tbuckley/cabot-search huggingface dataset:
Genetic Polymorphisms Predisposing the Interleukin 6–Induced APOBEC3B-UNG Imbalance Increase HCC Risk via Promoting the Generation of APOBEC-Signature HBV Mutations
Authors: Wenbin Liu, Jianfeng Wu, Fan Yang, Longteng Ma, Chong Ni, Xiaomei Hou, Ling Wang, Aijing Xu, Jiahui Song, Yang Deng, Linfeng Xian, Zixiong Li, Shuo Wang, Xi Chen, Jianhua Yin, Xue Han, Chengzhong Li, Jun Zhao, Guangwen Cao
Journal: Clinical Cancer Research (2019)

APOBEC3-UNG imbalance contributes to hepatitis B virus (HBV) inhibition and somatic mutations. We aimed to explore the associations between hepatocellular carcinoma (HCC) risk and genetic polymorphisms predisposing the imbalance.Experimental Design: Genetic polymorphisms at APOBEC3 promoter and UNG enhancer regions were genotyped in 5,621 participants using quantitative PCR. HBV mutations (nt.1600-nt.1945, nt.2848-nt.155) were determined by Sanger sequencing. Dual-luciferase reporter assay was applied to detect the transcriptional activity. Effects of APOBEC3B/UNG SNPs and expression levels on HCC prognosis were evaluated with a cohort of 400 patients with HCC and public databases, respectively.APOBEC3B rs2267401-G allele and UNG rs3890995-C allele significantly increased HCC risk. rs2267401-G allele was significantly associated with the generation of APOBEC-signature HBV mutation whose frequency consecutively increased from asymptomatic HBV carriers to patients with HCC. Multiplicative interaction of rs2267401-G allele with rs3890995-C allele increased HCC risk, with an adjusted OR (95% confidence interval) of 1.90 (1.34-2.81). rs2267401 T-to-G and rs3890995 T-to-C conferred increased activities of APOBEC3B promoter and UNG enhancer, respectively. IL6 significantly increased APOBEC3B promoter activity and inhibited UNG enhancer activity, and these effects were more evident in those carrying rs2267401-G and rs3890995-C, respectively. APOBEC3B rs2267401-GG genotype, higher APOBEC3B expression, and higher APOBEC3B/UNG expression ratio in HCCs indicated poor prognosis. APOBEC-signature somatic mutation predicts poor prognosis in HBV-free HCCs rather than in HBV-positive ones.Polymorphic genotypes predisposing the APOBEC3B-UNG imbalance in IL6-presenting microenvironment promote HCC development, possibly via promoting the generation of high-risk HBV mutations. This can be transformed into specific prophylaxis of HBV-caused HCC.
Alliance A091404: A phase II study of enzalutamide (NSC# 766085) for patients with androgen receptor-positive salivary cancers.
Authors: Alan Loh Ho, Nathan R. Foster, Alexander J. Zoroufy, Francis P. Worden, Katharine Andress Rowe Price, Douglas Adkins, Daniel W. Bowles, Hyunseok Kang, Barbara Burtness, Eric Jeffrey Sherman, Roscoe F. Morton, Nora Katabi, Pamela N. Munster, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2019)

