tbuckley/cabot-search huggingface dataset:
Abstract B075: The role of TET1 and hydroxymethylation in high-risk prostate cancer
Authors: Elien Smeets, Lien Spans, Stefan Prekovic, Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Christine Helsen, Steven Joniau, Frank Claessens
Journal: Cancer Research (2018)

Abstract The Ten-eleven translocation (TET) proteins are dioxygenases that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) as part of the DNA demethylation pathway. Gene silencing through cytosine methylation contributes to cancer formation, but how hydroxymethylation affects gene expression is largely unknown. In this work, TET1 and genomic hydroxymethylation were investigated in a high-risk prostate cancer cohort for which exome sequencing data are available (1). Immunohistochemical analysis of tumor versus nontumor prostate biopsies from high-risk prostate cancer showed a strong reduction of genome-wide 5hmC and milder but still significant reduction of 5mC levels in prostate cancer tissue compared to control tissue. Copy number analysis of high-risk prostate cancer showed a loss of the TET1 genomic region in 6 out of 39 samples of our cohort. As expected, the mRNA levels of TET1 were decreased in these tumor samples. Recently, an alternative promoter of TET1 was discovered. This promoter generates a novel isoform lacking the CXXC-domain, which is called TET1ALT (2). We therefore performed functional analyses of the two TET1 promoters in prostate cancer cells. Interestingly, the promoter controlling expression of the endogenous full-length TET1 is less active in prostate cancer cell line PC-3, while the alternative promoter generating TET1ALT is more active in these cells. This is shown by luciferase constructs driven by the two promoter regions. In conclusion, our findings indicate that there is a drop in (hydroxy)methylation levels in high-risk prostate cancer that correlates with decreased TET1 expression levels and in some cases by a copy number loss of TET1. We are currently working on a more detailed analysis of TET1 promoter usage and control. This will unravel the regulation of hydroxymethylation in prostate cancer, which is crucial for the understanding of prostate cancer development and progression. References: 1. Spans L, Van den Broeck T, Smeets E, et al. Genomic and epigenomic analysis of high-risk prostate cancer reveals changes in hydroxymethylation and TET1. Oncotarget 2016;7(17):24326-38. 2. Good CR, Madzo J, Patel B, et al. A novel isoform of TET1 that lacks a CXXC domain is overexpressed in cancer. Nucleic Acids Res 2017;45(14):8269-81. Citation Format: Elien Smeets, Lien Spans, Stefan Prekovic, Thomas Van den Broeck, Lisa Moris, Thomas Gevaert, Christine Helsen, Steven Joniau, Frank Claessens. The role of TET1 and hydroxymethylation in high-risk prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B075.
EFIRM liquid biopsy (eLB) to detect actionable mutations in NSCLC.
Authors: David T. Wong, Fang Wei, Wei Liao, Ziding Feng, David Chia, Yong Kim, Youlin Qiao, Qinghua Zhou
Journal: Journal of Clinical Oncology (2016)

8520 Background: Liquid biopsy to detect actionable mutations in NSCLC is in clinical practice primarily based on digital droplet PCR (ddPCR) and/or next generation sequencing (NGS) technologies with performance at ~70-80% concordance with tissue-based genotyping. Technologies that will permit 100% concordance detection (sensitivity) will provide the ultimate complementation to the tumor-specific fingerprint (specificity) for unambiguous detection of the tumor in a non-invasive setting. The electric field induced released and measurement (EFIRM) fulfilled this translational and clinical goal. Methods: A double blinded study enrolled 37 NSCLC patients at three lung cancer centers in China (SLCI/Sichuan, JCH/Nanjing and HCH/Henan). For each patient, both pre- and post- biopsy/surgery, saliva and plasma were collected. Codes were removed from samples and blinded. Tissues were genotyped for EGFR L858R and exon 19del genotyping by Cobas (Roche Molecular Systems) while saliva and plasma were assayed for same EGFR TKI-sensitive mutation by eLB. Results were sent to MD Anderson Cancer Center for concordance analysis with the tissue-based genotyping data from Cobas. Results: In this blinded study, using tumor tissue (surgery/biopsy) genotyping as gold standard (Cobas), eLB correctly predicted both EGFR exon 19del and L858R status for all 37 pre- and post- surgery/biopsy saliva samples (AUC = 1.0). Plasma from the same 37 patients’ pre- and post-surgery/biopsy were measured by eLB with AUC = 1.0 for exon 19del, and AUC = 0.96 for L858R. Signals in saliva are cleaner than that in plasma for L858R. For Exon 19del, both plasma and saliva have clean separation between mutants and wild types. Correlations between pre- and post- saliva assays are excellent (0.82 and 0.95), a bit lower but still high for pre- and post- plasma (0.70 and 0.93). Conclusions: This study confirmed the concordance performance of eLB for detecting EGFR mutations from pre- and post-biopsy serum and saliva samples for actionable EGFR mutations in NSCLC patients.
Bromodomain-containing protein 7 as tumour suppressor and prognostic biomarker in breast cancer.
Authors: Cristiana Lo Nigro, Ornella Garrone, Daniela Vivenza, Rodolfo Brizio, Fiamma Mantovani, Giannino Del Sal, Marco Carlo Merlano, Tim Crook
Journal: Journal of Clinical Oncology (2018)

