bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of homologous recombination DNA repair gene mutation status in patients with metastatic small cell lung cancer treated with cediranib and olaparib on NCI 9881 study.
Authors: Kim Joseph W. , Radke Marc R. , Hafez Navid , Soliman Hatem Hussein , Fu Siqing , Kato Shumei , Lara Primo "Lucky" N. , Vaishampayan Ulka N. , Abdul Razak Albiruni Ryan , Cardin Dana Backlund , Munster Pamela N. , Eder Joseph Paul , Shyr Yu , Ivy S. Percy , LoRusso Patricia , Swisher Elizabeth M. 
Published: June 2021

8563 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of homologous recombination DNA repair (HRR) genes and increases sensitivity of tumors to a poly-(ADP-ribose) polymerase (PARP) inhibitor in vitro and in vivo models of breast and ovarian cancer. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumor with a deleterious mutation in HRR genes. We hypothesized that cediranib induces HRR deficient phenotype by suppressing expression of HRR genes and cediranib and olaparib combination (C+O) results in an objectives response in patients with HRR proficient (HRP) advanced solid tumors. Herein, we report the biomarker data from analyses of targeted sequencing of 84 DNA repair (DR) genes with BROCA-HR assay in patients with metastatic small cell lung cancer (mSCLC). Methods: This multi-institutional phase 2 trial enrolled patients with mSCLC previously treated with a platinum-based chemotherapy. Patients received cediranib 30mg orally (po) daily plus olaparib 200mg po twice daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. A tumor biopsy was obtained from the patients with safely accessible metastatic tumor. HRR deficiency (HRD) was defined as presence of a deleterious mutation in any of the 10 key HRR-related genes per BROCA-HR assay including: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12 (somatic mutations only), NBN, PALB2, RAD51C, or RAD51D. Otherwise, the tumors were defined as HRR proficiency (HRP). Results: A total of 25 patients with SCLC received the study treatment. Fourteen patients had available tumor biopsy samples and/or germline available for BROCA-HR. One patient (7%) was determined to have a HRD tumor by a presence of PALB2 mutation. This patient had stable disease as a best overall response but came off study due to unequivocal clinical progression. Thirteen patients (93%) had a HRP tumor. Six of these (46%) patients had PR. Median PFS in patients with HPR tumors was 122 days. The most common gene alterations detected by BROCA-HR assay was TP53 (93%) and RB1 (79%). Other DR gene alterations noted from our study samples were MRE11, CKD12 PALB2, ERCC4, FANCB, and BAP1. Conclusions: HRD was infrequent in our mSCLC samples. C+O resulted in objective responses in 46% of mSCLC patients with HRP tumors. Mutations in TP53 and RB1 were the most common gene alterations. Further investigation in warranted to confirm this observation. Clinical trial information: NCT02498613.
Combination of quantitative features from H&E biopsies and CT scans predicts response to chemotherapy and overall survival in small cell lung cancer (SCLC).
