bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adding precision to 2018 ASCO/CAP HER2 testing guidelines in breast cancer with genomic profiling.
Authors: Brufsky Adam , Crozier Jennifer A. , Chuba Paul J. , Lee Sung Ho , Menicucci Andrea , Kling Heather M. , Yoder Erin , Audeh William ,   FLEX Investigators' Group
Published: May 2020

3570 Background: Biological heterogeneity of HER2 positive breast cancers has been suggested by a modest benefit of HER2-targeted therapies reported in the APHINITY and ExteNET trials. This highlights the need for improved biomarkers that more precisely identify patients who benefit from HER2-directed agents. The 80-gene molecular subtyping signature (80GS) classifies breast tumors into Luminal, HER2 or Basal type based on the gene expression of downstream signaling pathways. Previous work showed a substantial proportion of tumors identified as HER2 equivocal or HER2 positive by 2013 ASCO/CAP guidelines may be reclassified as non-HER2 type by 80GS. In 2018, ASCO/CAP HER2 IHC/ISH classification guidelines were revised to reduce the frequency of HER2 equivocal cases, for which treatment recommendations have been ambiguous. Here we evaluated concordance between HER2 status by 2018 ASCO/CAP guideline classification and 80GS molecular subtyping. Methods: Pathology reports are provided by physicians for samples that are tested with the 70-gene risk of distant recurrence signature (70GS) and 80GS as part of routine diagnostic care. This analysis includes data sent to Agendia (Irvine, CA) from January 2019 to January 2020. HER2 IHC/ISH results based on ASCO/CAP 2018 guidelines were available for 1453 samples. Results: Of 1453 samples, 1336 (92%) were HER2 negative, 99 (7%) were HER2 positive, and 18 (1.2%) were HER2 equivocal under 2018 guidelines. 80GS reclassified 57 of 99 (58%) HER2 positive tumors as Luminal and 11 of 99 (11%) as Basal; the remaining 31% were confirmed HER2. Furthermore, 55 of 99 (55%) HER2 positive tumors were also ER and PR positive by IHC, with 48 (87%) of these reclassified as Luminal type. Of HER2 negative tumors, 80GS classified 94 of 1336 (7%) as Basal and 2 of 1336 (0.15%) as HER2. Of HER2 equivocal tumors, 16 of 18 (89%) reclassified as Luminal and 2 of 18 (11%) as Basal. Conclusions: In this real-world diagnostic dataset, 2018 ASCO/CAP guidelines resulted in few HER2 equivocal tumors overall, confirming the positive impact of the revised guidelines. However, 80GS reclassified 69% of HER2 positive tumors to non-HER2 molecular subtypes, suggesting these tumors may have suboptimal responses to HER2-directed therapy compared to HER2 enriched. All HER2 equivocal tumors reclassified to non-HER2 subtypes. Molecular classification by 80GS adds further precision in classifying HER2 positive patients and potential to predict responsiveness to HER2-targeted therapies. Further studies are warranted to validate the utility of HER2 status based on 80GS.
89Zr-durvalumab PD-L1 PET in recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck.
Authors: Verhoeff Sarah , van de Donk Pim P , Aarntzen Erik H.J.G. , Miedema Iris Harriëtte Cornelia , Oosting Sjoukje , Voortman Jens , Brouwers Adrienne H. , Slingerland Marije , Heskamp Sandra , Van Herpen Carla M.L.- 
Published: May 2020

