bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of genomic landscape using comprehensive circulating cell-free tumor DNA next generation sequencing in advanced thyroid carcinoma.
Authors: Tarasova Valentina , Tsai Jill , McIver Bryan , Hallanger-Johnson Julie E. , Veloski Colleen , Agosto Salgado Sarimar , Masannat Jude , Drusbosky Leylah , Chung Christine H. 
Published: June 2022

3045 Background: Availability of targeted therapies in thyroid carcinoma (TC) has challenged the conventional treatment algorithms and established urgency for timely identification of targetable genetic abnormalities. Tissue-based next generation sequencing (NGS) is often limited by tumor insufficiency and slow turn-around time. Plasma-based circulating tumor DNA (ctDNA) NGS overcomes these barriers and has been widely adopted across advanced-stage solid tumors. To date, plasma-based NGS characterization of genomic alterations in TC has not been determined. Herein, we profile potential actionable mutations detected via ctDNA in patients with advanced TC subtypes. Methods: A retrospective analysis of Guardant Health, Inc database was performed using the commercially available Guardant360 plasma-NGS test on advanced metastatic TC samples collected between 2016 and 2021. Patients with papillary TC (PTC), follicular TC (FTC), poorly differentiated TC (PDTC), medullary TC (MTC), and anaplastic TC (ATC) were clustered into four groups (G1: ATC, G2: PTC, FTC, and PDTC, G3: MTC, and G4: unspecified TC). The landscape of genetic alterations, frequencies of alterations in clinically relevant genes, and tumor mutation burden (TMB) were analyzed. Results: Of the 1,108 patients included, 47.1% were male. The median age was 65 years old (range 13-98), and 0.18% (n = 5) patients were under 18 years old. Alteration frequencies of selected, clinically relevant genes are demonstrated in the table below. TMB analysis was performed on 315 samples, and the mean TMB was higher in G1 compared to G2, G3, and G4 (p = 0.0029, 0.0826, and 0.0112, respectively). Conclusions: Plasma-based comprehensive NGS by Guardant360 may be utilized in patients with advanced metastatic TC for detecting clinically relevant genetic alterations for the selection of available targeted therapies, immunotherapy, or determination of the clinical trial eligibility. Future validation of the clinical utility by analysis of paired tumor and plasma samples is warranted. [Table: see text]
A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors.
Authors: Li Jian , Zhao Jun , Cao Baoshan , Fang Jian , Li Xiaoyan , Wang Mengzhao , Ba Yi , Li Xingya , Li Zhihua , LIU Zhe , Wang Yongsheng , Cheng Ying , Bai Chunmei , Shen Lin 
Published: June 2022

3089 Background: KRAS G12C mutation occurs in approximately 4% of non-small cell lung cancer (NSCLC), 1-2% of colorectal cancer (CRC) and other solid tumors in China. JAB-21822 (Jacobio, Beijing, PRC) is a highly selective, covalent oral inhibitor of KRAS G12C. Methods: NCT05009329 is an ongoing first-in-human, open label phase I/II study of JAB-21822 in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of JAB-21822. Other objectives include preliminary efficacy, pharmacokinetics, and biomarkers. Here we report the results from the dose escalation phase of the trial. Results: As of January 28th, 2022, 53 patients with a median age of 62 years (39-79) were enrolled in 5 different dose levels: 200mg QD, 400mg QD, 800mg QD, 400mg BID and 400mg TID. Most patients (55%) had ≥ 2 prior lines of therapy. No dosing-limiting toxicities were observed. Two treatment-related adverse events (TRAEs) were G4 neutropenia (1 in 400mg BID and 1 in 400mg TID). The most common TRAEs (≥ 10%) included anemia (24.5%), total bilirubin increase (20.8%), direct bilirubin increase (15.1%), proteinuria (13.2%) and indirect bilirubin increase (11.3%). Only Grade 1 and 2 TRAEs were observed in the QD cohorts. A total of 33 patients (22 NSCLC, 9 CRC and 2 pancreatic cancer) had at least 1 post-baseline tumor assessment; in the 800mg QD cohort, overall response rate (ORR) and disease control rate (DCR) were 50% (5/10) and 100% (10/10), respectively, including 4 non-confirmed partial response (PR); in the 400mg QD cohort had an ORR and DCR of 80% (4/5) and 100% (5/5) respectively, including 2 non-confirmed PR. Patients with NSCLC (400mg QD and 800mg QD), the ORR and DCR were 70% (7/10) and 100% (10/10), respectively, including 5 non-confirmed PR. With respect to the pharmacokinetics analysis, JAB-21822 was rapidly absorbed with an average Tmax of 2 hr and reached higher plasma exposures (Cmax and AUC0-24h) after a single dose and multiple doses at C1D8. Conclusions: JAB-21822 was well tolerated with impressive preliminary efficacy in patients with heavily treated solid tumors harboring KRAS G12C mutation. The study is enrolling patients in the expansion phase. Multiple JAB-21822-based combination trials are also ongoing. Clinical trial information: NCT05009329.
