bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of rucaparib and irinotecan in advanced solid tumors with homologous recombination deficiency (HRD) mutations.
Authors: Dhawan Mallika Sachdev , Rahimi Roshun , Karipineni Silpa , Wilch Lauren , Zigman Erika , Aggarwal Rahul Raj , Grabowsky Jennifer A. , Munster Pamela N. 
Published: May 2020

3513 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for multiple tumor types with HRD mutations. In efforts to prolong durations of response, combination treatments of PARPi and chemotherapy are being explored. However, expected overlapping toxicities have previously limited the tolerability of PARPi-chemotherapy combinations. Preclinical studies suggest that the inhibition of PARP will prevent the repair of topoisomerase induced DNA strand breaks. In this Phase I trial, we test whether pulse dosing and alternate treatment schedules of rucaparib and irinotecan are safe and tolerable. Methods: Rucaparib and irinotecan were dose escalated in a 3+3 design. Patients with advanced solid tumors and somatic or germline known or suspected pathogenic mutations in HRD were accepted on trial. 15 patients have been enrolled in 3 cohorts and treated with rucaparib 400 mg BID (days 1-7) and irinotecan 65 mg/m2 (cohort 1) or 100 mg/m2 (cohort 2) every 2 weeks or 100 mg/m2 every 3 weeks (cohort 2i). Results: Tumor types on trial are heterogeneous and include pancreatic ductal adenocarcinoma (PDAC: 3), cholangiocarcinoma, neuroendocrine carcinoma of the pancreas, ovarian cancer/primary peritoneal carcinoma (3), prostate cancer, small bowel carcinoma, squamous cell carcinoma of the tonsil, testicular cancer, triple negative breast cancer, and urothelial carcinoma. 14/15 patients had 3+ prior lines of therapy. Mutation types include: 7 ATM, 3 BRCA1, 3 BRCA2, 1 CHEK2, and 1 PALB2. All patients were previously exposed to platinum chemotherapies; 8/15 had progressive disease while on platinum. 5/15 patients had prior PARPi with progression. There were 3 DLT events, all of which were related to grade 3 or 4 neutropenia. Of the 13 patients evaluable for response, there was one confirmed partial response (PR). 5 patients have remained on study for longer than 6 months and 3 patients with ATM mutations have remained on study for longer than one year (primary peritoneal cancer, small bowel carcinoma, PNET). 4/5 patients with clinical benefit had prior platinum progression and 1/5 had previously progressed on a PARPi. Our current recommended phase 2 dose is rucaparib 400 mg BID days 1-7 and irinotecan 100 mg/m2 every 3 weeks. Conclusions: The pulse dosing schedule of rucaparib and irinotecan has allowed for long term tolerability and exposure to both agents with encouraging efficacy in patients with ATM mutations. Further testing of PARPi and topoisomerase inhibitors at this schedule in patients with ATM mutations is planned. Clinical trial information: NCT03318445 .
Acquired genomic alterations in circulating tumor DNA from patients receiving abemaciclib alone or in combination with endocrine therapy.
Authors: Goetz Matthew P. , Hamilton Erika Paige , Campone Mario , Hurvitz Sara A. , Cortes Javier , Johnston Stephen R. D. , Jerusalem Guy Heinrich Maria , Graham Hillary , Wang Hong , Litchfield Lacey , Jansen Valerie Malyvanh , Martin Miguel 
Published: May 2020

3519 Background: An understanding of the mechanisms of acquired resistance to CDK4 & 6 inhibitors, either alone or with endocrine therapy (ET), is an unmet need. Abemaciclib is a CDK4 & 6 inhibitor approved for treatment of HR+, HER2- advanced breast cancer (ABC). Here we evaluated acquired genomic alterations detected in circulating tumor DNA (ctDNA) from patients (pts) treated with abemaciclib + nonsteroidal aromatase inhibitor (AI) or placebo + AI in MONARCH 3 or abemaciclib monotherapy in nextMONARCH 1. Methods: MONARCH 3 randomized postmenopausal women with HR+, HER2- ABC with no prior systemic therapy in the advanced setting to abemaciclib (150 mg Q12H) or placebo + AI. nextMONARCH 1 randomized women with HR+, HER2- metastatic breast cancer who had progressed on or after prior ET and CT to abemaciclib (150 mg Q12H) + tamoxifen, abemaciclib (150 mg Q12H), or abemaciclib (200 mg Q12H) + loperamide. Plasma from pts in the abemaciclib or placebo + AI arms (MONARCH 3) or abemaciclib monotherapy arms (nextMONARCH 1) was analyzed