tbuckley/cabot-search huggingface dataset:
Identification of DNA repair/replication genes mutations in determining response to immune checkpoint inhibitors in non-small cell lung cancer patients.
Authors: Meng-Xia Li, Guan Wang, Xiao Yang, Xianfeng Lu, Shiheng Zhang, Jiayue Xu, Dong Wang, Qiang Xu
Journal: Journal of Clinical Oncology (2017)

e14582 Background: Tumor mutational burden (TMB) is considered a promising predictive biomarker for immune checkpoint blockade (ICB) therapy response . However, the measurement of TMB relies on the whole-exome sequencing (WES), which is technically limited by sample volume and freshness, thus restricts its use in clinical practice. Since TMB is controlled by the balance between DNA damage and the repair, it is a rational approach to identify a subset of DNA repair/replication gene mutations associated with increased TMB as a surrogate, which could be monitored in clinic to predict ICB efficacy even busing limited archived tissues. Methods: The mutation status of 471 genes associated with DNA repair and replication were analyzed for the correlation with TMB and/or ICB therapeutic responses in three cohorts of NSCLC patients, which are: Cohort A, WES data of 100 Chinese NSCLC patients; Cohort B, WES data of NSCLC patients from TCGA database; Cohort C, WES data and therapeutic response to PD-1 mAb from a Science paper (Rizvi et al. 2015, Science). Results: We identified somatic mutations in 32 DNA repair/replication genes associated with high TMB in both Cohort A and Cohort B. In Cohort C, mutations were found in 20 out of these 32 genes, and the mutation status of 17/20 genes were associated with the clinical benefit of ICB therapy. Noteworthy, mutations of TP53, POLQ, MMS22L, HERC2, CEP164, BRCA1/2, FANCM and MSH4 were mostly common mutations associated with TMB in all 3 cohorts, and ERCC2 and ERCC6 were uniquely high mutated and associated with high TMB in Chinese Han people from Cohort A. Interestingly, EGFR activating mutations were inversely correlated with both high TMB and good ICB response. Conclusions: This retrospective study identified 17 DNA repair/replication-related genes, whose mutation status was associated with high TMB and/or ICB response. Mutational patterns of DNA repair genes are likely different between western and Chinese NSCLC patient population. The data also suggested that NSCLC patients carrying EGFR activating mutations are not preferential population for ICB therapy. Further data is needed to verify the validity of these observations.
Prognostic value of various subtypes of circulating DNA in ovarian cancer patients.
Authors: Tomas Minarik, Barbora Vlkova, Katarina Kalavska, Denisa Manasova, Michaela Kubickova, Andrej Jurik, Tibor Lengyel, Igor Slezak, Oliver Sadovsky, Bohumil Niznansky, Milan Krkoska, Lucia Kocova, Jozef Mardiak, Jozef Sufliarsky, Peter Celec, Michal Mego
Journal: Journal of Clinical Oncology (2017)

e17092 Background: Patients with ovarian cancer represent a heterogeneous population with a variable prognosis and response to chemotherapy. Circulating tumor DNA has been shown to have a prognostic value in different types of cancer including ovarian carcinoma. Whether total circulating DNA, which can be assessed much easier without knowing the tumor-specific mutations, has similar informative value is currently unknown. The aim of this study was to evaluate the prognostic value of circulating DNA in advanced ovarian cancer. Methods: This prospective study included 67 patients (pts) with ovarian cancer treated with 1 st line paclitaxel and carboplatin (25 pts) and bevacizumab (42 pts). Thirty-five patients had optimal debulking before chemotherapy. Circulating plasma DNA was quantified using real time PCR before administration of chemotherapy (67 pts) and after 6 cycles of chemotherapy (44 pts). Results: Total extracellular DNA (ecDNA), as well as extracellular DNA of nuclear (nDNA) and mitochondrial origin (mtDNA) significantly (p &lt; 0.05) decreased after 6 cycles of chemotherapy (by 54%, 63% and 52%, respectively. Patients with stage I disease had significantly lower mtDNA compared to patients with stage II-IV (8604 vs. 16984 ge/mL, p = 0.03). Patients with lower baseline nDNA had superior progression-free (HR=0.35 (0.14-0.86)) and overall survival (HR=0.18 (0.04-0.77). The prognostic value of nDNA was confirmed independent of tumor stage and confirmed in multivariate analysis. Conclusions: Our data suggest that ecDNA of both, nuclear and mitochondrial origin, could be added to prognostic markers in ovarian cancer. This is of importance as this analysis does not require the knowledge of tumor-specific mutations in contrast to the quantification of tumor-derived ecDNA. Analysis of the dynamics and cell type-specific source of the ecDNA could shed light on its biology in cancer and might help to direct the treatment of ovarian cancer.
Molecular profiling of advanced malignancies: A community oncology network experience.
Authors: Pritam Tayshetye, Dulabh K. Monga, Gene Grant Finley, Swati Vishwanathan, Candice Brem, Jan F Silverman
Journal: Journal of Clinical Oncology (2017)