3573 Background: Immune checkpoint inhibitors (ICI) targeting programmed cell death protein-1/ligand-1 (PD-1/PD-L1) have shown activity in R/M squamous cell carcinoma of the head and neck (SCCHN). Positron-emission-tomography (PET) with 89Zr-labeled anti-PD-L1 antibodies could aid in predicting response to ICI. We present the dose-finding results of the first-in-human 89Zr-durvalumab PD-L1 PET-imaging in patients with SCCHN participating in the ongoing phase II PINCH study (NCT03829007). Methods: Following baseline [18F]FDG-PET and CT/MRI imaging, patients with incurable R/M SCCHN received 37 MBq 89Zr-durvalumab and protein dose 2mg, 10mg or 50mg durvalumab. 89Zr-durvalumab PD-L1 PET-scan was acquired day 5 post-injection. Plasma pharmacokinetic analyses were performed at day 0 and 5. Standardized uptake values (SUV, mean ± SD) were measured in [18F]FDG-positive tumor lesion, liver, spleen, bone marrow and bloodpool. PD-L1-expression was assessed on archival tumor tissue using the Ventana PD-L1 (SP263) assay. Results: 14 patients were enrolled and no adverse events were reported. High tracer-retention was observed in liver and spleen, most prominent in patients receiving 2 or 10mg durvalumab. 89Zr-durvalumab accumulation within tumors and between patients was heterogeneous and not all [18F]FDG-positive lesions showed 89Zr-durvalumab uptake. Tumor lesions were visualized best using 10 or 50mg durvalumab (SUVpeak 2mg: 3.86 ± 0.79, 10mg: 7.46 ± 2.18, 50mg: 5.57 ± 1.74). Tumor-to-blood-ratios for 10mg durvalumab were highest (2mg: 2.27 ± 0.33, 10mg: 3.44 ± 0.76, 50mg: 1.73 ± 0.99; p = 0.019). PK-analyses confirmed visual prolonged tracer-retention in bloodpool with increasing protein dose. PD-L1-expression was equally distributed amongst dose-groups. Conclusions: This is the first study to show feasibility of 89Zr-durvalumab PD-L1 PET in SCCHN patients, demonstrating the highest tumor-to-blood radio with a total dose of 10mg durvalumab. So far, no correlation of tumor PD-L1 expression with 89Zr-durvalumab-uptake and PD-L1 expression on archival tissue was found. Next step will be to correlate 89Zr-durvalumab PD-L1 PET tumor uptake with durvalumab treatment response in the phase 2 part of the PINCH study. Clinical trial information: NCT03829007 .
Hyperprogression in cancer patients on immunotherapeutic agents.
Authors: Dey Sumi , Munavar Ali Midhhath Afza , Gunchick Valerie , Bugbee Joshua , Sahai Vaibhav 
Published: May 2020

3575 Background: Patients (pts) treated with checkpoint inhibitors (CPI) may uncommonly experience accelerated progression in their tumor burden when compared to their rate of progression prior to receiving CPI. This hyperprogression has been varyingly defined and no biomarker has yet been identified. Methods: We reviewed the database from the Tumor Response Assessment Core (TRAC) at University of Michigan to identify these patients. Hyperprogression was defined as increase in tumor burden per specific immune RECIST criteria by at least 40% from baseline on the first follow-up scan with a minimum increase of 10 mm, and at least 2 times rate of growth than observed prior to start of CPI therapy. Results: Out of 741 pts who underwent baseline and 1st follow-up assessment enrolled on 118 trials, 302 (34.4%) pts received immunotherapy alone or in combination with chemotherapy/targeted agents across 49 trials. Of them, 15 pts (5%) with 5 females (33%) and median age of 63 years (range, 44 -72) met criteria for hyperprogression. The primary cancers included lung (5), colorectal (2), renal (2), biliary (1), pancreatic (1), esophageal (1), bladder (1), small bowel (1), and melanoma (1). The median time to hyperprogression was 67 (range 42-110) days, and the mean survival was 7.9 months from trial enrollment. We did not identify any clinical factor or specific CPI therapy that associated with hyperprogression. Exploratory biomarker analysis of genomic (gene panel assay) and immune subsets of tissue microenvironment (multiplex staining) is underway. Conclusions: This is the largest cohort investigated for hyperprogression across multiple cancers in literature. The rate of hyperprogression observed is less than previously reported in literature, and physicians need to be aware of this possibility while administering CPI to their patients.
Preclinical evaluation of XPO1 inhibition in Wilms tumors.