by the Guardant360 assay to identify potential tumor-related genomic alterations including point mutations, indels, amplifications, and fusions acquired at EOT in comparison with baseline. Results: For MONARCH 3, commonly acquired alterations at EOT included ESR1 (17%), TP53 (10%), EGFR (8%), FGFR1 (7%), and PDGFRA (7%) in the abemaciclib + AI arm, and ESR1 (31%), TP53 (10%), and BRCA1 (7%) in the placebo + AI arm. Acquired alterations more frequent for abemaciclib + AI pts included RB1 (6%), MYC (5%), and AR (5%), compared to 0% in the placebo + AI arm (p = 0.008 RB1; p = 0.015 MYC or AR). In contrast, acquired ESR1 alterations were less frequent with abemaciclib + AI vs placebo + AI (17% vs 31%, p = 0.038). In nextMONARCH 1, the most commonly acquired alterations with abemaciclib monotherapy were in TP53 (10%), EGFR (9%), RB1 (9%), MYC (9%), and MET (8%). In addition, acquired alterations in ESR1 (6%) and AR (3%) were also found. PIK3CA alterations were not frequently acquired (abemaciclib + AI 1%, placebo + AI 6%, abemaciclib monotherapy 5%). Conclusions: Acquired genomic alterations potentially associated with emerging mechanisms of resistance to abemaciclib alone or in combination with AI may include RB1, MYC, or AR alterations, while the acquisition of ESR1 alterations was less common in pts treated with abemaciclib + AI compared to placebo + AI. These findings are hypothesis-generating and provide insight into mechanisms of resistance to abemaciclib vs ET. Clinical trial information: NCT02246621, NCT02747004 .
Pharmacokinetics, safety, and early activity of a nanoparticle micellar formulation of docetaxel in women with metastatic breast cancer: Results of two randomized trials (phase I and II).
Authors: Joerger Markus , Bjermo Helena , Blom Per , Heldring Nina Anna 
Published: May 2020

3526 Background: Docetaxel micellar (DM) is a nano-sized particle formulation of docetaxel in which a retinoic acid derivative is used as solubilizer with a high drug to excipient ratio possibly resulting in reduced systemic toxicity or hypersensitivity reactions due to the excipient. DM is given without standard use of premedication, avoiding steroid-associated immunosuppression. Here we present the pharmacokinetics (PK) after a single dose of DM or polysorbate-solubilized docetaxel (D) as well as safety and early activity including overall response rate (ORR) in female patients with metastatic breast cancer. Methods: The PK study was a two-cycle, cross-over study where 30 patients were included and randomized to either DM followed by D or D followed by DM, both given as a 1-hour intravenous infusion at a dose of 100mg/m2. The phase II study was a prospective, multicenter, open-label, third-party blinded, randomized, parallel group, active-controlled study including 200 patients to compare the early activity and safety of DM and D, both given as 100 mg/m2 1-hour intravenous infusion every 21 days (1 cycle) for a total of 6 cycles. Results: Bioequivalence of total docetaxel in plasma, AUC0-last and Cmax, was demonstrated for DM compared to D. The incidence of adverse events was higher in the D arm than in the DM arm for the majority of SOCs and PTs in the phase II study. Overall, Grade 3 or 4 AEs were reported for 82.7% of patients from DM arm and 99.0% of patients from D arm. Twelve (12.2%) patients in the DM arm and 24 (24.0%) patients in the D arm needed at least one dose reduction due to AEs. The primary efficacy endpoint in the phase II study was based on the assessment according to Response Evaluation Criteria in Soldid Tumors (RECIST) 1.1 and non-inferiority was not reached based on the pre-defined non-inferiority margin. A post-hoc analysis investigating the ORR based on tumour assessment at the end of chemotherapy, and non-inferiority of DM as compared to D was shown (ITT population). Conclusions: DM is bioequivalent to D regarding total drug in plasma and provides a docetaxel formulation that spares patients steroid premedication. An improved safety profile for DM compared to D was shown while additional efficacy data is needed for future development of DM. Eudra CT: 2012-005161-12 and 2013-004889-33. Clinical trial information: 2012-005161-12 and 2013-004889-33 .
Exosomal circular RNAs derived from serum: Promising biomarkers for therapeutic targets and prognosis of triple-negative breast cancer (TNBC).