Authors: Barrera Cristian , Khorrami Mohammadhadi , Jain Prantesh , Fu Pingfu , Butler Kate , Osme Abdullah , Toro Paula , Viswanathan Vidya Sankar , Chahar Satyapal , Dowlati Afshin , Madabhushi Anant 
Published: June 2021

8572 Background: Small Cell Lung Cancer (SCLC) is an aggressive malignancy with a rapid growth, and Chemotherapy remains mainstay of treatment. Identifying therapeutic targets in SCLC presents a challenge, partially due to a lack of accurate and consistently predictive biomarkers. In this study we sought to evaluate the utility of a combination of computer-extracted radiographic and pathology features from pretreatment baseline CT and H&E biopsy images to predict sensitivity to platinum-based chemotherapy and overall survival (OS) in SCLC. Methods: Seventy-eight patients with extensive and limited-stage SCLC who received platinum-doublet chemotherapy were selected. Objective response to chemotherapy (RECIST criteria) and overall survival (OS) as clinical endpoints were available for 51 and 78 patients respectively. The patients were divided randomly into two sets (Training (Sd), Validation (Sv)) with a constraint (equal number of responders and nonresponders in Sd)—Sd comprised twenty-one patients with SCLC. Sv included thirty patients. CT scans and digitized Hematoxylin Eosin-stained (H&E) biopsy images were acquired for each patient. A set of CT derived (46%) and tissue derived (53%) image features were captured. These included shape and textural patterns of the tumoral and peritumoral regions from CT scans and of tumor regions on H&E images. A random forest feature selection and linear regression model were used to identify the most predictive CT and H&E derived image features associated with chemotherapy response from Sd. A Cox proportional hazard regression model was used with these features to compute a risk score for each patients in Sd. Patients in Sv were stratified into high and low-risk groups based on the median risk score. Kaplan-Meier survival analysis was used to assess the prognostic ability of the risk score on Sv. Results: The risk score comprised nine CT (intra and peri-tumoral texture) and six H&E derived (cancer cell texture and shape) features. A linear regression model in conjunction with these 15 features was significantly associated with chemo-sensitivity in Sv (AUC = 0.76, PRC = 0.81). A multivariable model with these 15 features was significantly associated with OS in Sv (HR = 2.5, 95% CI: 1.3-4.9, P = 0.0043). Kaplan-Meier survival analysis revealed a significantly reduced OS in the high-risk group compared to the low-risk group. Conclusions: A combined CT and H&E tissue derived image signature model predicted response to chemotherapy and improved OS in SCLC patients. Image features from baseline CT scans and H&E tissue slide images may help in better risk stratification of SCLC patients. Additional independent validation of these quantitative image-based biomarkers is warranted.
Myasthenia gravis-associated thymoma and myasthenia gravis-free thymoma have distinct somatic mutation and gene expression profiles.
Authors: Zhang Yi , Li Xiaomo , Lu Gaojun , Ma Tonghui , Shi Kejian 
Published: June 2021

8573 Background: A significant proportion of thymoma patients have concurring autoimmune diseases such as myasthenia gravis (MG). However, the molecular signature of myasthenia gravis-associated thymoma (MGT) is largely unknown. Genomic and transcriptomic profiling of MGT may provide valuable insight to the etiology of MGT and facilitate the development of effective therapeutic approaches. Methods: To study the molecular signature of MGT, 26 thymoma patients were divided into two subgroups according to their clinical presentations. One group included 16 thymoma patients associated with MG (MGT) and the other group had 10 patients without MG (MGF). We profiled the genomic and transcriptomic changes of tumor samples from both subgroups with whole exome sequencing (WES) and RNA sequencing (RNA-seq). Results: The WES results indicated that more genes were mutated in the MGF subgroup than the MGT group, although the difference between two subgroups was not statistically significant. There were only five mutated genes ( NBPF1, HRAS, ATAD3B, IFITM3 and MUC4) appeared total mutation frequency exceeded 10%. NBPF1 is the most frequently mutated gene, seen in 25% of the MGTs (4/16) and 10% (1/10) of the MGFs. Neuroblastoma breakpoint family member 1 encoded by NBPF1 was involved in several cancer types including gastric cancer and neuroblastoma, but there is no report on the link of NBPF1 with thymoma or MG. Recent studies showed that NBPF1 is a negative regulator of Akt-p53-Cyclin D and PI3K/mTOR signal pathways. Recurrent mutations in HRAS was only observed in MGFs but not MGTs. Genes mutated in more than one patient were NBPF1, ATAD3B, RPDM9, LOC642131, ADAM21, CGNL1, MUC4 and MUC2 in the MGT subgroup, while only three genes HRAS, CSPG4 and IFITM3 were mutated in more than one patient in the MGF subgroup. Moreover, RNA-seq data identified 106 significantly differentially expressed genes, including 54 upregulated and 52 downregulated genes in the MGT subgroup, further pathway enrichment analysis revealed that the Hippo, Wnt, TGF‐β and focal adhesion signaling pathways were significantly downregulated in the MGT subgroup compared with the MGF subgroup. Conclusions: Our findings provide new insights for the etiology of thymoma with and without MG. mTOR signaling pathway is a key regulator of immune response. Importantly, the protein level of some components in the mTOR pathway was reduced in MG caused-atrophic muscle. Further investigation is warranted to examine the functional roles of NBPF1 in mTOR signaling regulation and the etiology of MG-associated thymoma.