Authors: Ortiz Michael Vincent , Siddiquee Armaan , You Daoqi , Mundi Prabhjot Singh , Marks Lianna , Guillan Kristina , Diolaiti Daniel , Aburi Mahalaxmi , Califano Andrea , Dela Cruz Filemon S. , Kung Andrew 
Published: May 2020

3580 Background: XPO1 is a nuclear export protein that selectively transports tumor and growth regulatory proteins out of the nucleus, thereby effectively inhibiting their function. We previously utilized the Virtual Inference of Protein-activity by Enriched Regulon analysis (VIPER) algorithm to discover that malignant rhabdoid tumors were dependent upon XPO1 inhibition and then evaluated a preclinical cohort using selinexor (KPT-330), the first-in-class selective inhibitor of nuclear export, to demonstrate that XPO1 inhibition was sufficient to cause cell cycle arrest, apoptosis, and disease control in multiple cell line and patient derived xenograft (PDXs) models. Our subsequent analysis revealed that the most common childhood kidney tumor, Wilms tumor, has even high higher inferred activity of XPO1 than rhabdoid tumors leading to our hypothesis that XPO1 inhibition is an effective therapeutic strategy to treat Wilms tumors. Methods: A panel of 9 Wilms tumor cell lines and 3 Wilms tumor PDXs were genomically characterized and tested to evaluate the pre-clinical efficacy of XPO1 inhibition in Wilms tumors. Results: Proliferation rate, increased XPO1 protein expression, and loss of function mutations in TP53 correlated with in vitro Wilms tumor cell line sensitivity to selinexor. Evaluation of co-segregation of all single nucleotide variant changes using with inferred activity of XPO1 on VIPER in all TGCA tumors demonstrates a strong association with TP53 alterations. XPO1 inhibition was effective in all Wilms tumor models tested, most significantly in MSKREN-57196, a favorable histology Wilms tumor PDX with somatic 1q gain as well as WTX and MYCN mutations, as well as in MSKREN-31827, a diffusely anaplastic TP53 mutant Wilms tumor PDX. Eltanexor (KPT-8602) is an XPO1 inhibitor with decreased CNS penetration and an improved toxicity profile; this drug was tested in these in vivo models and found to be at least as effective as selinexor. Conclusions: Somatic 1q gain in favorable histology Wilms tumors and TP53 mutations in diffusely anaplastic Wilms tumors have a particularly poor prognosis in the relapsed setting. Our study demonstrates that XPO1 inhibition may provide a rational therapeutic option to treat such high-risk Wilms tumors. Future clinical trials evaluating XPO1 inhibitors should evaluate its efficacy in children with relapsed Wilms tumors.
A phase Ib study of oral Chk1 inhibitor LY2880070 in combination with gemcitabine in patients with advanced or metastatic cancer.
Authors: Chu Quincy S. , Jonker Derek J. , Provencher Diane M. , Miller Wilson H. , Bouganim Nathaniel , Shields Anthony Frank , Shapiro Geoffrey , Sawyer Michael B. , Lheureux Stephanie , Samouelian Vanessa , Gotlieb Walter H. , Esfahani Khashayar , Zaknoen Sara L. , Smith Patricia S , Owen Joel , Fortier Caroline , Stille John R. , Vincett Darcy , Oza Amit M. 
Published: May 2020

3581 Background: LY2880070 (LY) is an oral, selective competitive inhibitor of checkpoint kinase 1 (Chk1). Chk1 inhibitors are known to increase the anti-tumor efficacy of agents such as gemcitabine (GEM), which induce replication stress. Synergy between these two agents has been applied to the clinical setting. Methods: This two-part, open-label multi-center study explores the safety, pharmacokinetics (PK), and anti-tumor activity of LY in patients with advanced or metastatic cancers. The primary objective of this study was to determine the maximum tolerated dose (MTD) for multiple escalating oral doses of LY in combination with GEM. Secondary objectives were to: 1) Characterize the dose-limiting toxicities (DLTs) and overall safety profile for LY; 2) Evaluate the PK of LY; and 3) Evaluate the anti-tumor activity of LY. Patients received LY in a variety of different dose regimens, in combination with GEM (50 to 800 mg/m2) on days 1, 8, and 15 (optional) of a 21-day cycle. Results: The combination of LY with GEM required lower doses of both LY (vs 200 mg BID monotherapy RP2D dose) and GEM (vs approved doses). The dose levels explored ranged from LY:GEM of 10 mg QD:800 mg/m2 to 50 mg BID:100 mg/m2. BID dosing of LY was implemented in order to maximize the total daily dose and avoid the adverse events that appeared to correlate with Cmax. Treatment-emergent adverse events in > 40% of patients included vomiting, nausea, and fatigue. DLTs included reduced platelet count (Gr2), fatigue (Gr3), diarrhea (Gr3), and thrombocytopenia (x2, Gr2). The t1/2 of LY was ~ 5 h, and was not significantly affected by combination with GEM. Two patients had a best overall response of SD for a duration of ≥ 6 cycles, and a confirmed PR was observed in an ovarian cancer patient who had failed multiple regimens. Conclusions: LY was tolerated in combination with lower dose GEM. The toxicity profile can be modulated by changing the dosing frequency from QD to BID while administering the same daily dose. LY may be good candidate for combination therapy with DNA damaging agents. Clinical trial information: NCT02632448 .
Preclinical evaluation of KZR-261, a novel small molecule inhibitor of Sec61.