Adaptive response analysis of colorectal cancer cells to low-dose oxaliplatin as a tool to deciphering mechanisms of synergistic drug interaction.
Authors: Tosi Diego , Robin Mathilde , Bini Marta , Marchive Candice , Djiane Alexandre , Heron-Milhavet Lisa , Bréhélin Laurent , Gongora Céline 
Published: June 2022

3091 Background: Using an in vitro dose matrix approach, we previously showed in multiple colorectal cancer cell lines a striking cytotoxic synergism between oxaliplatin at very low concentrations and the ATR inhibitor VE-822. We confirmed this finding in vivo, and, surprisingly, in this setting the oxaliplatin-induced cell addiction to VE-822 persists over several days after oxaliplatin elimination. We tried to elucidate the molecular mechanism of the latter phenomenon. Methods: We evaluated by RNAseq the gene expression changes induced in vitro by low-dose oxaliplatin in the colorectal cancer cell line HCT-116 after 24 and 48 hours of treatment. In order to untangle the functional significance of the adaptive response to oxaliplatin, we performed on the RNAseq data an extensive gene set enrichment analysis (GSEA) using gene set from all Molecular Signature Database v7.4 collections with the exception of C7. For ontology-based gene set collections, we clusterized the enriched gene sets using the semantic similarity methodology in order to increase the readability of global functional response. Results: Extensive GSEA showed that after 24 hours of oxaliplatin treatment cancer cells upregulate several gene sets involved in aspecific responses to cellular stress or to various type of extracellular stimulations, including other organisms, oxygen-containing compounds, abiotic stimuli and hypoxia. In addition, several gene sets involved in proteolysis and autophagy are upregulated, suggesting a rewiring of cell machinery. After 48 hours of oxaliplatin treatment, we observed the activation of ribosome function, mitochondrial assembly and synthesis of aminoacids and ribonucleosides. Finally, a widespread negative enrichment of gene sets involved in DNA repair-related was detected both at 24 and at 48 hours, with a far greater negative enrichment at 48 hours, which suggest a commitment of cancer cell to a major limitation of DNA repairing capability lasting several days following a DNA damaging insult. Analysis of leading edge genes from the DNA repair gene sets showed a profound repression both at 24 and 48 hours of the transcripts of BRCA1, BRCA2, ATM, CHK1, WEE1, BARD1, BRIP1, NEHJ1, RAD51, XRCC2, CLSPN, GEN1, DNA2, EXO1, TOPBP1, POLE, RMI1. Interestingly, ATR mRNA was minimally repressed both at 24 and at 48 hours, which could explain the long-standing in vivo dependence of cancer cell to ATR after a brief oxaliplatin exposure. Conclusions: Extensive GSEA was able to elucidate the molecular mechanism underlying synergistic interaction between oxaliplatin and VE-822. The impact of profiling cancer cell adaptive responses by extensive GSEA should be further evaluated in the setting of rational development of drug combinations.
Theranostic pairing: ABY-025/251 targeting HER2 with 68Ga and 188Re—Minimized radioligands using Affibody peptide scaffold technology.