6020 Background: A subset of salivary gland cancer (SGCs) express the androgen receptor (AR). This phase II trial evaluated the anti-androgen enzalumatide (Astellas) for patients with AR+ SGCs. Methods: Locally advanced/unresectable or metastatic AR+ SGCs were enrolled (AR status was centrally confirmed). Prior therapy with AR-targeted drugs was allowed. Enzalutamide 160 mg orally once daily was given (1 cycle= 28 days). The primary endpoint was confirmed response (RR) according to RECIST v1.1 within the first 8 cycles. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. A Simon-Optimal two-stage design was used to detect a 20% RR (vs. 5%) (alpha = 5%; beta = 90%). &gt; 1 response(s) in the first 21 would trigger accrual to 41; &gt; 4 responses would be considered promising. Results: 46 eligible patients (pts) were enrolled (40 M, 6 F; median age 65) in 22 months. In the first 21 pts, we initially had 2 confirmed PRs allowing for full study accrual, though one was later changed to stable disease. Among the 46 pts, 7 had PR as best response, though only 2 were confirmed within the first 8 cycles (4% (95% CI: 0.5-15%). Two other PRs did not count towards the primary endpoint due to 1) development beyond 8 cycles (cycles 12-18) and 2) a confirmatory scan completed &lt;4 weeks apart. The other 3 pts with unconfirmed PR developed progression of disease (PD) after the first PR scan. 24 pts had stable disease; 15 pts PD as best response. Among 11 pts previously treated with AR-targeted therapy, best responses were 1 confirmed PR, 7 SD, 3 PD. With a median follow-up of 11.7 months (mo), OS at 12 mo was 66% (95% CI: 52-83%), PFS at 12 mo was 24% (95% CI: 14-42%), and median PFS was 5.5 mo (95% CI: 3.7-7.3). Conclusions: This is the first prospective trial evaluating an antiandrogen alone for AR+ SGCs. The failure to meet the protocol-defined measure of success was due in part to the lack of durability of initial responses. The clinical activity observed suggests the AR-dependence of AR+ SGCs, even among those previously treated with other hormonal therapies. Support: U10CA180821, U10CA180882; Astellas; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02749903.
Circular RNA circTRIM33–12 acts as the sponge of MicroRNA-191 to suppress hepatocellular carcinoma progression
Authors: Peng-Fei Zhang, Chuan-Yuan Wei, Xiao-Yong Huang, Rui Peng, Xuan Yang, Jia-Cheng Lu, Chi Zhang, Chao Gao, Jia-Bin Cai, Ping-Ting Gao, Dong-Mei Gao, Guo-Ming Shi, Ai-Wu Ke, Jia Fan
Journal: Molecular Cancer (2019)

Recently, the dysregulation of circular RNA (circRNA) have been shown to have important regulatory roles in cancer development and progression, including hepatocellular carcinoma (HCC). However, the roles of most circRNAs in HCC are still unknown.The expression of circular tripartite motif containing 33-12 (circTRIM33-12) in HCC tissues and cell lines was detected by qRT-PCR. The role of circTRIM33-12 in HCC progression was assessed by western blotting, CCK-8, flow cytometry, transwell and a subcutaneous tumor mouse assays both in vitro and in vivo. In vivo circRNA precipitation, RNA immunoprecipitation, luciferase reporter assays were performed to evaluate the interaction between circTRIM33-12 and miR-191.Here, we found that circTRIM33-12, is downregulated in HCC tissues and cell lines. The downregulation of circTRIM33-12 in HCC was significantly correlated with malignant characteristics and served as an independent risk factor for the overall survival (OS) and recurrence-free survival (RFS) of patients with HCC after surgery. The reduced expression of circTRIM33-12 in HCC cells increases tumor proliferation, migration, invasion and immune evasion. Mechanistically, we demonstrated that circTRIM33-12 upregulated TET1 expression by sponging miR-191, resulting in significantly reduced 5-hydroxymethylcytosine (5hmC) levels in HCC cells.These results reveal the important role of circTRIM33-12 in the proliferation, migration, invasion and immune evasion abilities of HCC cells and provide a new perspective on circRNAs in HCC progression.
Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).
Authors: Shota Fukuoka, Hiroki Hara, Naoki Takahashi, Takashi Kojima, Akihito Kawazoe, Masako Asayama, Takako Yoshii, Daisuke Kotani, Hitomi Tamura, Yuichi Mikamoto, Ayako Sugama, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Yosuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara
Journal: Journal of Clinical Oncology (2019)