e24047 Background: Multiple genetic and epigenetic factors drive initiation and progression in Breast cancer (BC). Bromodomain-containing protein 7 (BRD7) is a bromodomain-containing protein, mainly localized in the nucleus, which acts as transcriptional p53 co-activator. BRD7 is down-regulated in a number of cancer types and this correlates with clinical outcomes. However, its potential involvement and prognostic value in BC are poorly understood. We investigated expression, CpG island methylation and sub-cellular localization of BRD7 in BC cell lines and clinical cases. We then assessed its prognostic significance in correlation with clinicopathologic features and clinical outcome. Methods: BRD7 expression was analysed by qRT-PCR and IHC in 13 BC cell lines. Expression was assessed by IHC in 50 primary BCs and 14 paired metastatic lesions. CpG island methylation was quantified by pyrosequencing. BCs were divided for nuclear and non-nuclear BRD7 localization and then stratified for high and low BRD7 expression. Effect of BRD7 and OS/PFS was evaluated by univariate and multivariate Cox regression analyses. Results: BRD7 was expressed at levels similar to normal breast epithelium and the CpG island unmethylated in all cell lines. Methylation analysis was successful in 42 FFPE BC samples, with 26,2% of them methylated (11/42). IHC on primary tissues revealed that BDR7 is mainly nuclear (34/50: 68%). Patients with BRD7 nuclear localization (N = 34) showed smaller tumours (p = 0.012), a longer OS (p = 0.002) and a lower relapse rate (p = 0.03). Moreover, nuclear BRD7 expression is associated with wild-type TP53 (p = 0.04) and unmethylated BRD7 (p = 0.04), compared to the non-nuclear cases (N = 16). No difference was seen in nodal status, grading, clinical stage, histology, ER, PR, HER2 and Ki-67. Patients (N = 12) showing both nuclear localization and high BRD7 expression presented the smallest tumours (10/12 = 83%) and both a longer OS (p = 0,005) and PFS (p = 0,001). Among the 4/14 patients with nuclear localization in their primary tumours, 3 (75%) presented a diffuse or negative BRD7 in the paired metastasis. Conclusions: BRD7 is a strong candidate for BC tumor suppressor and prognostic biomarker.
Safety of osimertinib plus chemotherapy in EGFR-mutant NSCLC.
Authors: Zofia Piotrowska, Stephen V. Liu, Alona Muzikansky, Nicolas Marcoux, Mandeep Banwait, Sara Stevens, Kelly Goodwin, Tracey E Lafferty, Jennifer Ackil, Elizabeth A Krueger, Rebecca Suk Heist, Jessica Jiyeong Lin, Justin F. Gainor, Aaron N. Hata, Alice Tsang Shaw, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2018)

