tbuckley/cabot-search huggingface dataset:
Discovery and disclosure of incidental genetic information obtained through high throughput sequencing.
Authors: Erin Wysong Hofstatter, Melinda Lynne Yushak, Sara Bouberhan, Gang Han, Lianne Epstein, Lajos Pusztai
Journal: Journal of Clinical Oncology (2015)

e17779 Background: Next generation sequencing platforms are increasingly being used in the oncology clinic. There is controversy over how, and if, to disclose germline variants that can be discovered during NGS. This study assessed patient preferences regarding disclosure of incidental genetic findings. Methods: We developed a cross-sectional 45 item questionnaire of ambulatory breast, GI, and lung oncology patients. Basic descriptive statistics and the proportional odds logistic regression were used for analysis. Holm-Bonferroni method was used to determine significance among all independent variables. Results: Between February 2014 and January 2015, 413 of 855 eligible patients responded to the survey (48%). Participants had a mean age of 59, were predominantly Caucasian (78%), female (74%), college-educated (44%) and comfortable with basic genetic information (65%). Thirty-six percent had stage 0-III disease while 41% had stage IV disease. Sixty-five percent of respondents would pursue tumor profiling even if a mutation were found that could cause a disease other than cancer. Most patients (77%) wanted to know if they had a mutation that increased their risk of a serious but preventable illness, but only 56% desired information for a mutation causing a serious and unpreventable illness. Sixty five percent stated they would want to know all genetic information found. However, when specifically questioned, only 49% of respondents wanted to know about variants of uncertain significance. Only 14% did not want to learn about a mutation that was potentially heritable. Having considered these scenarios, most patients (59%) would agree to undergo tumor profiling if offered by their physician. Caucasians (OR 2.7, CI 1.6-4.7), men (1.8, CI 1.1-2.9), and those with prior knowledge of tumor profiling (OR 2.6, CI 1.6-4.3) were more likely to agree. Tumor type, stage, education, family history and other demographic factors were not significant. Conclusions: A majority of oncology patients express interest in pursuing tumor profiling despite the possibility of discovering incidental genetic findings. However, there is wide variability in what information patients wish to learn.
Racial disparities in survival of adult T-cell leukemia/lymphoma patients in the United States: A SEER database analysis.
Authors: Renju V. Raj, Sanjib Basu, Lisa N Boggio, Henry C. Fung, Stephanie A. Gregory, Parameswaran Venugopal, Elizabeth Shima Rich
Journal: Journal of Clinical Oncology (2012)

e16503 Background: Adult T cell Leukemia/Lymphoma (ATL) is an aggressive lymphoproliferative disorder etiologically linked to Human T cell Lymphotropic Virus -1 (HTLV-1). HTLV-1 infection is endemic in areas of Japan, the Caribbean, South America, and Africa. ATL runs a very aggressive clinical course. It is a rare malignancy in the United States (US), and epidemiologic data are limited. We undertook a Surveillance Epidemiology and End Results (SEER) based database analysis to identify survival data of ATL patients (pts) with emphasis on race and ethnicity. Methods: We used the SEER 17 Registry data (1973-2008) for pts with a confirmed diagnosis of ATL. ICD-O-3 code 9827/3 was used to identify pts with ATL. The following exclusion criteria were used: diagnosis at death certificate or autopsy, no follow-up records, diagnosis of second malignancies or lack of documentation of sex or age at diagnosis. The Kaplan Meier method was used to evaluate survival in different races. Statistical tests were done utilizing R statistical software. Results: 272 patients were included in the final analysis (126 females; 146 males). Pts were stratified by race: White (155), Black (80), Other (33), Unknown (4). Median age (yr) of diagnosis in Blacks (51.5) was lower than in Whites (65) and other races (65). Average age of diagnosis in Blacks was significantly lower compared to Whites (p=0.002) and non-Blacks (p=0.0008). Survival analysis of the study group showed a median overall survival (OS) of 13 mo (95%CI 10-16). Whites had a higher median OS (21 mo) compared to blacks (5 mo); the difference in survival was strongly significant (Log-rank p-value &lt; 0.001). Differences in survival between blacks or whites compared to other ethnic and unknown racial groups (n=37) were not statistically significant. Conclusions: ATL is a rare malignancy with poor prognosis in the US. Epidemiologic data on survival are limited. Blacks tend to have an earlier onset of disease and a poor prognosis compared to whites. The reasons for this aggressive course and earlier age of diagnosis in blacks are unknown.
Abstract P093: Analysis Commons: Team Science in a Big-data Environment for Genetic Epidemiology
Authors: Jennifer A Brody, Alanna Morrison, Joshua C Bis, Jeffrey O’Connell, Jennifer Huffman, Joshua P Lewis, Bruce M Psaty, Eric Boerwinkle, L A Cupples
Journal: Circulation (2017)