2522 Background: Immune suppressive cells such as regulatory T cells (Tregs) or tumor-associated macrophages (TAMs) may contribute to resistance to anti-PD-1/PD-L1 inhibitors (A-PD1). Regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, reduced TAMs in tumor models. The combination of regorafenib plus A-PD1 exhibited superior tumor growth suppression compared to either treatment alone in murine models. Methods: In this study, we enrolled patients (pts) with previously treated, advanced GC or CRC. The pts received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase to further establish the safety and determine the preliminary efficacy. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose. Results: Fifty pts were enrolled (25 GC; 25 CRC) until October 2018. The median prior treatment line was 3 (range 2-8). During dose-escalation, 3 DLTs were observed with regorafenib 160 mg, including grade (G) 3 maculopapular rash, mucositis and proteinuria, while there was no DLT with 80 or 120 mg. In the dose expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg owing to frequent G3 skin toxicities. Grade ≥ 3 treatment related adverse events occurred in 17 pts; the common events ( &gt; 5%) being rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%). Objective tumor response was observed in 19 pts (38%) including 11 MSS GC, 7 MSS CRC and 1 MSI-H CRC for response rates of 44% in GC and 29% in MSS CRC. Three of the 7 A-PD1 pretreated GC pts achieved a partial response. The pre- and post-treatment tumor samples showed a reduction of FoxP3 hi CD45RA - Tregs fraction at the tumor response. Conclusions: The combination of regorafenib 80mg plus nivolumab had a manageable safety profiles and encouraging anti-tumor activity in MSS GC and CRC pts, which warrants further investigations in a larger cohort. Updated biomarker analysis will be presented. Clinical trial information: NCT03406871.
Genomic characterization of brain metastases (BM) in high-grade serous ovarian cancer (HGSOC).
Authors: Renata Duchnowska, Anna Maria Supernat, Rafał Pęksa, Marta Łukasiewicz, Tomasz Stokowy, Monika Umińska, Ewa Iżycka-Świeszewska, Anna Kowalczyk, Waldemar Och, Monika Rucinska, Wojciech P Olszewski, Tomasz Mandat, Bozena Jarosz, Michał Bieńkowski, Wojciech Biernat, Jacek Jassem
Journal: Journal of Clinical Oncology (2019)

e13580 Background: BM are a rare occurrence in ovarian cancer (OC) and their molecular characteristics is virtually unknown. DNA damage repair (DDR) deficiency is prevalent in OC, and co-mutated TP53 and any DDR denotes high tumor mutation burden (TMB). We genetically characterized a unique series of high-grade serous ovarian cancer (HGSOC) patients who developed BM to identify alterations of potential clinical relevance. Methods: Whole-exome sequencing (2x150bp, SureSelectXT Library Prep Kit, Illumina’s NovaSeq platform) was performed in matched BM, primary tumors (PT) and normal tissue. DNA was extracted from FFPE samples using QIAamp DNA FFPE Tissue Kit (Qiagen, Germany). All mutations were checked with Catalogue of Somatic Mutations in Cancer (COSMIC) and Integrative Genomics Viewer (IGV). Results: Study group included 10 HGSOC patients (International Federation of Gynecology and Obstetrics classification (FIGO) II-IV, mean age at diagnosis 48 years, range 35-59). Median time from primary HGSOC diagnosis to BM was 38 months (range, 18 to 149). TP53 somatic mutations were found in both primary tumor (PT) and BM in 8 patients. The other 2 cases harbored TP53 mutations not reported in COSMIC catalogue: p.S60L and intronic TP53 mutation preceding p.I322 (IGV). In 9 cases TP53 mutations coexisted with germline or somatic DNA damage repair deficiency. Four cases contained BRCA1 mutations (all germline), and none harbored germline BRCA2 mutation. Other mutated genes included MLH1 (2 somatic, 2 germline), ATR (4 germline, 1 somatic), AMT (1 somatic), RAD50 (1 somatic), ERCC4 (1 somatic), FANCD2 (1 somatic) and RPA1 (1 germline). Three mutation signatures defined in the COSMIC database were indentified in BM: 6, 20 and 30. In 6 cases these mutations were shared in PT, and in another 4 their presence in PT could not be determined due to technical reasons. Median survival from BM was 31 months (range, 5 to 184). Conclusions: Genomic analysis of BM provides an opportunity to identify potentially clinically informative alterations. Mutational profiles in PT are generally reflected in BM. Detected genetic alterations suggest their potential sensitivity to PARP inhibitors and immunotherapy.
A GINECO randomized phase II assessing addition of an aromatase inhibitor to oral vinorelbine in pretreated metastatic breast cancer patients.
Authors: Pierre Heudel, Antoine Arnaud, Jean-Sebastien Frenel, Sylvie Chabaud, Benoit You, Laetitia Stefani, Claire Garnier-Tixidre, Helene Simon, Dominique Beal-Ardisson, Jean-Philippe Jacquin, Francesco Del Piano, Alain Lortholary, Claudiu Cornea, Tifenn Lharidon, Remy Largillier, Fabien Brocard, Eric Legouffe, Mustapha Atlassi, Anne-Claire Hardy-Bessard, Thomas Denis Bachelot
Journal: Journal of Clinical Oncology (2019)