e21231 Background: Osimertinib (osi) is a potent, CNS-penetrant 3rd-generation EGFR TKI. Though older TKIs did not add benefit to chemo (IMPRESS, Soria et al 2015), combining osi with chemo to prolong CNS control is of clinical interest, particularly among pts with brain metastases (CNS+). However, the safety of osi plus chemo is not well established. Methods: This is a retrospective analysis of pts with advanced EGFR-mutant NSCLC treated off-label with concurrent chemo and osi. We collected pt demographics, toxicities and treatment duration. Results: 18 pts received 25 chemo regimens with osi, including: carboplatin (carbo)/pemetrexed (pem) (n = 8), carbo/paclitaxel (1), carbo/nab-paclitaxel (1), pem (6), docetaxel (3), docetaxel/ramucirumab (1), gemcitabine (gem) (3), nab-paclitaxel (1) and vinorelbine (1). Starting osi dose was 80mg in 17 pts; 160mg in 1 pt. 16/18 pts were previously T790M+, and all had progressed on 3rd-generation EGFR TKI monotherapy before the addition of chemo. Median number of prior therapies was 3 (range, 2-6). 14/18 pts had a history of CNS+. We saw 1 grade 4 neutropenia (pem) and 5 grade 3 neutropenias (carbo/pem-1; pem-2; gem-1; carbo/nab-paclitaxel-1; Table). 3 pts received GCSF support. Other grade 3 toxicities were rare: 1 AST/ALT elevation (carbo/pem), 1 thrombocytopenia (carbo/pem) and 1 anemia (carbo/pem), and all were reversible. Side effects led to treatment delay (n = 5), osi dose-reduction (2) and discontinuation of regimen (2). We observed no pneumonitis. In this small cohort, the median duration of treatment (mDOT) on platinum doublet/osi was 6.9 mo (95% CI 1.4-NR); mDOT on pem/osi was 4.3 mo (95% CI 1.3-NR). Clinically significant CNS progression (requiring radiation or hospice) was observed on 5/25 regimens; all in pts with CNS+. Conclusions: Osimertinib does not appear to add significant toxicity to various chemo regimens and mDOT on platinum doublet/osi compares favorably to mPFS of platinum/pem in AURA3. The majority of pts did not progress in the CNS. A prospective study of carbo/pem/osi in pts with systemic progression on osi is planned to quantify CNS protection. Adverse Event (n = 25) Any Grade Grade ≥ 3 AST/ALT Elevation 9 (36%) 1 (1%) Anemia 20 (80%) 1 (1%) Neutropenia 11 (44%) 6 (24%) Thrombocytopenia 17 (68%) 1 (1%)
Influence of job assignment on melanoma (MEL) incidence in commercial aircrew.
Authors: Lee D. Cranmer
Journal: Journal of Clinical Oncology (2017)

e21058 Background: Commercial cabin and cockpit aircrews are at increased cutaneous MEL risk. Occupational and social factors have been invoked to explain this. However, the two groups work in on-board environments with different types/levels of potential exposures. Meta-analysis is conducted to address the hypothesis that differences exist in aircrew MEL risk based on location of in-aircraft job assignment, reflecting differential etiologic occupational exposures. Methods: Medline was searched with the keywords “Cancer,” “Aviation,” and “Melanoma.” Included studies: (1) primarily focused on cutaneous MEL; (2) were in commercial aircrew; (3) measured risk vs a general population; (4) measured risk by Standardized Incidence Ratio (SIR) with 95% confidence intervals (CI); (5) defined the gender distribution; and (7) defined cabin vs cockpit job assignment. Summary SIRs and CIs were calculated using maximum-likelihood, random effects meta-analysis. Values obtained were compared to one another using a z-test, with p &lt; 0.05 pre-specified for null hypothesis rejection. Results: 6 primary studies were identified in the initial search. These were screened for other pertinent references. The secondary search yielded an additional 9 primary studies. For cabin crew, 10 study groups from 6 studies were included. 411,561 person-years of follow-up among 28,093 subjects (86% female) were included (SIR 2.18, 95% CI 1.83-2.60). For cockpit crew, data from 9 studies representing 830,670 person-years of follow-up among 45,986 subjects (1% female) were included (SIR 2.44, 95% CI 1.94-3.08). z-test for the difference indicated that the two SIR values were not statistically different ( z= 0.77, p = 0.441). Conclusions: Though cockpit crew demonstrate an increased SIR vs cabin crew, this is not statistically significant. These results suggest that occupational exposures in different locations within commercial aircraft does not influence MEL risk. Other factors, such as cosmic radiation, non-aircraft occupational exposures and avocational exposures, should be the targets of further assessment.
NCI 10066: A phase 1 / 2 study of olaparib in combination with ramucirumab in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Michael Cecchini, Patricia LoRusso, Yu Shyr, S. Percy Ivy, Jeffrey Sklar, Kirsten Dooley, Jill Lacy
Journal: Journal of Clinical Oncology (2018)