Preliminary safety and efficacy results from phase 1 studies of DZD9008 in NSCLC patients with EGFR Exon20 insertion mutations.
Authors: Yang James Chih-Hsin , Wang Mengzhao , Mitchell Paul , Fang Jian , Nian Weiqi , Chiu Chao-Hua , Zhou Jianying , Zhao Yanqiu , Su Wu-Chou , Camidge D. Ross , Yang Tsung-Ying , Zhu Viola Weijia , Millward Michael , Fan Yun , Huang Wen Tsung , Cheng Ying , Jiang Liyan , Zheng Li , Ye Xiuhui , Janne Pasi A. 
Published: June 2021

9008 Background: There are no approved targeted therapies for EGFR exon20 insertion (exon20ins) mutant NSCLC. DZD9008 is a rationally designed selective, irreversible EGFR exon20ins inhibitor being studied in two ongoing phase 1/2 studies (NCT03974022 and CTR20192097). Methods: The objectives of the studies are to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor efficacy of DZD9008 in NSCLC with EGFR or HER2 mutations. Both studies include dose escalation and expansion cohorts. Pooled analysis is applied to define recommended phase 2 dose (RP2D). Results: Between July 9, 2019 and February 5, 2021, 97 NSCLC patients with EGFR or HER2 mutations were dosed with DZD9008 (dose range: 50 mg to 400 mg, once daily). M/F: 44/53; 59 with EGFR exon 20. DZD9008 was well tolerated up to 400 mg (MTD) once daily. The DLTs were diarrhea and cardiac arrhythmia. The most common TEAEs were diarrhea (grade 3, 5.2%) and skin rash (grade 3, 1%). DZD9008 showed approximately dose-proportional PK, with a half-life of around 50 hours. Fifty-six patients with > 16 different EGFR exon20ins mutations had > 1 post-treatment efficacy assessment. Prior therapies: median 2 (range 1 - 10), prior chemotherapy 92.9% (52/); prior TKI 44.6% (25/56) including 1 patient had poziotinib treatment; 42.9% (24/56) with brain metastasis. Partial response was observed at ≥ 100 mg dose levels. At the RP2D dose of 300 mg once daily, the objective response rate was 48.4% (15/31), and disease control rate (DCR) was 90.3% (28/31). Responses were observed in 2 patients with prior JNJ-61186372 treatment. Anti-tumor activity was observed across different EGFR exon20ins mutation subtypes. By data cut-off, the median treatment duration was 100 days (range 1 – 422). The longest duration of response was over 6 months, and 18 out of 22 responders are still responding. Conclusions: DZD9008 showed a favorable safety profile and promising anti-tumor efficacy in pre-treated NSCLC with EGFR exon20ins mutations. The updated data will be presented at the meeting. DZD9008 is currently in phase II clinical development (NCT03974022). Clinical trial information: NCT03974022.
Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227.
Authors: Paz-Ares Luis G. , Ciuleanu Tudor-Eliade , Lee Jong-Seok , Urban Laszlo , Bernabe Caro Reyes , Park Keunchil , Sakai Hiroshi , Ohe Yuichiro , Nishio Makoto , Pluzanski Adam , Ramalingam Suresh S. , Brahmer Julie R. , Borghaei Hossein , O'Byrne Kenneth John , Hellmann Matthew D. , Memaj Arteid , Bushong Judith , Tran Phuong , Reck Martin 
Published: June 2021

9016 Background: 1L NIVO + IPI was shown to provide durable long-term overall survival (OS) benefit vs chemo regardless of tumor programmed death ligand 1 (PD-L1) expression in patients (pts) with advanced NSCLC in CheckMate 227 Part 1 (NCT02477826); 3-year OS rates were 33% vs 22% in pts with PD-L1 ≥ 1% (HR, 0.79 [95% CI, 0.67–0.93]) and 34% vs 15% in pts with PD-L1 < 1% (HR, 0.64 [95% CI, 0.51–0.81]). Here we report updated results from the study with 4 years’ minimum follow-up. Methods: Adults with previously untreated stage IV / recurrent NSCLC, no known EGFR/ ALK alterations , and ECOG performance status ≤ 1 were enrolled; pts were stratified by squamous (SQ) and non-squamous (NSQ) histology. Pts with PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to receive NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO alone (240 mg Q2W), or chemo. Pts with PD-L1 < 1% (n = 550) were randomized 1:1:1 to receive NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1% was the primary endpoint. Results: With minimum follow-up of 49.4 months (database lock, Feb 18, 2021), pts were at least 2 years beyond the protocol-specified end of immunotherapy treatment. Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free. Among responders, 34%, 30%, and 7% remained in response, respectively. In an exploratory analysis in pts with PD-L1 ≥ 50%, 4-year OS rates were 37% (NIVO + IPI), 26% (NIVO), and 20% (chemo). In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo). At 4 years, 12% (NIVO + IPI), 7% (NIVO + chemo), and 0% (chemo) remained progression free. Among responders, 31%, 13%, and 0% remained in response, respectively. Among pts who progressed on NIVO + IPI vs chemo, 7% vs 40% (PD-L1 ≥ 1%), and 9% vs 33% (PD-L1 < 1%), received subsequent immunotherapy. Benefit with NIVO + IPI vs chemo was observed for both SQ and NSQ histology (Table). With long-term follow-up, no new safety signals were identified. Conclusions: With 4 years’ minimum follow-up, 1L NIVO + IPI continued to provide durable, long-term OS benefit vs chemo in pts with advanced NSCLC regardless of PD-L1 expression or histology. Clinical trial information: NCT02477826. [Table: see text]
Whole-exome sequencing in advanced-stage sensitizing EGFR mutation non-small cell lung cancer: Explore resistance biomarkers to EGFR TKI treatment.
Authors: Vinayanuwattikun Chanida , Sitthideatphaiboon Piyada , Teerapakpinyo Chinachote , Korphaisarn Krittiya , Poungvarin Naravat , Chantranuwatana Poonchavist , Shuangshoti Shanop , Aporntewan Chatchawit , Sriuranpong Virote 
Published: June 2021

9039 Background: Despite the development of predictive biomarkers to shape treatment paradigms and outcomes, 10-20% of de novo EGFR TKI resistance advanced non-small cell lung cancer (NSCLC) in the presence of EGFR mutation remains the issue of concern. Methods: We explored clinical factors in 332 advanced NSCLC who received EGFR TKI and molecular characteristics through 65 whole exome sequencing of various EGFR TKI responses including; de novo (progression within 3 months), intermediate response (IRs) and long-term response (LTRs) (durability > 2 year). Results: Uncommon EGFR mutation subtype was a significant variable in de novo resistance vs. IRs and LTRs with odd ratios of 6.83 ([95% CI 2.36 – 19.80], p-value < 0.001) and 16.84 ([95%CI 1.66 – 171.45, p-value 0.02), respectively. The remaining sensitizing EGFR mutation subtype (exon 19 del and L858R) accounted for 75% of de novo resistance. Genomic landscape analysis was conducted, focusing in 10 frequent oncogenic signaling pathways with functional contributions; cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGF-β, p53 and β-catenin/Wnt signaling. Cell cycle pathway was the only significant alteration pathway among groups with the FDR p-value of 6×10-4. We found only significant q-values of < 0.05 in 7 gene alterations; CDK6, CCNE1, CDK4, CCND3, MET, FGFR4 and HRAS which enrich in de novo resistance [range 36-73%] compared to IRs/LTRs [range 4-22%]. Amplification of CDK4/6 was significant in de novo resistance, contrary to IRs and LTRs (91%, 27.9% and 0%, respectively). The presence of co-occurrence CDK4 /6 amplification correlated with poor disease outcome with HR of progression-free survival of 3.63 [95% CI 1.80-7.31, p-value < 0.001]. Conclusions: The presence of CDK4 /6 amplification in pretreatment specimen serve as a predictive biomarker for de novo resistance in sensitizing EGFR mutation.
Features in genomics and tumor immune microenvironment in NSCLC treated with neoadjuvant PD-1 blockade.