Authors: Yang Sujin , Tang Jinhai 
Published: May 2020

3528 Background: Exosomes are well known by the "exosomal shuttle" that delivers oncogenic microRNAs (miRNAs), mRNAs, circular RNAs (circRNAs) and proteins to the recipient cells and tumor microenvironment, and may be used as promising biomarkers for disease diagnosis. This study aims to provide a theoretical basis to use stable exosomal circRNAs as new biomarkers for predicting the development, metastasis and therapeutic targets of TNBC. Methods: A strategy combining RNA-sequencing technique, bioinformatic analysis and RT-qPCR was used to determine the level of differential expressed circRNAs in serum exosomes samples (n = 43) from TNBC patients compared with non-TNBC patients. The expression of circHSDL2 were also detected in tumor tissues (n = 20) from TNBC patients and breast cancer cell lines by qRT-PCR. Cell cycle analysis, the wound healing assays and transwell assays were used to investigate the function of circHSDL2 in proliferation, invasion and metastasis of TNBC cells. FISH, dual-luciferase reporter and functional assays were performed to confirm the interaction between circHSDL2 and let-7a-2-3p in TNBC cells. Results: We profiled the circRNAs in the serum exosomes samples from TNBC patients and non-TNBC patients by RNA sequencing and detected 803 significantly differentially-expressed circRNAs. After bioinformatic analysis, circHSDL2 was chose to further study. RT-qPCR results showed that higher expression of circHSDL2 in TNBC cell lines and tumor tissues from TNBC patients. Moreover, overexpression of circHSDL2 promoted TNBC cells proliferation and invasion, while knockdown of circHSDL2 inhibited TNBC cells proliferation and invasion. Mechanistically, circHSDL2 acted as a "miRNAs sponge" to absorb let-7a-2-3p; let-7a-2-3p inhibited TNBC cell invasion and metastasis. Kaplan-Meier plots showed lower expression of let-7a-2-3p was connected to poor prognosis in TNBC metastasis patients from TCGA database. Conclusions: The expression of circHSDL2 was found significantly upregulated in serum exosomes and tumor tissues from TNBC patients. Moreover, circHSDL2 could promote cell proliferation, invasion and metastasis in TNBC cells. CircHSDL2 might be function as competing endogenous RNAs (ceRNAs) by targeting let-7a-2-3p in the progression of TNBC. Therefore, this study provides a fresh perspective on novel therapeutic targets and potential biomarkers for TNBC from exosomal circRNAs.
Subcellular partitioning of Kaiso (ZBTB33) as a biomarker to predict overall breast cancer survival.
Authors: Singhal Sandeep K , Sens Donald , Sens Mary Ann , Byun Jung , Yancey Ryan , Caban Ambar , Boisvert Heike , Hennek Stephanie , Bobrow Mark , Ahmed Shakir , White Jason , Aukerman Andrew , Yates Clayton , Vanguri Rami , Bareja Rohan , Lenci Romina , Siervi Adriana De , Napoles Anna , Vohra Nasreen A. , Gardner Kevin 
Published: May 2020

3534 Background: The epigenetic transcriptional regulator, Kaiso (ZBTB33) has been identified as a member of the C2H2 zinc finger proteins containing a BTB/POZ -zinc finger family of transcription factors that are implicated in development of cancer. Although, our understanding of clinical relevance of subcellular distribution (cytoplasmic/nuclear) Kaiso in the growth and survival of human Breast cancer (BC) is limited. Methods: We examined a cohort of 555 BC patients who underwent surgery for their primary BC in Greenville, NC using AI and SM approach. Results: The sub-classification BC shows, cytoplasmic Kaiso is differentially enriched in ER- BC (p=0.001) compared nuclear Kaiso (p=0.8) and is significantly enriched in the more aggressive classes LumB (p=0.0017), HER2+ (p=0.05) and TNBC (p=6.1e-07) with respect to LumA BC patients. Additionally, the survival analysis of different compartments of Kaiso demonstrates that high cytoplasmic Kaiso (HR = 16.29 (7.6 – 34.8), p = 5.5e−13) is much more predictive of poor survival compared to nuclear Kaiso (HR = 2.83 (2.02 – 3.8), p = 6.1e−11). At gene expression level, ZBTB33 mRNA levels do not correlate with either nuclear (Spearman correlation: -0.03157, p= 0.7267) or cytoplasmic levels (Spearman correlation: -0.03526, p= 0.6962) of Kaiso. Surprisingly, ZBTB33 mRNA abundance is predictive of poor overall BC survival as demonstrated in two independent publicly available BC cohorts Metabric (HR = 2.14 (1.49 − 3.08), p = 2.7e−05) and Gyorffy B et al. (HR = 1.81 (1.55 − 2.12), p = 2.5e−14). Nuclear and cytoplasmic levels of Kaiso do not show significant differences based on race p=0.27 and p=0.1 respectively. Conclusions: Our data suggest subcellular distribution of high Kaiso is associated with poor prognosis of BC survival and subcellular localizations of Kaiso may play differential biological roles in BC prognosis.
