tbuckley/cabot-search huggingface dataset:
Safety and preliminary antitumor activity of U3-1402: A HER3-targeted antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC.
Authors: Pasi A. Janne, Helena Alexandra Yu, Melissa Lynne Johnson, Conor Ernst Steuer, Michele Vigliotti, Corinne Iacobucci, Shuquan Chen, Channing Yu, Dalila B. Sellami
Journal: Journal of Clinical Oncology (2019)

9010 Background: Treatment options are limited for EGFRm NSCLC resistant to EGFR TKIs. HER3 is expressed in a majority of NSCLC tumors. U3-1402 is a HER3-targeted antibody drug conjugate with a fully human HER3-targeted antibody, novel cleavable peptide-based linker, and topoisomerase I inhibitor payload. Methods: An ongoing multicenter phase 1 dose escalation and expansion study is assessing U3-1402 safety/tolerability and preliminary activity in metastatic or unresectable EGFRm NSCLC patients (pts) who are T790M negative after disease progression while on erlotinib, gefitinib or afatinib; or develop disease progression while on osimertinib regardless of T790M status. Dose escalation is based on dose-limiting toxicities (DLTs) and guided by the modified Continuous Reassessment Method. U3-1402 is administered via intravenous infusion in 21-day cycles. Pretreatment tumor tissue is required. Results: As of 11 Nov 2018, 15 pts (6 M; 9 F) were enrolled across 3 dose levels (3.2, 4.8, 6.4 mg/kg). Median age was 63 y; 10 pts had EGFR exon 19 deletion and 5 EGFR L858R mutation. Median sum of longest diameters (SLD) at baseline was 69 (range 22–143) mm. All pts had prior EGFR TKIs; 14 had 2nd line or later osimertinib. Six had prior chemotherapy. All 11 evaluable tumors demonstrated HER3 expression (median HER3 membrane H-score 188, range 150–290). Five pts discontinued treatment: 4 due to progressive disease, 1 due to adverse event (AE). All Grade (Gr) treatment-emergent AEs (TEAEs) in ≥20% of pts were nausea (60%), vomiting (40%), fatigue (33%), decreased appetite (27%), and alopecia (20%). Gr≥3 TEAEs were nausea (1/15; Gr3; related), hypoxia (1/15; Gr3; unrelated), and platelet count decreased (2/15; both Gr4 at 6.4 mg/kg and considered DLTs). In 13 evaluable pts, all but 1 had a decrease in SLD (median best change −29%, range +10% to −67%), 2 had confirmed partial response per RECIST v1.1 (best changes −44%, −67%). Conclusions: U3-1402 showed a manageable safety profile and preliminary antitumor activity in EGFR TKI-resistant EGFRm NSCLC. Evaluation of candidate biomarkers, including HER3 expression, which correlate with U3-1402 response is ongoing. Clinical trial information: NCT03260491.
Correlation of <i>CHAF1A</i> with adjuvant chemotherapy outcome and microsatellite instability in gastric cancer.
Authors: Deqiang Wang, Deyu Chen, Bo Shen, Xiaofeng Chen, Martin Qi, Xiaoqin Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2019)

e15511 Background: Clinical outcomes of adjuvant chemotherapy in gastric cancer (GC) have considerable stage-independent variability, which underscores the need for predictive molecular markers. Previous studies indicated that CHAF1A played a critical role in tumor growth, but whether it was associated with adjuvant chemotherapy in GC was still unknown. This retrospective study investigated the prognostic value of CHAF1A in adjuvant chemotherapy of GC. Methods: A total of 325 stage IB-III patients with fluoropyrimidines (FU)-based adjuvant chemotherapy after curative D2 gastrectomy meeting eligibility criteria were selected. CHAF1A protein expression was determined by immunohistochemical method. The primary outcomes were Overall survival (OS) and Disease-free survival (DFS). Kaplan-Meier method was used to estimate survival curve and Cox model for multifactor analysis. Results: CHAF1A mRNA was overexpressed in GC tissues and positive CHAF1A protein expression was not associated with OS and DFS in overall patients treated by FU-based chemotherapy ( P = 0.391 and 0.511, respectively). However, as stratified by tumor sites, positive CHAF1A expression was associated with poor OS and DFS in non-cardia cancer ( P = 0.009 and 0.007, respectively) but not in cardia cancer ( P = 0.229 and 0.112, respectively). Multivariate analysis indicated that CHAF1A expression level was still an independent predictor for both OS (HR = 2.42; 95% CI: 1.12-5.20; P = 0.024) and DFS (HR = 1.91; 95% CI: 1.03-3.54; P = 0.039) in non-cardia GC. Furthermore, CHAF1A was correlated with the status of microsatellite instability ( P = 0.025). Conclusions: CHAF1A might be a predictor for outcomes of FU-based adjuvant chemotherapy in patients with non-cardia GC, but needed further prospective studies to confirm.
A phase II, open labeled, single-arm study of dose-dense paclitaxel plus carboplatin in advanced or recurrent uterine corpus cancer: KCOGG1303 study.
Authors: Kensuke Hori, Shin Nishio, Kimio Ushijima, Yuka Kasamatsu, Eiji Kondo, Kazuhiro Takehara, Reisa Kakubari, Kimihiko Ito
Journal: Journal of Clinical Oncology (2019)