e23111 Background: Many genomic alterations have been identified that are critical to the malignant phenotype. Some of these, termed “driver mutations”, are critical for tumor proliferation and progression. The landscape of targeted therapy has expanded as well. Next-generation sequencing (NGS) of tumors reveals cancer-related genomic alterations and provides therapeutic recommendations for specific targeted therapy. We analyzed our experience with FoundationOne, a validated NGS genomic profile in a community oncology network. Methods: NGS results from May 2014 to September 2016 from a community oncology network in Western Pennsylvania were analyzed. Medical records were reviewed for primary site, stage, biopsy site, timing of testing, prior treatment, FDA-approved therapy in patient’s and other tumor types and potential clinical trials based upon mutations detected. Endpoints determined were percentage of patients with targetable mutations and those in whom treatment decisions were made based on NGS results. Results: 157 NGS results were available for analysis. 38.2% cases were tested early in the disease course (at diagnosis, during or shortly after first-line treatment) and 61.8% at progression. FDA-approved targeted agent for a specific mutation was found in 14% of the primary tumor type and 19.8% of other tumor types. Clinical trials were available for 93% cases. The NGS results were utilized in treatment decisions in 28 patients of which, 9 were tested early and 19 at disease progression. Of the 28, 11 were initiated on a targeted agent. Median duration of targeted therapy was 2.6 months. 9 patients were on appropriate targeted agent prior to testing. 8 patients were unable to start the targeted agent because of insurance denial, clinical deterioration or patient preference. Conclusions: NGS is a valuable tool for personalizing cancer care. From our experience, the actual number of patients starting a targeted agent based on NGS results is low. It nevertheless can provide additional treatment options and facilitate clinical trial enrollment. Optimal timing of testing (early vs late), financial implications of testing and using targeted therapy and survival benefit of targeted therapy need further studies.
P01.158 Effect of radiation therapy on microstructural changes in the brain in patients with glioblastoma. A diffusion tensor imaging study
Authors: A Rydelius, A Rundcrantz, S Engelholm, S Kinhult, J Lätt, P C Sundgren
Journal: Neuro-Oncology (2018)

Curative intended postoperative treatment for patients with glioblastoma is radiotherapy (RT), usually with concomitant temozolomide. Commonly, glioblastoma patients are evaluated with magnetic resonance imaging (MRI), including diffusion-weighted imaging. The diffusional properties of the tumor provide valuable information for tumor grading, treatment follow-up but also as an emerging field for investigating microstructural changes in tissues. Previous studies of diffusion MRI have suggested that irradiation of the brain results in alteration in the microstructure of the parenchyma, which can be expected to influence patient symptoms and radiation related side effects. The aim of this study was to evaluate microstructural changes in white and gray matter after irradiation to the brain by using advanced MRI technique, such as diffusion tensor imaging (DTI). MR-DTI was analyzed in 29 newly diagnosed glioblastoma patients, 11 females, 18 males, in a pilot study from a still ongoing longitudinal prospective MRI study. Each patient underwent MRI examinations at baseline (start of radiation therapy), at 3, 6, 15, and 26 weeks after baseline and in 11 cases additionally after 52 weeks. At each occasion the diffusion images were co-registered to the T1-MPRAGE, where manually drawn regions of interest (ROI) were placed in following structures: genu, splenium and corpus (body) of the corpus callosum, hippocampus and amygdala bilaterally, using an in-house developed MATLAB tool. Tumor infiltrated areas were excluded. ROI locations were confirmed on mean diffusivity (MD)-maps, further diffusional properties of fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) were evaluated for each structure. No significant changes between examinations were seen in MD, FA, RD or AD values in any of the structures. Neither were there any significant changes in any of the parameters when correlating to gender, age or the radiation dose given for each specific structure. The present study could not demonstrate any longitudinal changes after 6–12 months in measured MD, FA, AD and RD in evaluated structures. These findings suggest that irradiation, as performed today, has less negative effects on brain structures than previously been reported. This may be an effect of the refined RT methods, used today. Cognitive testing from the same patient population indicates no deterioration of cognitive function compared to baseline at follow up 3 and 12 months post-irradiation, which may support this hypothesis. An individual treatment follow-up might still be beneficial, and remains to be evaluated. Long time follow up including 2 years is planned.
Preliminary safety data from KEYNOTE-059: Pembrolizumab plus 5-fluorouracil (5-FU) and cisplatin for first-line treatment of advanced gastric cancer.
Authors: Charles S. Fuchs, Atsushi Ohtsu, Josep Tabernero, Eric Van Cutsem, Jiang Dian Wang, Baohoang Lam, Rita Dalal, Minori Koshiji, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2016)