1043 Background: For ER+/HER2- metastatic breast cancer (mBC), efficacy of endocrine therapy + chemotherapy combination remain an open question. We hypothesized that continuing ER targeted therapy after progression in combination with chemotherapy may improve disease control. The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy,oral vinorelbine, 50mg/3 time a week (OV) for AI pre-treated, ER+/HER2- mBC patients. Methods: Eligible patients had to have progressed on endocrine therapy and one or two lines of chemotherapy. They were randomized between vinorelbine (OV) and vinorelbine + AI (OV+AI). Primary end point was progression-free survival (PFS). To show an increase of median PFS (from 3.5 to 5.5 month, HR 0.636), with alpha = 5% and power = 80%, 130 evaluable patients were needed. Results: 121 patients were Included (OV = 61; OV+AI = 60). Median age was 68 (range: 49-87), Median time from metastatic diagnosis was 3.2 years (range 0 - 16.9). 109 patients (90%) had visceral metastases. They all had previously received an AI and had been treated with one line (N = 66, 54.5%), or 2 lines (N = 55, 45.5%) of chemotherapy. Median PFS was increased from 2.3 months with OV to 3.7 months with OV+AI, but this difference was not significant (HR 0.73 [95 % CI 0.50-1.06], log-rank test: P = 0.09) 81 patients (67%) had at least one adverse event (AE) of grade ≥ 3 (40 (66%) for OV vs 41 (68%) for OV+AI). The most common grade ≥ 3 AE were: GT gammas (23%), neutropenia (18%), arterial hypertension and lymphopenia (17%). The occurrence of 3 toxic deaths (OV = 1; OV+AI = 2) secondary to febrile aplasia motivated the early cessation of this clinical trial. 9 patients (5 OV (10%) and 4 OV+AI (8%) presented an objective complete or partial response. Conclusions: The addition of AI to OV over OV alone in AI resistant mBC was associated with a non-significant improvement of PFS, but both PFS are lower than expected. Metronomic OV schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open. Clinical trial information: EudraCT Number: 2015-000401-39.
Abstract 15384: Association of Breast Arterial Calcification With Coronary Artery Calcification in Younger versus Older Women
Authors: Quan M Bui, Avinash Toomu, Paula Anzenberg, Emily Liu, Jamie Marsal, Taelor Getz, Mohammad Eghtedari, Lori B Daniels
Journal: Circulation (2018)