A pan-cancer analysis of ARID1A as a potential biomarker for immune checkpoint therapy.
Authors: Yang Dongyong , Xu Yuan , Huang Linlin , Guo Zhifeng , Fan Jimin , Chen Tingting , Xie Wenzhuan , Huang Mengli 
Published: May 2020

3540 Background: AT-rich interactive domain 1A (ARID1A), encoding a subunit of the BAF (SWI/SNF) chromatin remodeling complex, is correlated with the origination and progress of tumor. Previous research on ARID1A gene revealed that ARID1A deficiency was associated with mismatch repair (MMR) and higher tumor mutation burden (TMB) level in cancer, which might cooperate with immune checkpoint blockade therapy. Methods: Next generation sequencing (NGS) data of 10336 pan-cancer patients were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). NGS data of 15849 pan-cancer patients from Chinese clinical dataset were analyzed to explore the association between ARID1A gene mutation and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. 853 advanced NSCLC patients from two independent cohorts (OAK study cohort and POPLAR study cohort) were used to analyze the correlation between ARID1A alteration and the efficacy of immune checkpoint blockade immunotherapies (ICIs). Results: In total, 8.62% (891/10336) of pan-cancer patients in MSKCC harbored ARID1A mutation and 8.47% (3188/37628) in Chinese cohort. In MSKCC cohort, the highest ARID1A mutation frequency tumor type was endometrial cancer (31.64%, 69/218), bladder cancer (26.95%, 114/423) and hepatobiliary cancer (17.18%, 61/355) come in second and third, respectively. While in Chinese cohort, the top three ARID1A mutation frequency tumor types were endometrial cancer (39.29%, 88/224), gastric carcinoma (17.80%, 318/1787) and urothelial carcinoma (17.18%, 83/483), respectively. ARID1A gene mutation was also associated with higher TMB in the Chinese pan-cancer cohort (P < 0.0001). The highest medium TMB level of ARID1A mutation tumor type was Urothelial carcinoma with 18.63 Muts/Mb (n = 65). In addition, the TMB level and prognositic analysis were performed on patients in two independent NSCLC cohorts with ICIs, TMB level of ARID1A mutant group was higher than wild-type group with significant difference (P < 0.0001). The overall survival (OS) of ARID1A mutation group were significantly shorter than wild-type group (OS, median, 6.80 vs 10.28 months; HR, 1.47; P = 0.0474), and a decreasing trend on progression-free survival (PFS) without significant difference (median, 1.46 vs 2.99 months; HR, 1.27; P = 0.1584). Conclusions: The results indicated that ARID1A gene mutation was associated with a higher TMB level in Chinese pan-cancer patients, and patients harboring these genes mutations might easily benefit from ICIs.
First in-human study of in vivo imaging of ex vivo labeled CAR T cells with dual PET-MR.
Authors: Singla Ritu , Wall Dominic M , Anderson Samuel , Zia Nicholas , Korte James C , Kravets Lucy , McKiernan Gerard , Butler Jeanne , Gammilonghi Amanda , Arora Jyoti , Solomon Ben J , Hicks Rodney J. , Cain Timothy , Darcy Phillip K. , Cullinane Carleen , Neeson Paul J. , Ramanathan Rajesh , Shukla Ravi , Bansal Vipul , Harrison Simon J. 