TPS4137 Background: Gastric cancer remains a significant health problem in the US and globally with more than 951,600 annual cases worldwide. Moreover, the incidence of GEJ-centered adenocarcinoma is increasing dramatically in Western countries. First line chemotherapy has a < 12month median survival. In 2nd line, ramucirumab, a monoclonal antibody against VEGFR2 is approved as single agent or with paclitaxel. Hypoxia mimetic agents such as ramucirumab down-regulate homologous recombination and sensitize tumors to Poly ADP ribose polymerase inhibition (PARPi). Gastric cancer is also known to have a homologous recombination deficiency (HRD) subtype. We therefore proposed combining the PARPi olaparib with ramucirumab in metastatic gastric and GEJ adenocarcinoma. Methods: The study is sponsored by the Clinical Therapy Evaluation Program and is active throughout the Extended Therapeutics Clinical Trials Network. A phase 1 3+3 dose escalation is followed by an open-label single arm phase 2. The primary objective of phase 1 is to establish the safe dose of olaparib with ramucirumab. The phase 2 primary objective is to measure efficacy by the objective response rate (ORR). Eligible patient received ≥ 1 line of prior chemotherapy, no prior angiogenesis inhibitors or PARPi, have measurable disease, usual laboratory parameters, and ECOG PS 0-1. Phase 1 will enroll 9-18 patients depending on DLT. In phase 2, the BROCA-HR gene panel is an integrated biomarker. This panel includes 87 DNA repair genes, 17 of which would be expected to confer HRD when mutated. In gastric cancer these HRD genes are mutated in up to 35% of tumors reported in COSMIC and TCGA. However, given the uncertainty of the biomarker distribution in our study, 40 patients will be enrolled in phase 2 and the ORR will be stratified by biomarker distribution. The H0 is ORR of < 5% based on the historical control for ramucirumab. The H1 is 25% ORR for the BROCA-HR positive cohort and 20% for the negative cohort. A pre-treatment biopsy for BROCA-HR testing is required. Other studies include detecting mutational signatures, PAR substrate analysis, and PDX generation. Phase 1 is currently enrolling. Clinical trial information: NCT03008278.
Potential therapeutic genomic alterations in desmoplastic small round blue cell tumor.
Authors: Joanne Xiu, Ajaz Bulbul, Sadaf Rashad
Journal: Journal of Clinical Oncology (2017)

11066 Background: Desmoplastic Small Round Blue Cell Tumor (DSRCT) originates from a cell with multilineage potential. A molecular hallmark of DSCRT is the EWS-WT1 reciprocal translocation. Ewing’s and DSRCT are treated similarly due to similar oncogene activation pathways and DSRCT has been represented in very limited numbers in sarcoma studies. Methods: Thirty-five DSRCT tumors were tested with a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). Specific tests performed included sequencing (NextGen), protein expression (IHC) and gene amplification (CISH or FISH). Tumor mutational load (TML) was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Molecular alterations were compared to 88 Ewing sarcomas (ES). Chi-square tests were used for comparison and statistical significance was determined as p &lt; 0.05. Results: In the 35 DSRCT tumors, high expression of TOP2A were seen in 63%, TOPO1 in 63%, PTEN in 62%, androgen receptor (AR) in 59%, EGFR in 42% of tumors; low expression of TUBB3 was seen in 44%, MGMT in 45%, TS in 48%, RRM1 in 57% and ERCC1 in 76% of tumors. When compared to ES, no significant difference was seen in protein expressions with the exception of a significantly higher overexpressson of AR in DSRCT (59% vs. 3%, p = 1.7E-10) and TUBB3 (56% vs. 29%, p = 0.03). Tumor expression of PD-L1 (Ab: SP142) was not seen in the 4 DSRCT and 10 ES tested. NextGen revealed a TP53 mutation (7%) and a FOXO3 mutation (L382fs) in DSCRT, while 6 TP53 mutations (13%), 2 APC mutations (L1129S and I1307K), 1 BRCA1(c.301+1G &gt; A) and 1 CTNNB1 (T41A) mutation were identified in ES. Tumor mutational load evaluated in the 3 DSRCT and 11 ES tumors averaged 6 and 5 mutations per megabase, respectively. Conclusions: Molecular profiling on 35 DSRCT tumors and comparison with Ewing’s sarcoma revealed low immunogenicity ( &lt; 10 Mutations/MB) and low frequency of actionable mutations including PD-L1 in both tumor types. High AR expression could present as a potential therapeutic target for DSRCT while taxanes may be more effective in Ewing’s sarcoma compared to DSCRT based on TUBB3 expression. Genomic and Molecular assessment may help determine the ideal regimen that will help achieve maximal tumor debulking.
Integrated clinical experience with ONC201 in H3 K27M glioma.
Authors: Andrew S. Chi, Sharon L. Gardner, Isabel Arrillaga, Patrick Y. Wen, Tracy Batchelor, Matthew David Hall, Yazmin Odia, Wafik Tharwat Zaky, Soumen Khatua, Nicole A. Shonka, Ziad Khatib, Rohinton Tarapore, Lee Schalop, Joshua E. Allen, Wolfgang Oster, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2018)