Introduction: Breast arterial calcification (BAC), seen on mammograms, has emerged as a potential risk stratification tool and surrogate marker of cardiovascular disease (CVD) that comes with no ad...
Triple blinded prospective study assessing the impact of genomics: EndoPredict and artificial intelligence Watson for Oncology (WFO) on MDT’s decision of adjuvant systemic therapy for hormone receptor positive early breast carcinoma.
Authors: S.P. Somashekhar, Ramya Yethadka, Rohit Kumar C, Ashwin K Rajgopal, Amit Rauthan, Poonam Patil
Journal: Journal of Clinical Oncology (2019)

e18013 Background: : Decision on adjuvant systemic therapy in hormone positive early breast carcinoma is the only grey area in breast carcinoma management. This study was done to investigate the concordance between the results of genomic test, artificial intelligence and tumor board decision and implications of the same in clinical practice. Methods: This was a triple blinded, prospective study. Decision regarding the adjuvant systemic therapy was done by the multidisciplinary tumor board (MDT)after reviewing the pathology reports &amp; the results correlated with Endopredict test reports &amp; artificial intelligence(Watson for Oncology). Results: Total of 42 patients included. Mean age was 58.3 years, 71.4% were post-menopausal. Breast conservation was done in 47.6%. 64.2% were T1-2N0 stage. Infiltrating ducal carcinoma was major type (83.3%). Decision by MDT to give adjuvant chemotherapy was for 25 patients (59.5%) &amp; hormonal therapy for rest. Recommendation by Watson for oncology was to give adjuvant chemotherapy in 50%. Endopredict score (EPclin) resulted in a low-risk group of 22 patients (52.3%), while 15(47.6%) had a high risk EPclin score. Discordance between the endopredict test, Watson &amp; tumor board was for 11 patients (26.1%): 3 patients had high risk score, but the tumor board decision was to give hormonal therapy due to the age factor. 8 patients had low risk score, but tumor board decision was to give adjuvant chemotherapy. Extremes of age, premenopausal status, intermediate grade &amp; high Ki 67% values were the factors associated with discordance. The treatment decision changed for 4 patients (4/11, 36%) after reviewing the endopredict test and Watson recommendation. Conclusions: Tumor board decision can be more scientific &amp; evidence based with the help of genomics &amp; a learnt colleague in the form of Watson for Oncology. Even though the clinical experience is the important determinant of adjuvant therapy, genomic test with artificial intelligence, which includes the scientific evidence, will guide in decision making. Long term follow up is needed for the validation in our clinical setting.
The mutation profile of EGFR in resectable Chinese lung cancer patients.
Authors: Wenjun Mao, Ruo Chen, Jingyu Chen, Feng Liu, Yijun He, Shugao Ye, Rongguo Lu, Martin Qi, Mingfeng Zheng
Journal: Journal of Clinical Oncology (2019)

e20519 Background: The frequency of EGFR mutation in Asian advanced lung cancer patients is about 40% and the application of EGFR tyrosine kinase inhibitors (TKIs) has become a standard treatment therapy. Several studies showed that usage of EGFR TKIs in adjuvant or neo-adjuvant therapy was promising, while the mutation profile of EGFR mutations in resectable Chinese lung cancer patients was still scanty. Our study investigated EGFR mutation profile and its correlation with clinicopathological factors. Methods: 343 resectable patients with lung cancer were selected for eligibility criteria, and tumor tissues were collected for gene detection. EGFR genetic testing was performed by amplification refractory mutation system PCR (ARMS-PCR) with specific sensitive mutation sites. The clinicopathological factors of study population were recorded based on pre-design protocol. Chi-square or fish exact test were used to statistic analysis Results: A total of 343 patients were enrolled in study. 42.6% (146/343) patients were male, 20.4% (68/333) patients were smokers, the adenocarcinoma accounted for 93.8 % (319/340), and stage 0, I, II, III was 7.3% (25/343), 68.8% (236/343), 8.5% (29/343), 15.5% (53/343), respectively. The frequency of EGFR mutation was 54.2% (186/343) in whole population, and the proportion of EGFR L858R, 19Del, 719X, 768I, 861Q mutation was 31.2% (107/343), 21.3% (73/343), 1.2% (4/343), 1.0% (3/343), 1.0% (3/343), respectively. 1.2% (4/343) patients presented EGFR co-mutation (EGFR G719X/S768I; L858R/S768I; G719X/S768I; L858R/L861Q) .The mutation frequency of EGFR mutation was associated with sex, smoking, differentiation, pathology (P = 0.0076, &lt; 0.0001, &lt; 0.0001, &lt; 0.0001, respectively). In subgroup analysis, the incidence of two main mutation types, EGFR L858R and 19del, were associated with disease stage (P = 0.044) and age (P = 0.035). Conclusions: EGFR mutation in resectable lung cancer was a common phenomenon as advanced stage and our study might provide useful informations for using EGFR-TKIs in further adjuvant or neo-adjuvant therapy.
Decisions on adjuvant chemotherapy for patients with breast cancer based on clinical and evolving Oncotype DX criteria.
Authors: Jamal Zekri, Meteb Owaish Al-Foheidi, Maaz Kamal Alata, Ayman Ahamd Rasmy, Haleem J. Rasool, Hossam A. Abdelrahman, Adnan Hussain, Yasser Sorour, Miral Mashhour
Journal: Journal of Clinical Oncology (2019)