Authors: Liu Yongsheng , Sorensen Jens Benn , Brun Nikolai C. , Frejd Fredrik Y. , Tolmachev Vladimir 
Published: June 2022

3093 Background: HER2 expressing tumors such as subsets of metastatic breast cancer and gastro-esophageal tumors can be targeted using specific antibodies or antibody-drug-conjugates (ADCs). However, some tumors remain refractory to treatment. External radiation therapy is unsuited to advanced metastatic disease. Targeted molecular radiation therapy has proven useful in other tumors such as neuroendocrine tumors or prostate cancer using 177Lu. 188Re is a beta emitting isotope that when chelated to the ABY-251 Affibody molecule has the potential to precisely target HER2 expressing tumors locally. The ABY-251 Affibody molecule is a very small, structured protein scaffold with a molecular weight of only 7 kDa targeting HER2 with high affinity (KD = 100pM). ABY-251 can be manufactured by chemical synthesis. A diagnostic analog molecule ABY-025 was also developed with chelation to 68Ga ideal for PET visualization. Methods: A pre-clinical study in mice was conducted to investigate tumor/tissue uptake, followed by a clinical diagnostic study for visualization in HER+ patients with metastatic breast cancer, to be followed by a theranostic study in humans. Results: Pre-clinical Study: A preclinical study in mice has previously demonstrated high contrast uptake in HER2 tumor tissue using the diagnostic analog ABY-025. Off target accumulation was seen in kidney tissue using the diagnostic ABY-025, which in the ABY-251 therapeutic molecule has been reduced by further engineering of the molecule. This molecule has now been proven to increase survival in mice bearing HER2+ tumors. Median survival in the treated animals was 68 days as compared to 29 and 27.5 days in animals treated with vehicle and non-labelled peptide respectively. Clinical diagnostic study ph1/2: ABY-025 was studied in HER2+ patients with metastatic breast cancer. In a study of 16 women with refractory metastatic breast cancer (>2 prior lines of therapy, 12 IHC positive and 4 IHC negative) 9 out of 10 patients showed high HER2 expression levels as measured with ABY-025 PET despite ongoing treatment with HER2 targeted therapy. Persistent high 68Ga-ABY-025 tumor uptake in patients despite treatment with standard HER2-targeted therapies is a sign of therapeutic drug resistance. These patients would be eligible for treatment with the therapeutic analog ABY-251 using 188Re generated beta radiation for tumor eradication. Clinical therapeutic study (planned): ABY-251 is in development to soon enter therapeutic clinical Ph1/2a trials in patients with refractory HER2+ tumors and positive tumor imaging using ABY-025 as a theranostic pair. Conclusions: A radiopharmaceutical theranostic approach diagnosing HER2+ patients with metastatic disease using 68Ga-ABY-025 for targetability and subsequent treatment using 188Re-ABY-251 seems feasible and is currently in clinical trials. Clinical trial information: NCT01858116.
A study of senaparib in combination with temozolomide for the treatment of patients with advanced solid tumors and extensive-stage small cell lung cancer.
Authors: Gao Bo , Lin Chia-Chi , Bai Li-Yuan , Chung Wei-Pang , Kao Wan-Chen , Zielinski Robert , Shim Byoung Yong , Hong Min Hee , Kim Sang-We , Liu Chien-Ying , Hsieh Chih-Yi , Cai Sui Xiong , Tian Ye Edward , Liu Lan , Niu Tiantian , Halcro Clare , Li Baoyue , Ma Ning , Zhang Congcong , Chen Xiangna 
Published: June 2022

3102 Background: Senaparib (or IMP4297) is a PARP inhibitor with a novel chemical structure. Preliminary data demonstrate senaparib has significant anti-tumor activity with good tolerability in some patients with advanced solid tumors. DNA damage caused by temozolomide, a non-classic oral alkylating agent, can sensitize tumors to the effects of PARP inhibitors. In a xenograft model, synergistic antitumor effect was observed with the combination of senaparib and temozolomide, supporting this trial (NCT04434482). Methods: This is a phase Ⅰb/Ⅱ dose-escalation and dose-expansion study. Patients with advanced solid tumors were enrolled for dose escalation to evaluate the safety, tolerability using a modified “3+3” design. Low dose temozolomide (20 to 30 mg, once daily, days 1 to 21) in combination with continuous senaparib (40 to 80 mg, once daily, days 1 to 28) of each 28-day cycle was evaluated. Dose expansion will establish anti-tumor activity and safety of the combination in patients with extensive stage small cell lung cancer (ES-SCLC). Results: A total of 14 patients were enrolled for dose escalation as follows: Cohort 1 (1 patient; senaparib 40 mg plus temozolomide 20 mg), Cohort 2 (3 patients; senaparib 60 mg plus temozolomide 20 mg), Cohort 3 (7 patients; senaparib 80 mg plus temozolomide 20 mg), Cohort 4 (3 patients; senaparib 80 mg plus temozolomide 30 mg). One DLT (Grade 4 thrombocytopenia) was observed in Cohorts 3 and 4. The MTD and RP2D were determined as: senaparib 80 mg plus temozolomide 20 mg. Anaemia, neutropenia and thrombocytopenia were the only Grade ≥3 TEAEs occurring in > 1 patient. All AEs were manageable, and no treatment related deaths were reported. The ORR was observed in 3 of 12 (25.0%) evaluable patients, including 2 confirmed PR and 1 unconfirmed PR. The DCR was 83.3% (10 of 12 evaluable patients). Two patients remain on treatment for more than 1 year. Conclusions: Preliminary results suggest that low dose temozolomide (D1-21 of a 28-day cycle) in combination with continuous senaparib is generally well tolerated with encouraging anti-tumor activity. Recruitment for dose expansion for ES-ECLC patients has commenced (Sep 2021). Clinical trial information: NCT04434482.