2059 Background: ONC201 is a DRD2 antagonist in Phase II trials for cancers that exhibit dysregulation of the dopamine pathway. We previously reported an objective response in the first recurrent H3 K27M midline glioma patient who received ONC201 and that H3 K27M gliomas exhibit enhanced sensitivity to the compound in vitro. Here, we report the clinical experience with ONC201 to date in adult and pediatric H3 K27M glioma. Methods: As of February 1, 2018, 14 patients with H3 K27M glioma have received single agent ONC201 and had at least one post-treatment MRI. This includes 9 adult patients (8 glioblastoma, 1 diffuse midline glioma) and 5 pediatric patients (3 DIPG, 2 other diffuse midline gliomas). All patients had recurrent disease, except for 2 DIPG patients who had completed radiotherapy. Seven patients were enrolled on a clinical trial and seven were enrolled on compassionate use protocols. ONC201 was orally administered at 625 mg to adult patients and scaled based on body weight for pediatric patients. All but one patient were dosed once a week. Results: Six out of the 14 patients remain on therapy with a median follow up of 5.4 months (range: 2.9-22.6) with durable radiographic and/or clinical stability or improvement. This includes the first responder who has now been on treatment for 22 months with a 96% overall regression. All 6 patients who experienced benefit had 1-2 prior lines of therapy, whereas 5 patients who had at least 3 prior lines of therapy did not experience benefit. Among the five patients with thalamic glioma, two experienced complete regressions of their thalamic lesions while another underwent a 30% regression. One patient with previously-irradiated DIPG that exhibited a 300nM IC50 ex vivo has experienced improvements in hemiparesis and other disease-related symptoms. Another previously-irradiated DIPG patient has experienced improvements in her facial palsy and other disease-related symptoms, along with a 40% regression. Conclusions: Preliminary clinical data indicates ONC201 induces durable radiographic regressions and clinical benefit in a subset of patients with H3 K27M glioma. The clinical activity of ONC201 in pediatric and adult H3 K27M gliomas is being evaluated in ongoing clinical trials. Clinical trial information: NCT03295396, NCT02525692, NCT03416530.
Prognostic value of lymph node yield in locally advanced rectal cancer with neoadjuvant chemoradiotherapy.
Authors: Yaqi Wang, Menglong Zhou, Lifeng Yang, Jing Zhang, Weijuan Deng, Lijun Shen, Ye Yao, Liping Liang, Zhen Zhang
Journal: Journal of Clinical Oncology (2018)

e15680 Background: It is recommended that a lymph node yield (LNY) of at least 12 is necessary for colorectal cancer. However, it is debated whether it is applicable to locally advanced rectal cancer (LARC) with neoadjuvant chemoradiotherapy (neo-CRT). Some studies showed that lower LNY was related to good tumor response. This study aimed to examine factors associated with LNY and its prognostic value in those patients. Methods: Between 2006 and 2014, 495 LARC patients following neo-CRT and surgery were retrospectively analyzed. Clinicopathological features, overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS) and distant metastasis free survival (DMFS) were recorded. The chi-square test was used to compare differences in the distributions of clinicopathological variables by LNY group ( < 12 and ≥ 12). Univariate and multivariate analyses were performed using the Kaplan-Meier method and the Cox proportional hazards regression in all patients and subgroups. Results: Of the 495 patients, a LNY of less than 12 were found in 287 (57.98%) cases. There were no differences in the distributions of the clinicopathological variables by LNY group, including age, gender, distance from anus, type of surgical procedure, tumor grade, cTNM and ypTNM. And no association was found between LNY group and tumor regression grade (TRG) (P = 0.499). Univariate analysis showed that LNY ≥ 12 group had better OS (P = 0.030), DFS (P = 0.012) and DMFS (P = 0.011) compared with LNY < 12 group, not LRFS (P = 0.293). In multivariate analysis, LNY ≥ 12 was an independent good prognostic factor of OS (HR 0.522, 95%CI 0.338-0.804, P = 0.003), DFS (HR 0.595, 95%CI 0.430-0.823, P = 0.002) and DMFS (HR 0.583, 95%CI 0.398-0.853, P = 0.005), not LRFS (HR 0.597, 95%CI 0.326-1.091, P = 0.093). However, subgroup analyses showed that LNY had no association with prognosis (all P > 0.05) in patients with negative lymph nodes or good tumor response (TRG = 0 and 1). Conclusions: Increased LNY ( ≥ 12) was an independent good prognostic factor in LARC with neo-CRT, and lower LNY ( < 12) is not related to good tumor response. These patients probably still need enough number of LNY ( ≥ 12) even though they received neoadjuvant chemoradiotherapy.