5584 Background: We studied the effectiveness and safety of dose-dense paclitaxel plus carboplatin in advanced or recurrent uterine corpus cancer. Methods: The patient eligibility criteria were women aged 20–75 years with histologically confirmed uterine corpus ; FIGO stage III who had residual tumors, FIGO stage IV, and recurrence after first-line radical treatment, or second-line chemotherapy or radiotherapy. They received paclitaxel (80 mg/m 2 , days 1, 8, 15) + carboplatin (area under the curve 5, day 1 every 3 weeks). The primary endpoint was the response rate (RR). The secondary endpoints were feasibility, progression-free survival, overall survival, and adverse effects. The threshold RR was set to 40%. The expected RR of this treatment was set to 60%; the number of necessary cases calculated with a type I error of 5% and power of 80% was 44. Considering the existence of dropped cases, we set the target number of cases in this study to 48. Results: Forty-eight patients were registered, and 45 were eligible to receive the treatment. The median age of the patients was 61 years (43–76). Twenty-two patients had recurrence; the others had primary advanced corpus cancer. On histology, there were 10 cases of serous carcinoma, 3 cases of endometrioid carcinoma G3, 2 cases of carcinosarcoma, and 2 cases of clear cell carcinoma. Twenty-eight patients (62%) could receive 6 or more cycles of chemotherapy. The RR (complete, 13 cases; partial, 20 cases) was 73.3% (60.7–86.0 95% confidence interval). Conclusions: Dose-dense paclitaxel plus carboplatin was safe and effective for advanced or recurrent uterine corpus cancer. Clinical trial information: R000019874 UMIN000017138.
Association of Step Volume and Intensity With All-Cause Mortality in Older Women
Authors: I-Min Lee, Eric J. Shiroma, Masamitsu Kamada, David R. Bassett, Charles E. Matthews, Julie E. Buring
Journal: JAMA Internal Medicine (2019)