Genomic landscape of SMARCA4-deficient lung tumors by clinical RNA sequencing.
Authors: Pham Brian , Ma Weijie , Call Greg , Ashok Arya , Mauer Elizabeth , Kamangar Elham , Li Tianhong 
Published: June 2022

3118 Background: SMARCA4-deficient lung cancer is an undifferentiated lung cancer subtype associated with poor prognosis and morphological features that make them challenging to distinguish from sarcoma. These tumors are known to be resistant to standard of care surgery, radiation, and chemotherapy. Recent case reports suggest that these tumors might be resistant to immunotherapy. An assessment of the genomic and transcriptomic features of SMARCA4-deficient thoracic tumors may identify potential novel targets and treatment strategies for this new WHO lung cancer classification. Methods: We retrospectively analyzed de-identified NGS data from 8,484 thoracic formalin-fixed, paraffin-embedded tumor biopsies from lung cancer patients sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; whole-exome capture RNA-seq). Tumor-normal match sequencing was performed for all tumors, enabling the detection of incidental germline alterations across 46 genes. SMARCA4-deficiency was defined as tumors with a pathogenic or likely pathogenic SMARCA4 single nucleotide variant, insertion/deletion, or copy number alteration. Statistical significance was determined using Fisher's exact test and Wilcoxon rank-sum tests. Results: SMARCA4-deficiency was detected in 370 (4.4%) tumors, of which over 80% were stage III or IV. SMARCA4-deficient tumors included more male patients (63% vs 49%, p < 0.001) and younger age at diagnosis (median 64 vs 68 years, p < 0.001). There were more patients with high tumor mutational burden (TMB-H, ≥10 mutations per megabase) (34% vs 15%, p < 0.001), and fewer patients with positive PD-L1 immunohistochemical staining (44% vs 54%, p = 0.009) compared to SMARCA4 wild-type tumors. Microsatellite instability status occurred at similar low frequencies across SMARCA4-deficient vs wild-type tumors (0.8% vs 0.5%, p = 0.5). SMARCA4-deficient tumors showed enrichment for somatic mutations in TP53 (71% vs 47%, q < 0.001), STK11 (22% vs 6.8%, q < 0.001), KEAP1 (15% vs 4.2%, q < 0.001), and CDKN2A (15% vs 5.9%, q < 0.001) compared to wild-type. Tumor normal-match sequencing identified incidental germline mutations in MUTYH (2.2%), ATM (1.1%), ATP7B (0.5%), and MSH6 (0.5%) for SMARCA4-deficient tumors. RNA-sequencing analysis confirmed reduced transcriptional expression of SMARCA4 (p < 0.001), CD274 (PD-L1; p < 0.001), TNFRSF18 (p < 0.001), and TNFRSF4 (p = 0.035) in deficient tumors vs wild-type. Furthermore, SMARCA4-deficient tumors revealed reduced infiltration of CD4+ T cells (19% vs 22%, p < 0.001). Conclusions: This study reveals the unique genomic and transcriptional characteristics of SMARCA4-deficient lung tumors. Further studies are needed to assess the impact of immunotherapies and targeted therapies among this patient population.
Molecular characterization of cancers with ALK gene fusions in nonlung tumors.
