 is 240 mg BID days 1-14. The most common toxicities (all causality, all grade) were: anorexia/nausea (n = 15, 26%), leukopenia (n = 11, 19%) and anemia (n = 11, 19%). 51 pts are evaluable for efficacy; we observed 1 complete response (1.9 %, melanoma), 12 confirmed partial responses (23.5%; 2 gastric, 10 melanoma all of which were post-immunotherapy), 18 stable disease (35.3%) and 20 disease progression (39.2%). The overall confirmed response rate from the dose escalation is 25.5%. Genomic analysis of baseline plasma (27 pts) revealed enrichment of NF1 somatic mutations and activating NRAS mutations amongst melanoma pts (6/18 and 4/18, respectively). Cyclical changes in interleukin-12 levels were observed in three pts with disease control which could reflect an immunological component to the mechanism of response. We will present a comprehensive case report of a patient with dramatic and durable response. Conclusions: We conclude that AZD6738 can be safely combined with weekly paclitaxel and propose a recommended phase II dose and schedule. The combination of AZD6738 and paclitaxel demonstrated promising anti-tumor activity with durable responses, especially in melanoma pts after failing anti-PD1 therapy. Clinical trial information: NCT02630199 .
Phase I monotherapy dose escalation of RGX-202, a first-in-class oral inhibitor of the SLC6a8/CKB pathway, in patients with advanced gastrointestinal (GI) solid tumors.
Authors: Bendell Johanna C. , Strauss James Fredric , Fakih Marwan , McRee Autumn Jackson , Hendifar Andrew Eugene , Rosen Lee S. , Cercek Andrea , Rowinsky Eric Keith , Szarek Michael , Gonsalves Foster , Kurth Isabel , Andreu Celia , Busby Robert , Spector Scott , Darst David Martin , Tavazoie Masoud , Raza Syed , Lebaka Narayan , Wasserman Robert , Janjigian Yelena Yuriy 
Published: May 2020

3504 Background: About 65% of advanced colorectal cancer (CRC) patients (pts) have creatine kinase B (CKB) expressing tumors. CKB expressing (CKB+) GI cancer cells import creatine via the creatine transporter SLC6a8 and utilize it to generate intracellular ATP. RGX-202, a small molecule inhibitor of SLC6a8, reduces intracellular creatine and ATP levels, leading to apoptosis. RGX-202 treatment triggers complete tumor regressions in multiple CKB+ preclinical models, including KRAS mutant CRC. Methods: RGX-202-001 is a phase I escalation/expansion study of RGX-202 +/- FOLFIRI in pts with advanced GI tumors. The primary safety objective during dose escalation is to identify the maximum tolerated dose (MTD), or the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed. The primary efficacy objective is to estimate the antitumor activity of RGX-202 by RECIST. Results: As of January 31, 2020, 17 pts have been treated in 4 single agent dose escalation cohorts: 600 mg BID (3 pts), 1200 mg BID (4 pts), 2400mg BID (5 pts) and 3600mg BID (5pts) given continuously. No DLTs were observed and an MTD was not reached. Treatment-related adverse events (TRAEs) occurring in > 2 pts are shown in the Table. There were no Grade 4 TRAEs. At the highest dose, 2 of 3 CRC pts had prolonged disease control: a patient with a KRAS G13D mutant cancer had SD for 14 weeks; and a patient with KRAS G12V mutant (MSS) cancer had a confirmed PR ongoing at 30 weeks. Exposure to RGX-202 was greater than dose-proportional and the average AUC0-24 ranged from ~15,700 ng-hr/mL in cohort 1 to 241,097 ng-hr/mL in in Cohort 4. Serum and urine creatine levels, pharmacodynamic markers of SLC6a8 inhibition, correlated with systemic exposure to RGX-202. Conclusions: Among 17 patients treated with single agent therapy, no DLTs occurred; notably, exposures predicted to be sufficient to inhibit human tumor growth from preclinical models were achieved along with concomitant pharmacodynamic effects. These data, along with a durable PR observed in the highest dose cohort, support further development of RGX-202. Consequently, dose escalation in combination with FOLFIRI in patients with advanced GI cancers is underway with plans for expansion in CKB+ CRC pts. Clinical trial information: NCT03597581 . [Table: see text]