A goal of 10 000 steps/d is commonly believed by the public to be necessary for health, but this number has limited scientific basis. Additionally, it is unknown whether greater stepping intensity is associated with health benefits, independent of steps taken per day.To examine associations of number of steps per day and stepping intensity with all-cause mortality.This prospective cohort study included 18 289 US women from the Women's Health Study who agreed to participate by wearing an accelerometer during waking hours for 7 days between 2011 and 2015. A total of 17 708 women wore and returned their devices; data were downloaded successfully from 17 466 devices. Of these women, 16 741 were compliant wearers (≥10 h/d of wear on ≥4 days) and included in the analyses, which took place between 2018 and 2019.Steps per day and several measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; time spent at a stepping rate of ≥40 steps/min, reflecting purposeful steps).All-cause mortality.Of the 16 741 women who met inclusion criteria, the mean (SD) age was 72.0 (5.7) years. Mean step count was 5499 per day, with 51.4%, 45.5%, and 3.1% of time spent at 0, 1 to 39 (incidental steps), and 40 steps/min or greater (purposeful steps), respectively. During a mean follow-up of 4.3 years, 504 women died. Median steps per day across low-to-high quartiles of distribution were 2718, 4363, 5905, and 8442, respectively. The corresponding quartile hazard ratios (HRs) associated with mortality and adjusted for potential confounders were 1.00 (reference), 0.59 (95% CI, 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60), respectively (P < .01). In spline analysis, HRs were observed to decline progressively with higher mean steps per day until approximately 7500 steps/d, after which they leveled. For measures of stepping intensity, higher intensities were associated with significantly lower mortality rates; however, after adjusting for steps per day, all associations were attenuated, and most were no longer significant (highest vs lowest quartile for peak 1-minute cadence, HR = 0.87 [95% CI, 0.68-1.11]; peak 30-minute cadence, HR = 0.86 [95% CI, 0.65-1.13]; maximum 5-minute cadence, HR = 0.80 [95% CI, 0.62-1.05]; and time spent at a stepping rate of ≥40 steps/min, HR = 1.27 [95% CI, 0.96-1.68]; P > .05).Among older women, as few as approximately 4400 steps/d was significantly related to lower mortality rates compared with approximately 2700 steps/d. With more steps per day, mortality rates progressively decreased before leveling at approximately 7500 steps/d. Stepping intensity was not clearly related to lower mortality rates after accounting for total steps per day.
Genome assembly of a tropical maize inbred line provides insights into structural variation and crop improvement
Authors: Ning Yang, Jie Liu, Qiang Gao, Songtao Gui, Lu Chen, Linfeng Yang, Juan Huang, Tianquan Deng, Jingyun Luo, Lijuan He, Yuebin Wang, Pengwei Xu, Yong Peng, Zhuoxing Shi, Liu Lan, Zhiyun Ma, Xin Yang, Qianqian Zhang, Mingzhou Bai, San Li, Wenqiang Li, Lei Liu, David Jackson, Jianbing Yan
Journal: Nature Genetics (2019)

Maize is one of the most important crops globally, and it shows remarkable genetic diversity. Knowledge of this diversity could help in crop improvement; however, gold-standard genomes have been elucidated only for modern temperate varieties. Here, we present a high-quality reference genome (contig N50 of 15.78 megabases) of the maize small-kernel inbred line, which is derived from a tropical landrace. Using haplotype maps derived from B73, Mo17 and SK, we identified 80,614 polymorphic structural variants across 521 diverse lines. Approximately 22% of these variants could not be detected by traditional single-nucleotide-polymorphism-based approaches, and some of them could affect gene expression and trait performance. To illustrate the utility of the diverse SK line, we used it to perform map-based cloning of a major effect quantitative trait locus controlling kernel weight—a key trait selected during maize improvement. The underlying candidate gene ZmBARELY ANY MERISTEM1d provides a target for increasing crop yields. A high-quality reference genome of the maize SK inbred line and analyses between the tropical SK line and two other maize genomes, B73 and Mo17, provide insights into structural variation and crop improvement.
The Cancer Molecular Screening and Therapeutics Program (MoST): Actionable mutation frequencies in a population with rare and less common cancers.
Authors: Subotheni Thavaneswaran, Mandy L. Ballinger, John Grady, Mark Cowley, Anthony Joshua, Lucille Sebastian, Emily Collignon, Audrey Silvestri, Maya Kansara, Mark Pinese, Katrin Marie Sjoquist, Wendy Hague, Chee Khoon Lee, John Simes, David Morgan Thomas
Journal: Journal of Clinical Oncology (2019)