Authors: Lowe Eric , Fan R. Andrea , Jiang Jing , Johnson Henry W. B. , Kirk Christopher J. , McMinn Dustin , Millare Beatriz , Muchamuel Tony , Qian Yu , Tuch Brian Benjamin , Whang Jennifer A. , Zuno Patricia 
Published: May 2020

3582 Background: Secreted and transmembrane proteins play key roles in malignant transformation and growth, including in autocrine growth factor expression, receptor oncogene signaling, and immune system evasion. Biogenesis of these proteins involves translocation of the nascent polypeptides into the endoplasmic reticulum (ER) through the Sec61 channel, providing an untapped therapeutic target for a broad spectrum of malignancies. Here we describe preclinical activity of KZR-261 and related inhibitors of Sec61-dependent protein secretion. Methods: Sec61 inhibition with KZR-261 and related analog KZR-834 were evaluated using cell lines overexpressing proteins of interest tagged with luciferase. In vitro anti-tumor activity was assessed against a panel of 346 cell lines across 25 tumor types. Quantitative proteomic profiling by mass spec and gene expression profiling by RNAseq were conducted following treatment in multiple solid and heme tumor cell lines. Anti-tumor efficacy was evaluated in athymic nude mice implanted with the cancer cell lines H82 (SCLC), HT29 (CRC), BxPC3 (Pancreatic), 22RV1 (Prostate), H929 (Myeloma) and RL (NHL). Activity was also evaluated in a MC38 syngeneic colon tumor model. Results: KZR-261 and KZR-834 exhibited nanomolar potency against many therapeutic targets, including immune checkpoints, VEGF-A, VEGFR and EGFR. Broad in vitro anti-cancer activity was observed with KZR-834, which potently decreased cell viability across both solid and heme tumor types including CRC, Pancreatic, HNSCC, HCC, Lymphoma and Myeloma. Global proteomic analysis observed more than 1.5 fold downregulation of < 10% of detected Sec61 client proteins following treatment, while gene expression profiling revealed upregulation of ER stress response genes in sensitive versus resistant cell lines. Analysis of the TCGA database also found these genes upregulated in a number of different tumor types. In vivo, weekly IV administration was well tolerated and induced a dose dependent anti-tumor response at doses below the MTD in solid and heme xenograft models. In the syngeneic MC38 model, administration of KZR-834 in combination with anti-PD1 antibody resulted in greater anti-tumor activity than either single agent. Conclusions: Novel Sec61 inhibitors potently block expression of secreted and membrane proteins, translating into anti-tumor activity against many tumor types in vitro and in vivo, suggesting broad therapeutic potential. Clinical trials are being planned with KZR-261 to understand safety and early efficacy of this novel compound and therapeutic target.
Results of a completed phase I trial of CBL0137 administered intravenously (IV) to patients (Pts) with advanced solid tumors.
Authors: Sarantopoulos John , Mahalingam Devalingam , Sharma Neelesh , Iyer Renuka V. , Ma Wen Wee , Ahluwalia Manmeet Singh , Johnson Saramarie , Purmal Andrei , Shpigotskaya Polina , Hards Ann , Leonov Andrey , Gurova Katerina , Gudkov Andrei , Zakurdaeva Kristina , Miller Langdon L. , Dowlati Afshin 
Published: May 2020

3583 Background: The novel curaxin CBL0137 intercalates into DNA, interfering with histone/DNA binding. Consequent trapping of histone chaperone FACT leads to MYC, NF-kB, and HSF1 inhibition, p53 activation, and an IFN response. CBL0137 shows broad nonclinical antitumor activity (Gasparian et al. Sci Transl Med. 2011; 3(95):95ra74). Methods: This dose-ranging study assessed the CBL0137 maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and CBL0137 safety, pharmacokinetics (PK), and efficacy in adults with advanced treatment-refractory solid tumors. CBL0137 was administered IV on Days 1, 8, and 15 of repeated 28-day cycles until progressive disease (PD) or unacceptable toxicity. Doses were escalated using a 3+3 design based on Cycle 1 dose-limiting toxicities (DLTs). PK was assessed through 168 hours after Day 1. Efficacy was evaluated every 8 weeks. Results: The study enrolled 83 pts (M/F [n] = 49/34; median [range] age = 64 [33-85] years; ECOG status [n] = 1/2 [32/51]), with cancer types (n) of colorectal (23), prostate (7), glioblastoma (6), liver (6), non-small-cell (5), and others (36) across 17 dose levels from 10 to 700 mg/m2/infusion. Durations of therapy ranged to 24 months. Cycle 1 DLTs (n type) were observed at 240 mg/m2 (1 Gr 3 photosensitivity), 400 mg/m2 (1 Gr 3 anemia), 700 mg/m2 (1 Gr 4 thrombocytopenia, 1 Gr 4 neutropenia/Gr 4 thrombocytopenia), and 650 mg/m2 (1 Gr 3 thrombocytopenia, 1 Gr 4 neutropenia/Gr 3 thrombocytopenia). Nausea and vomiting were successfully prevented with dexamethasone/serotonin antagonists. Photosensitization was effectively managed with sun protection. Peripheral venous thrombosis required central vein infusion in subjects with glioblastoma. PK showed dose-proportional increases in plasma CBL0137 area under the concentration-time curve (AUC), a high mean (range) volume of distribution (Vd) of 1,030 (655-1460) L/m2 consistent with extensive tissue distribution and DNA intercalation, and an average mean (range) half-life (t1/2) of 24.7 (10.3-40.7) hours without dose dependence. The best response was stable disease: 2 pts with liver cancer had tumor control for 9 and 24 months and a maximum tumor regression of 10%; 2 pts with prostate cancer had tumor regressions by 11% and 22%; 1 pt with uterine cancer had a 20% tumor regression. Conclusions: CBL0137 administered IV was generally well tolerated with manageable toxicities The MTD and RP2D were estimated at 540 mg/m2 due to myelosuppressive DLTs. PK were predictable. Preliminary evidence of antitumor activity supports Phase 2 testing. Clinical trial information: NCT01905228 .
Activity of SY-5609, an oral, noncovalent, potent, and selective CDK7 inhibitor, in preclinical models of colorectal cancer.
Authors: Johannessen Liv , Ke Nan , Sawant Priyanka , Dworakowski Wojciech , D'Ippolito Anthony , Hu Shanhu , Rajagopal Nisha , Eaton Matthew , Hodgson Graeme 
Published: May 2020

3585 Background: Colorectal cancer (CRC) is driven by genetic alterations that result in constitutive activation of oncogenic transcription factors (eg β-catenin, MYC) and of mitogenic signaling and cell cycle progression (driven by oncogenic mutations in KRAS and BRAF). CDK7 is a key regulator of transcription, through phosphorylation of the CTD domain of RNA Polymerase II, and of cell cycle progression, through phosphorylation of the cell cycle kinases CDK1, 2, 4, and 6. This dual role of CDK7 suggests inhibitors of CDK7 may be effective in the treatment of CRC. SY-5609 is an oral, noncovalent, potent and highly selective CDK7 inhibitor in phase 1 clinical development for patients with advanced solid tumors including CRC (NCT04247126). Here we report on the activity of SY-5609 in patient-derived xenograft (PDX) models of CRC. Methods: SY-5609 was administered once daily (QD) by oral gavage for 21 days (end of treatment, EOT) to mice bearing PDX models of CRC. The relationship between SY-5609 dose, pharmacodynamic (PD) changes in xenograft tissue, tumor growth inhibition (TGI), and mouse body weight (BW) was evaluated across a range of doses. SY-5609 TGI activity was also evaluated at sub-maximum-tolerated-dose levels across a panel of 30 independent CRC models including BRAF-, KRAS-, and non-BRAF/KRAS-mutant (wild type) models (n = 10 per group). Results: SY-5609 induced dose-dependent TGI in BRAF-mutant CRC PDX tumors, with tumor regressions observed at well tolerated doses (no BW loss at EOT), and no tumor regrowth for 2+ weeks after treatment was discontinued. Dose-dependent TGI was associated with dose-dependent PD changes in PDX tumor tissue. Across 30 PDX models, SY-5609 at well-tolerated doses (average BW loss of 0% at EOT across all models) induced ≥50% TGI in 67% (20/30) of models. Deep responses (≥90% TGI or regressions) were observed in 23% (7/30) of models, with enrichment for deep responses in BRAF mutant models (50%, 5/10) relative to KRAS mutant (10%, 1/10), and wild type (10%, 1/10) models. Conclusions: Daily oral dosing of the CDK7 inhibitor SY-5609 induces robust TGI, including regressions, in CRC PDX models at well-tolerated doses. Dose-dependent TGI is associated with dose-dependent PD changes in CRC PDX tumor tissue. These results highlight the therapeutic potential of SY-5609 in CRC and support the evaluation of SY-5609 in CRC patients in early phase clinical trials. SY-5609 is in phase 1 clinical development for patients with advanced solid tumors including CRC (NCT04247126).