4037 Background: Standard first-line treatment for advanced gastric cancer includes combination chemotherapy with a platinum agent and a fluoropyrimidine. Pembrolizumab (pembro) has shown promising antitumor activity as monotherapy in patients with advanced gastric cancer. We report preliminary safety data for patients with advanced gastric cancer treated with pembro + cisplatin + 5-FU in the multicohort, phase 2 KEYNOTE-059 study (NCT02335411). Methods: Eligible patients were aged ≥ 18 y and had HER2– advanced gastric or gastroesophageal junction adenocarcinoma, ECOG PS 0-1, and no prior systemic therapy for metastatic disease. Patients received pembro 200 mg + 5-FU 800 mg/m2 (or capecitabine 1000 mg/m2 in Japan) + cisplatin 80 mg/m2 Q3W for 6 cycles followed by pembro + 5-FU (or capecitabine) for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Results: Of the 18 patients treated, 67% were men, and median age was 58 y. As of the Oct 9, 2015 data cutoff date, median follow-up duration was 5.5 mo (range, 4.0-7.3). There were no treatment-related deaths and only 1 patient (6%) discontinued treatment because of an AE (stomatitis), which was considered by the investigator to be unrelated to pembro or chemotherapy. 17 patients (94%) experienced treatment-related AEs of any grade, most commonly stomatitis (n = 7, 39%), decreased appetite (n = 6, 33%), nausea (n = 5, 28%), and neutropenia/decreased neutrophils (n = 11, 61%) without neutropenic fever and unrelated to pembro. 12 patients (67%) experienced grade 3-4 treatment-related AEs; none were attributed to pembro. AEs attributed to pembro occurred in 7 patients (39%); the most common were diarrhea, dysgeusia, hyperthyroidism, and nausea (n = 2 each); all were grade 1/2. 8 patients (44%) experienced AEs of special interest, regardless of attribution by investigator, including hyperthyroidism, hypothyroidism, infusion-related reaction, pruritus, and vasculitis; all were grade 1/2. Conclusions: These data suggest the combination of pembro, cisplatin, and 5-FU has a manageable safety profile as first-line therapy in patients with advanced gastric cancer. Clinical trial information: NCT02335411.
Detection of ALK, RET, ROS1, NTRK1 and MET rearrangements and actionable mutations using next generation sequencing in patients with non-small cell lung cancer
Authors: A. Harlé, W. Dietmaier, I. Vogl, K. Neumann, F. Haumaier, A.D. Beggs, V. Pestinger, D. Grand, A. Tallet, J.-L. Merlin
Journal: Annals of Oncology (2018)