Published: May 2020

3557 Background: This is a first in human in-vivo biodistribution of ex-vivo labelled CAR T cells assessed in a cohort of patients. Cells were labelled with novel Cu-64 labelled superparamagnetic iron oxide nanoparticles (SPION) and infused IV into patients with solid tumors & tracked using clinical dual PET-MR. The study validates the clinical translation of CAR T cell in-vivo tracking in real time. Methods: Cu-64 radioisotope was bound to silica coated SPION using electrolysis plating with tin & palladium seeding. Cellular uptake of Cu-64 SPION was facilitated with a transfecting agent. Functional assays including 51Chromium release, cytometric bead array demonstrated that labelling process did not affect cytotoxicity & cytokine secretion (TNFα & IFN-g). T cells were transduced with retroviral vector constructs encoding for second-generation chimeric T-cell receptor specific for carbohydrate Lewis Y antigen. Modified T-cells were expanded ex-vivo & were labelled with Cu-64 (~300 MBq) prior to re-infusion (3 x108 labelled cells). Scanning is performed with Siemens 3T dual PET-MR scanner. Results: In this first in human in-vivo study (HREC/16/PMCC/30) a cohort of patients received ex-vivo labelled CAR T cells to determine how many labelled cells distribute to solid tumor sites within 3-5 days. Our results demonstrate that cells can be efficiently labelled (≤60%) with high cell viability (≥85%) at a sensitivity sufficient to detect labelled cells at tumor site for up to 5 days. An observed trend in SUVmean & SUVmax provided insight into efficacy & individual response to therapy. Early time points showed moderate uptake of labelled cells in lungs posterior basal segments without increased activity over next few days, suggesting a transient process. Mild, diffuse bone marrow & relatively intense uptake of labelled cells in liver & spleen suggests margination of cells to reticulo-endothelial system. Distinct PET signal at some of the tumor sites at 24 h suggests antigen specific localization & time taken to reach these sites. Excretion via hepatobiliary indicated reabsorption from GI tract & re-circulation of labelled cells. Minimal uptake in brain & heart supported safety profile of labeling agent. Conclusions: This is first in human in-vivo study to provide highly valuable visual and dynamic data in real time and provides insight into individual responses to therapy. CAR T cell functionality largely remain unchanged due to labeling process. The findings indicate that labelled cells traffic to tumor sites at later time points & remain persistent for extended period of time.
Exomes and transcriptomes to reveal actionable findings in patients with negative-targeted panel sequencing.
Authors: Zhao Eric Y. , Torchia Jonathon , Fortuna Alexander , Torti Dax , Yu Celeste , Shah Elizabeth , McCarthy Aoife , Stockley Tracy , Sabatini Peter , Bartlett John , Siu Lillian L. , Bedard Philippe L. , Pugh Trevor John 
Published: May 2020

3562 Background: Next generation sequencing targeted panels increasingly inform clinical decisions, but may miss actionable findings detectable by whole exome sequencing (WES) and RNA-seq. There has been no direct comparison of WES plus RNA-seq against targeted panel sequencing to determine its added utility. To address this, we performed WES and RNA-seq analysis in a cohort of 100 patients with no actionable findings on prior panel sequencing. Methods: Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE; NCT02906943) has sequenced 2,106 patients using a 161-gene Oncomine or 555-gene Hi5 panel. 100 patients (98 Hi5, 2 Oncomine) were chosen for further sequencing. Tumor (100x coverage) and normal (50x) exomes and tumor transcriptomes were sequenced on Illumina HiSeq2500 or NextSeq550. Interpretation included knowledgebase annotation (e.g. OncoKB, CIViC), mutation signatures, homologous recombination deficiency (HRD) scores, gene expression, and pathway analysis. Findings were deemed “actionable” if they could directly inform management or trial eligibility. Results: WES and RNA-seq identified one or more novel actionable findings in 38 patients. Of these, the main actionable finding was tumor mutation burden (TMB), mutation signature, or HRD score in 19 (50%), a copy number variant in 16 (42%), a fusion in 2 (5%), and a point mutation in 1 (2.6%). WES identified a MALAT1-GLI1 fusion in a cancer of unknown primary (CUP) whose transcriptome was consistent with gastric cancer, together suggesting the diagnosis of a rare gastroblastoma. To date, two cases have received exome-supported targeted therapy: (1) a metastatic high grade serous ovarian cancer, HRD-high, treated with olaparib then cisplatin for a combined 15 months, and (2) a metastatic neuroendocrine rectal tumor with RICTOR amplification treated with everolimus starting in Dec 2016 until last follow-up in Sep 2019. Of 62 patients with no actionable finding, expanded sequencing identified one or more known cancer drivers in 25 (40%): 17 CNVs, 3 fusions, and 5 point mutations or indels. In 16 patients, an oncogenic variant found on panel was not captured by WES, and may represent artifacts, germline mutations, or subclonal/localized variants. Conclusions: WES and RNA-seq expanded detection of actionable biomarkers and oncogenic mutations, especially CNV, TMB/signatures, and HRD. Two cases have undergone exome-supported targeted treatment. We performed the first WES of a rare gastroblastoma, originally a CUP but reclassified by expanded fusion detection and RNA-seq.