Authors: Wang Shuhang , Li Ning , Mao Beibei , Ying Jianming , Tao Xiuli , Tang Wei , Zhang Lei , Geng Xiao , Zhang Fan , Xue Qi , Wu Lijia , Zhang Henghui , Gao Shugeng , He Jie 
Published: June 2021

9063 Background: Results from several clinical trials have preliminarily demonstrated the safety and effectiveness of single PD-1 inhibitors in neoadjuvant setting for resectable non-small cell lung cancer (NSCLC). However, only around 40% patients could achieve Major Pathological Response. How to select patients who could benefit from single PD-1 blockade remains elusive. Methods: In this study, we aimed to assess the association of PD-L1 expression, tumor mutation burden (TMB), copy number alteration (CNA, including copy number gain and loss) burden with the pathological response to neoadjuvant PD-1 blockade. We also evaluated the dynamic changes of tumor immune microenvironment (TIME) by analyzing pre-immunotherapy treatment tumor biopsy samples from twenty-nine NSCLC patients as well as the matched post-surgery samples after neoadjuvant sintilimab treatment and resection. Targeted DNA sequencing (543 genes), PD-L1 immunochemistry staining (22C3) and multiplex immunofluorescence (CD4, CD8, CD9) were applied. Results: The degree of pathological regression and major pathological response (MPR), were positively correlated with tumor proportion score (TPS) of PD-L1 (R = 0.40, p = 0.04) and negatively correlated with copy number gain (CNgain) burden (R = -0.44, p = 0.04). Of note, the combination of CNgain burden and TPS can better stratify MPR patients compared to CNgain or TPS alone. Whereas, TMB only had a marginal association with pathological response (R = 0.32, p = 0.15). Additionally, PD-1 blockade led to an increase in CD8+PD-1-T cells in the tumor region (p = 0.04, Mann-Whitney U test for paired samples) and a reduction in Tregs and M2 macrophages in the stromal region (p < 0.05, Mann-Whitney U test for paired samples). Further investigation showed that the degree of CD8+PD-1-T cell increase was significantly associated with MPR (p < 0.05, Mann-Whitney U test). Intriguingly, we also observed a substantial reduction in CD19+ cells in the non-MPR group but not in the MPR group, indicating the involvement of B cells in improving neoadjuvant immunotherapy response in NSCLC patients. Conclusions: TPS and CNgain burden were correlated with pathological response to neoadjuvant immunotherapy in NSCLC patients. This may provide potential selective indicators for future clinical trials of neoadjuvant immunotherapy. The dynamic changes of components in the tumor immune microenvironment may provide novel insight into the immune responses induced by neoadjuvant PD-1 blockade therapy.
Association between improvements in survival of metastatic NSCLC patients and targeted- and immuno-therapy.
Authors: Ramagopalan Sreeram , Leahy Thomas P. , Ray Joshua , Wilkinson Samantha , Sammon Cormac J. , Subbiah Vivek 
Published: June 2021

9090 Background: Significant improvements in mortality among NSCLC cancer patients in the US over the past two decades have recently been reported based on SEER data. The timing of these improvements led to suggestions that they are primarily a result of the introduction of new and innovative treatments, however few studies have directly investigated this. Methods: We utilised the US Flatiron Health database to identify a cohort of non-biomarker (EGFR/ALK/ROS1/BRAF) positive metastatic NSCLC (mNSCLC) patients and a separate cohort of ALK positive (ALK+) patients diagnosed between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilised to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort. Results: We identified cohorts of 30,076 (54.7% Males) non-biomarker positive and 652 (45.4% males) ALK+ mNSCLC cancer patients in the database eligible for the analysis. Survival in both cohorts improved over time. After adjustment for differences in baseline characteristics the hazard of death in non-biomarker positive patients diagnosed in 2015, 2016, 2017, 2018 and 2019 was observed to be 14%, 13%, 16% 19% and 21% lower respectively than that in those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these innovative treatments. Similarly, decreases in the hazard of death were only observed in ALK+ patients diagnosed in 2018 and 2019 relative to 2012 and were no longer observed following adjustment for the use of ALK inhibitors. Conclusions: Our findings expand on the SEER data and provide direct evidence linking improvements in survival of NSCLC patients over the past decade with the introduction of innovative therapies.[Table: see text]