3136 Background: Personalizing therapy will arguably have no greater impact than on patients (pts) with rare (&lt; 6 per 100,000 population) or less common cancers (6-12/100,000). MoST combines a molecular screening platform and biomarker-driven treatments for pts with advanced cancer, with a particular focus on rare and less common cancers (RLC). Methods: Molecular screening was performed using in-house and commercial panels on archival tumor tissue. A Molecular Tumor Board by consensus reported on pathogenic variants with potential therapeutic actionability. Tiers of actionability were defined as: Tier 1–eligible for a MoST substudy; Tier 2–clinical evidence of efficacy in any cancer type, Tier 3—preclinical evidence. The clinical and molecular characteristics of the first 1,000 pts are presented here. Results: Pts were recruited from Sept 2016 to Dec 2018. A report was issued in 94% of cases in a median of 7.7 weeks from consent. In 6%, there was insufficient tissue. The median age at cancer diagnosis was 35 years (range 4-85 years), and 49% were male. Pts had a median of 2 lines of prior systemic therapy (0-11), and a median baseline ECOG performance status of 0 (range 0-3). 82% of pts had RLCs. A total of 2642 pathogenic variants were reported, of which 1144 (43%) were deemed therapeutically actionable. 651(57%) of actionable variants (AVs) occurred in RLC (Table). Most commonly, AVs were found in the cell cycle, homologous recombination repair (HR) and fibroblast growth factor (FGF) pathways. 559(66%) of pts had at least one AV identified, 30% tier 1, 63% tier 2 and 6% tier 3, including 66% of RLC. In 30% of cases, a tumor mutational burden &gt;11 mutations/ megabase was reported. Conclusions: Here we report a high frequency of AVs in RLC, providing a rational basis for assessing the potential of personalized therapy in a population with a historically unmet need for effective treatment. Clinical trial information: ACTRN12616000908437. [Table: see text]
Phase 2 trial of Lu-177-DOTATATE in inoperable pheochromocytoma/paraganglioma.
Authors: Frank Lin, Jaydira Del Rivero, Jorge A. Carrasquillo, Abhishek Jha, Melissa K Gonzales, Liza Lindenberg, Baris Turkbey, Emily Lin, Esther Mena, Corina Millo, Clara Chen, Peter Herscovitch, Peter L. Choyke, Karel Pacak
Journal: Journal of Clinical Oncology (2019)

TPS4159 Background: Pheochromocytoma/paraganglioma (PHEO/PGL) is a rare malignancy that arises from chromaffin cells of typically the adrenal medulla but can also be of extra-adrenal origin. These tumors produce excessive catecholamines such as epinephrine and norepinephrine which causes labile hypertension, tachycardia, and flushing. Lu-177-DOTATATE (Lu-177-dodecanetetraacetic acid‐tyrosine-3-octreotate) is a radiolabeled somatostatin analog that is FDA approved for somatostatin receptor-positive neuroendocrine tumors. It is being being investigated in PHEO/PGL, which overexpress somatostatin receptors. Amino acid solutions containing lysine/arginine (L/A) are routinely co-administered with Lu-177-DOTATATE for renal radioprotection, although solutions containing other amino acids are also used. Methods: This is a prospective, single center, open label Phase 2 study evaluating the efficacy of Lu-177-DOTATATE in PHEO/PGL. Ninety patients will be enrolled, divided into two cohorts of 45 patients each ( SDHx mutation vs. apparent sporadic). Lu-177-DOTATATE is given at a fixed dose of 200 mCi with a co-administration of L/A amino acid solution q8 weeks for 4 cycles. The primary endpoint is the progression-free-survival (PFS) rate at 6 months. Secondary endpoints include response rate, overall survival, time to progression, quality of life measures, and examination of potential biomarkers such as biochemical profiles, Ga-68-DOTATATE PET, and F-18-FDG PET scans. Eligibility criteria include inoperable disease (including non-metastatic), histological confirmation of PHEO/PGL, evidence of disease progression by RECIST 1.1, ECOG performance status of 1 or better, and a positive Ga-68-DOTATATE PET scan. Exclusion criteria include prior treatment with systemic radionuclide therapy such as I-131-MIBG, brain parenchymal metastases, and standard organ dysfunction limitations. Interim analysis using a Simon two-stage optimal design will be performed separately for each cohort after enrollment of 18 patients. First patient accrual to this ongoing study was in the Fall of 2017, and as of February 2019, fourteen patients have been accrued. Preliminary results will be reported at the completion of stage 1 for each cohort. Clinical trial information: NCT03206060.
Interim results of a phase I/IIa trial of a therapeutic CMV vaccine against recurrent glioblastoma (GBM).
Authors: Andrew B. Lassman, David A. Reardon, Eudocia Quant Lee, Fabio Massaiti Iwamoto, Francisco Diaz-Mitoma, David E Anderson, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2019)