Background: Targeted therapies have been developed this last decade and considerably improved PFS and OS of patients with NSCLC. Next-Generation Sequencing (NGS) is commonly used for the detection of actionable mutations in a panel of genes and FISH or IHC are the gold-standard assay for the detection of rearrangements of ALK, RET, ROS1, NTRK1 and MET. The aim of this study is to evaluate the suitability and reliability of NGS assay for the detection of rearrangements compared to the results obtained using FISH and IHC. Methods: 86 FFPE samples, primary tumors or micro biopsies of patients with NSCLC, were analyzed in 7 European labs for this study. All samples were qualified by a senior pathologist prior to analysis. DNA and RNA were extracted from FFPE samples using Qiagen AllPrep kit. TruSight™ Tumor 15 and INCa panel kits were used for DNA library preparation and Archer® FusionPlex® panel kit for RNA library preparation. Both libraries were finally pooled and analyzed using illumina MiSeq sequencing system. Data were finally analyzed using Variant Studio software or Biomedical Genomics Workbench and Ingenuity Variant Analysis for SNV or indel and Archer Analysis software for rearrangements. SNV, indel and rearrangements found for each sample were finally compared to FISH and IHC results and previous DNA sequencing data when available in the labs. Results: 86 DNA and RNA libraries were sequenced. Among 86 samples 8 failed fusion quality control, due to too low amount or too degraded input RNA. No FISH and IHC results were available for 12 samples. Rearrangements were found for 28 samples, 22, 5 and 1 with an ALK, ROS1 and RET rearrangements respectively. Among 74 samples with previously known rearrangements, all samples showed full concordance with previous methods. Conclusions: RNA based NGS is a suitable and reliable alternative to FISH and/or IHC for the detection of rearrangements of ALK, RET, ROS1, NTRK1 and MET genes for the theragnostic management of patients with NSCLC. Further investigations are needed to determine if an "all NGS strategy" is more likely cost-effective and faster than a "FISH and NGS strategy". Legal entity responsible for the study: Institut de Cancérologie de Lorraine. Funding: Illumina. Disclosure: A. Harlé: All reagents used in this study were provided free of charge by Illumina and Archer. I. Vogl: Works at Genolytic GmbH. All other authors have declared no conflicts of interest.
Apatinib for EGFR-TKIs resistant NSCLC patients: Initial clinical experience.
Authors: Na Zhou, Chuantao Zhang, Man Jiang, Helei Hou, Lantao Zhao, Dong Liu, Jing Cong, Hua Zhu, Xiaochun Zhang
Journal: Journal of Clinical Oncology (2017)

e14059 Background: The 3 rd generation TKI is still not available for Chinese NSCLC patients with EGFR-mutant who develop acquired resistance following treatment with 1 st EGFR tyrosine kinase inhibitors (EGFR-TKIs). Apatinib, a novel small molecule TKI targeted VEGFR2, recommended as third-line treatment for metastatic gastric cancer patients, might be used as an alternative strategy for these patients. This study is an initial clinical experience about Apatinib for EGFR-mutant NSCLC patients with 1 st TKI resistance. Methods: Eight patients pathological diagnosed as adenocarcinoma with EGFR mutant were enrolled between January, 2016 and January, 2017. All patients had undergone TKI treatment and disease progression. They had an ECOG performance status (PS) of 0–1. 250 mg-500mg/day of Apatinib was continuously administered for two months, during which we observed the curative effect and adverse events closely. Informed consent was obtained from each patient before enrollment. Results: Computed tomography (CT) scan evaluation revealed that partial response (PR) occurred in 25% (2/8) patients and other 75% (6/8) showed stable disease (SD). There was no progressive disease (PD) occurred. Hypertension is one of the most frequent adverse reactions, which appeared in 50% (4/8) patients who were getting to be normal under antihypertensive agent. Others like hand-foot syndrome, anergy and temple elevated urine protein also appeared and could be better controlled. Conclusions: Apatinib is a safe and effective oral targeted drug on EGFR-mutant NSCLC patients with TKI resistance. It could provide a new therapy strategy for them before taking osimertinib. To further investigate the role of Apatinib in drug resistant EGFR-mutant NSCLC, large sample and additional clinical trials are needed. Table1. Clinicopathologic Characteristics of Patients. [Table: see text]
Trabectedin (T)-related liver toxicity: Results of a pharmacokinetic study with T in patients with hepatic dysfunction (OVC1004) and experience from a phase 3 clinical trial (SAR3007).
Authors: Emiliano Calvo, Analia Azaro, Luc Dirix, Manon Huizing, Francis Mark Senecal, Patricia LoRusso, Lorrin Yee, Chi Fung Keung, Spyros Triantos, Youn C. Park, Roland Elmar Knoblauch, Trilok V. Parekh, George D. Demetri, Margaret vonMehren
Journal: Journal of Clinical Oncology (2016)

11064Background: Trabectedin (T) has been extensively studied in treating sarcomas and ovarian cancer. Metabolized primarily by liver, T is also associated with transient transaminase elevation, wi...
P04.50 Doxycycline impairs mitochondrial function and protects human glioma cells from hypoxia-induced cell death: implications of using Tet-inducible systems
Authors: B Sauer, A Luger, N I Lorenz, A L Engel, Y Braun, M Voss, P N Harter, J P Steinbach, M W Ronellenfitsch
Journal: Neuro-Oncology (2018)