Authors: Zhang Jin , Han Yushuai , Wang Weiran , Xu Mengxiang , Zhu Jianhua , Ma Tonghui 
Published: June 2022

3121 Background: ALK gene rearrangement is known as “diamond mutation”. Targeted tyrosine kinase inhibitors have perfect therapeutic effects on ALK fusion lung cancer patients (pts), but the molecular characteristics of ALK fusions in other cancers have not been systematically elucidated. Methods: We retrospectively analyzed the NGS data of ALK fusion-positive Chinese tumor pts (n = 1068) to characterize ALK fusions in pan-cancer (excluding lung cancer) pts. Results: A total of 66 ALK fusion-positive pts with 13 types of cancer (excluding lung cancer) were screened, including 0.4% (24/5800) of brain tumor pts, 0.1% (11/7725) of gastrointestinal cancer pts, 0.4% (7/1741) of thyroid cancer pts, 0.5% (8/1732) of sarcoma pts, 0.2% (4/2031) of liver cancer pts, 0.6% (3/540) of melanoma pts, 9% (2/22) of inflammatory myofibroblastic tumor pts, 2.5% (2/79) of embryonal tumor pts, 0.4% (1/282) of lymphoma pts, 3.2% (1/31) of parotid carcinoma pts, 0.1% (1/985) of breast cancer pts, 0.4% (1/241) of prostatic cancer pts and 0.3% (1/320) of ovarian cancer pts. Herein, we reported 28 ALK fusion patterns, of which the most common partners were EML4 (n = 24) and STRN (n = 8), and mainly occurred in brain tumors (14/24, 58.8%) and thyroid cancers (6/8, 75%), respectively. In addition, there were 8 ALK fusion modes that were never reported before. Of the ALK fusion patterns described above, 92.4% (61/66) of fusions were located at the most canonical site of ALK (exon20), preserving the intact kinase domain. Meanwhile, rare fusion positions in the ALK gene were also found, such as PPP1CB-ALK(ex2:ex4), NUP107-ALK(ex20:ex3), COL14A1-ALK(ex8:ex4), BRAF-ALK(ex9:ex4), which preserve the extracellular and transmembrane domains, as well as RASD2-ALK(ex2:ex24), of which the breakpoint in ALK gene may disrupt the formation of kinase domain. Conclusions: We demonstrated the rarity of ALK gene fusions in nonlung cancers. Analyzing the ALK fusion characteristics of these cancer may help to clarify their pathogenesis and provide ideas for new drug treatment.[Table: see text]
Molecular reflex testing in non-small cell lung cancer: An optimal approach?
Authors: Hooper Kari , Witten Toni , Leader Benjamin , Fesko Yuri Anthony , Kruzel Mark 
Published: June 2022

3127 Background: Molecular testing of non-squamous non-small cell lung cancer (NSCLC) tumors can guide appropriate treatment decisions and improve patient outcomes, but guideline complexity and frequent revision may negatively affect adherence. To assist oncologists in making timelier informed treatment decisions, we implemented a pathologist-directed molecular reflex pathway for non-squamous NSCLC at our clinical laboratory. Testing patterns and adherence to NCCN testing guidelines before and after implementation were reviewed. Methods: This retrospective cohort analysis included patients with diagnosed NSCLC who had molecular testing performed without a molecular reflex testing pathway in place (April 2016-March 2018, cohort A) and after the pathway was implemented (April 2018-March 2020, cohort B) at our clinical laboratory. TATs were calculated using dates of biopsy specimen submission and of molecular testing completion. Molecular testing methods (e.g., polymerase chain reaction, next-generation sequencing [NGS]), genetic alterations tested for and identified, PD-L1 by immunohistochemistry, and specimen quantity not sufficient (QNS) for testing were obtained from patients’ clinical laboratory reports. NSCLC diagnosis and cancer stage were obtained from electronic medical records, and adherence to NCCN guidelines (i.e., under-tested, over-tested genetic alterations) was evaluated according to specimen submission. Results: The mean TAT was 35.1 days for cohort A (n = 123) and 15.8 days for cohort B (n = 168), though the median in both was 14 with a range of 6 – 674 days in cohort A and 9 – 44 in cohort B (Table).Targetable genetic alterations were identified in 12.4% of patients in cohort A and 61.3% in cohort B; 46.3% in cohort A and 60.1% in cohort B had ≥1% positive PD-L1 staining. QNS results declined from 16.7% (n = 20) in cohort A to 12.5% (n = 21) in cohort B. Non-NCCN guideline testing was observed in 86.7% of patients in cohort A and 25.6% in cohort B, with those in cohort A being primarily under-tested (70%) and those in cohort B being over-tested. Only 13.3% of cohort A had alignment with NCCN guidelines for appropriate time of testing. Conclusions: Implementation of a pathology-driven molecular reflex pathway for non-squamous NSCLC was associated with increased identification of potentially targetable genetic alterations and improved adherence to NCCN NSCLC testing guidelines, along with reduction in QNS results. Though the TAT mean decreased after pathway implementation, the median did not change, offsetting the often increased lab TAT for NGS methodology vs. PCR and FISH alone. [Table: see text]