2048 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4 + and CD8 + T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. Subjects are vaccinated monthly until tumor progression, with immunomonitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. In phase I, eligible patients were age 18-70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 subjects in each cohort and DSMB safety review of the first 3 subjects in each cohort prior to enrolling additional subjects. Results: The DSMB identified no DLTs or safety concerns with any of the doses. Grade 2, 3 or 4 AEs occurred in 66%, 22% and 11% of participants, respectively, but were not related to vaccine administration. Twelve men and 6 women were enrolled with a median age 54 (range 39-66). Prior therapies included radiotherapy, temozolomide, and nivolumab. Immunological analyses demonstrate robust boosting of CMV-specific antibody titers and T cell responses against both gB and pp65 antigens in some but not all subjects, across all dose cohorts. Boosting of IFN-gsecreting T cells (measured by ELISPOT) exceeded the assay threshold for several subjects. Stable disease by MRI of 3 months or greater has been observed in 2 subjects in the high dose cohort and 1 subject in the low dose cohort and may correlate with vaccine response. Conclusions: The phase IIa extension phase of the trial planned to begin in Q2 2019 is designed to explore efficacy in an additional 10 subjects that will receive the optimal vaccine dose and includes the additional requirements of unifocal, measurable enhancing tumor 1-3 cm across at first recurrence and no prior immunotherapy. Clinical trial information: NCT03382977.
Molecular Classification of Epithelial Ovarian Cancer Based on Methylation Profiling: Evidence for Survival Heterogeneity
Authors: Clara Bodelon, J. Keith Killian, Joshua N. Sampson, William F. Anderson, Rayna Matsuno, Louise A. Brinton, Jolanta Lissowska, Michael S. Anglesio, David D.L. Bowtell, Jennifer A. Doherty, Susan J. Ramus, Aline Talhouk, Mark E. Sherman, Nicolas Wentzensen
Journal: Clinical Cancer Research (2019)

Ovarian cancer is a heterogeneous disease that can be divided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes.A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC).Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P = 9.1 × 10-7) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P = 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P = 0.007).DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer.See related commentary by Ishak et al., p. 5729.
Metabolites as mediator for alleviating adverse effects in chemotherapy: A new finding from a recent study of Japanese traditional Kampo medicine, rikkunshito (RKT).
Authors: Hiroyuki Suzuki, Takuya Inoue, Hironori Takagi, Masayuki Watanabe, Yuki Ozaki, Satoshi Muto, Naoyuki Okabe, Takeo Hasegawa, Yutaka Shio, Hiroyuki Minemura, Kenya Kanazawa, Katsuya Ohbuchi, Takahisa Fukushima
Journal: Journal of Clinical Oncology (2019)

e18292 Background: In Japan, RKT is used for chemotherapy-induced anorexia. There is considerable variation in the therapeutic response to RKT. We assessed the efficacy of RKT on anorexia induced by cisplatin (CDDP) therapy in lung cancer patients (pts) from the clinical and the plasma metabolomics perspectives. Methods: The study was a double-blind, randomized trial evaluating pts with age ≥20 y with lung cancer assigned to receive regimen including CDDP, ECOG PS 0 to 1. Pts were administered RKT or placebo from the beginning of 1 st course of chemotherapy (Day1) until just before starting the 2 nd course (21 or 28 consecutive days). The clinical endpoints were the change in mean dietary intake in hospital (MDIH), QOL and nutritional indices. Plasma samples were collected at Day1, Day7 and Day22 (22 nd or 29 th day) for metabolome analyses. Results: 60 pts were enrolled between Nov 2014 and Aug 2017. 29 were allocated to RKT and 31 to placebo. The ANCOVA estimate of treatment effect in MDIH (baseline adjusted RKT-Placebo difference) was not significant (-6.7; 95% C.I. -61.1 to 47.8). Regarding QOL, there was no significant results in changes of QLQ-C30 Global Health Status. Among the related subscales, Pain in Day22 in PPS analysis was the only significant item (-17.0; -29.7 to -4.2). Regarding QLQ-LC13 , Alopecia in Day22 was the only significant item (-21.3; -36.9 to -5.8). The changes in nutritional indices did not show any significant difference, either. In metabolome analysis, CDDP drastically influenced metabolites, such as essential amino acids. RKT did not significantly change them compared to the placebo. In contrast, the changes of acetylglycine and arabinose in plasma strongly correlated with those in dietary intake and pain only in the RKT. Conclusions: In this exploratory study, no significant difference was observed in the MDIH. Although, pain and alopecia observed in QOL were significantly improved in the RKT. Some plasma metabolites were found to correlate with improvement in dietary intake or QOL. This is the first suggestive evidence that the efficacy of RKT would be variable depend on the metabolic profile. Clinical trial information: JAPIC CTI-142747.