e12009 Background: Oncotype-DX assay recurrence score (ODX-RS) cut-off values have recently changed in response to the results of the TAILOR-X trial. We aim to explore decisions for ACT based on physicians’ clinical assessment and on evolving ODX-RS. Methods: Patients who underwent ODX testing after curative surgical resection of estrogen receptor positive (ER+), Her2 non-over-expressed (Her2-) and lymph node negative (LN-) BC were included. Patients with micro-metastases to LNs were excluded. Data was collected retrospectively from the electronic records. Management of these patients was guided by the results of the old ODX-RS-1 (&lt;18, 18-30 &amp; ≥31) risk grouping. For the purpose of this study, treatment decisions were also assumed according to TAILOR-X results (ODX-RS-2). Decisions of 3 medical oncologists on ACT were solicited by blinding them to the RS values to investigate inter-physicians discrepancy and concordance with ODXA RS-1&amp;2. Results: Sixty six consecutive patients fulfilled the inclusion criteria. Median age was 50.5 (range: 21-73) years. There was one male patient and 37 out of 65 females (56.9%) were pre-menopausal. Median tumor size was 21.5 (range: 10-55) mm and the grade were I, II and III in 6 (9.1%), 46 (69.7%) and 41 (21.2%) patients respectively. The 3 oncologists’ had discrepancies about ACT recommendations in 29 (44%) patients. Based on majority opinion (≥2 oncologists), ACT would have been recommended to 22/41 (53.7%) and 24/46 (52.2%) patients with low risk tumors according to ODXA RS-1 and ODXA RS-2 respectively. Similar number of patients (n=12) would have received ACT regardless of ODXA RS cut-off value (table). Conclusions: Decisions on ACT for patients with ER+/Her2-/LN- early BC should be guided by ODX-RS to prevent overtreatment and discrepancies in management. Broadly, ODXA RS-1 and ODXA RS-2 seem to guide ACT decisions in similar proportions of patients. Nevertheless minor differences exist and need to be studied in larger cohorts. [Table: see text]
Bedaquiline Microheteroresistance after Cessation of Tuberculosis Treatment
Authors: Margaretha de Vos, Serej D Ley, Kristin B Wiggins, Brigitta Derendinger, Anzaan Dippenaar, Melanie Grobbelaar, Anja Reuter, Tania Dolby, Scott Burns, Marco Schito, David M Engelthaler, John Metcalfe, Grant Theron, Annelies van Rie, James Posey, Rob Warren, Helen Cox
Journal: New England Journal of Medicine (2019)

Bedaquiline Microheteroresistance A patient in South Africa was treated with a multidrug regimen for multidrug-resistant tuberculosis; the regimen included bedaquiline, to which the isolate was sus...