Inducible gene expression is an important tool in molecular biology research to study protein function. Most frequently, the antibiotic doxycycline is used for regulation of so-called tetracycline (Tet)-inducible systems. In contrast to stable gene overexpression, these systems allow investigation of acute and reversible effects of cellular protein induction. Recent reports have already called for caution when using Tet-inducible systems as the employed antibiotics can disturb mitochondrial function and alter cellular metabolism by interfering with mitochondrial translation. Reprogramming of energy metabolism has lately been recognized as an important emerging hallmark of cancer and is a central focus of cancer research. Therefore, the scope of this study was to systematically analyze dose-dependent metabolic effects of doxycycline on a panel of glioma cell lines with concomitant monitoring of gene expression from Tet-inducible systems. Experiments were performed with the human cell lines LNT229, G55, U343MG and SVG. Cell density was determined by CV staining. Hypoxic cell death was quantified by LDH release and PI staining. Mitochondial protein content was measured by Western Blotting. Oxygen consumption was determined with a fluorescence-based assay. Glucose concentration was measured in supernatants. We report that doxycycline doses commonly used with inducible expression systems (0.01–1 µg/mL) substantially alter cellular metabolism: Mitochondrial protein synthesis was inhibited accompanied by reduced oxygen and increased glucose consumption. Furthermore doxycycline protected human glioma cells from hypoxia-induced cell death. An impairment of cell growth was only detectable with higher doxycycline doses (10 µg/mL). Our findings describe settings where doxycycline exerts effects on eukaryotic cellular metabolism, limiting the employment of Tet-inducible systems. Possible effects of doxycycline on cell metabolism have to be taken into consideration when employing such inducible systems.
Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026.
Authors: Naoki Furuya, Tatsuro Fukuhara, Haruhiro Saito, Kana Watanabe, Shunichi Sugawara, Shunichiro Iwasawa, Yoshio Tsunezuka, Ou Yamaguchi, Morihito Okada, Kouzou Yoshimori, Ichiro Nakachi, Akihiko Gemma, Koichi Azuma, Koichi Hagiwara, Toshihiro Nukiwa, Satoshi Morita, Kunihiko Kobayashi, Makoto Maemondo
Journal: Journal of Clinical Oncology (2018)

9006 Background: Development of treatment for EGFR-mutated non-small-cell lung cancer (NSCLC) had been focused on monotherapy of gefitinib, erlotinib, or afatinib. Combinations of EGFR-TKIs and VEGF inhibitors are one of candidates for next strategy for EGFR-mutated tumor. We conducted a phase III study comparing BE to E. Methods: Chemotherapy-naïve pts with advanced non-squamous NSCLC harbouring EGFR-mutation were randomly assigned to receive either combination with erlotinib (150 mg daily) plus bevacizumab (15 mg/kg iv q3w) or erlotinib (150 mg daily). Status of EGFR mutations in plasma samples were monitored routinely during the study treatment and a second-line treatment. The primary endpoint was PFS. Secondary endpoints were OS, RR, safety, and QoL. We hypothesized that hazard ratio of PFS was 0.63. It was estimated that 147 events would be needed for the study to have a power of 80% and a two-sided significance level of 5%. Accordingly, this study was planned to enroll 214 pts in total. Results: Between Jun 3, 2015, and Aug 31, 2016, 228 pts with EGFR mutations were enrolled. There were one cessation prior to the study treatment and one withdrawal of consent; the remaining 226 pts were assigned to BE (n = 112) and E (n = 114). The interim analysis preplanned was performed at 117 PFS events using full analysis set of 224 pts except for both an ineligible case and a case lost to follow-up in E. Pts were followed up for a median of 12.4 months. The interim analysis showed that the study met its primary endpoint. At data cutoff (Sept 21, 2017), median PFS was 16.9 months (95% CI 14.2-21.0) in BE and 13.3 months (11.1-15.3) in E (p = 0.0157) (HR 0.605, 95% CI 0.417-0.877). Though hemorrhage, proteinuria, and hypertension as toxicities significantly increased in BE compared to in E, there was no significant difference among other toxicities between BE and E. Five cases had low-grade pneumonitis in E but no pneumonitis in BE. There was no treatment-related death. Conclusions: In this study, BE as a combination of EGFR-TKIs and VEGF inhibitors achieved durable response and good tolerability. This regimen is considered as a new standard treatment in EGFR-mutated NSCLC. Clinical trial information: UMIN000017069.