The growing volume and complexity of whole-genome sequence (WGS) and multi-omic data requires new analytic approaches beyond those developed for the GWAS era. In response to this challenge, we present an Analysis Commons, which brings together genotype and phenotype data from multiple studies along with a suite of powerful and validated analysis tools into a secure cloud-computing framework that is equitably accessible by associated investigators. This framework is designed to address the emerging challenges of multi-center WGS analyses—data sharing mechanisms, phenotype harmonization, -omics integration, annotation—and the need for flexible, secure, efficient, high-performance computing for numerous users. The Analysis Commons is built on the DNAnexus cloud platform, which provides large parallel compute resources and robust security protocols. To permit multi-center data sharing, we implemented two parallel data sharing approaches: (1) a multi-lateral consortium agreement that enables data sharing across multiple studies, and (2) coordinated dbGaP applications among groups of institutions. Investigators with detailed knowledge of the phenotypes and contributing studies harmonize data from multiple sources for maintenance in a central database. The Analysis Commons supports multiple association-analysis software packages, as well as tools for annotation and visualization. Importantly, approved investigators have full access to the combined data sets, facilitating the rapid development and deployment of new methods. We demonstrate the Analysis Commons model with an analysis of fibrinogen in 3999 participants from the Old Order Amish Study and the Framingham Heart Study with WGS from the Trans-Omics for Precision Medicine (TOPMed) Program. We performed and validated single-variant and SKAT analyses using GENESIS and MMAP pipelines, accounting for relatedness with linear mixed models. We confirmed a known association of a nonsynonymous variant in FGG (p=2.5e-9, MAF=0.34%, rs148685782) . No other single variant or SKAT association was significant after correcting for the number of tests. Analyses were run in parallel across 1408 cores and took less than one hour of wall-clock time. The Analysis Commons offers the necessary infrastructure support for analysis of WGS and multi-omic data in a setting that empowers phenotype, analytic, and computational experts to transform raw data into knowledge of the determinants of cardiovascular health.
Adjuvant phase III trial to compare intense dose-dense adjuvant treatment with EnPC to dose dense, tailored therapy with dtEC-dtD for patients with high-risk early breast cancer (GAIN-2).
Authors: Volker Moebus, Helmut Forstbauer, Grischa Wachsmann, Andreas Schneeweiss, Angelika Ober, Ekkehard von Abel, Petra Krabisch, Heinz-Gert Hoeffkes, Karin Kast, Bernd Christensen, Michael Niedermeier, Mustafa Deryal, Christoph Uleer, Yvonne Fauster, Thomas Goehler, Sibylle Loibl, Valentina Nekljudova, Gunter Von Minckwitz
Journal: Journal of Clinical Oncology (2013)

TPS1137 Background: Intense dose-dense (idd) chemotherapy (CT) significantly improves overall survival in breast cancer patients. Two preceding trials explored iddETC vs a dd combination of EC-TX (GAIN) and dtEC-dtD vs conventional dosed FEC-D (Panther). Nab-paclitaxel (nP) provides a better toxicity profile and higher efficacy compared to solvent based taxanes and might be preferred in an idd regimen. Methods: This is a multicenter, prospective, randomized, open-label phase III trial comparing iddEnPC or dtEC-dtD as adjuvant CT. Pts with uni- or bilateral primary high risk node-positive (N + ) breast cancer (BC) and centrally confirmed ER/PR/HER2 and Ki-67 status can be included. Luminal A pts are only recruited with N+ ≥4. Randomization to iddEnPC or dtEC-dtD will be stratified by biological subtype defined by hormone receptor, HER2 and Ki-67. The iddEnPC arm will receive epirubicin (150mg/m 2 ) q2w x3 followed by nP (260-330mg/m 2 , dose to be determined in run-in phase) q2w x3, followed by cyclophosphamide (2g/m 2 ) q2w x3. The dtEC-dtD arm will receive EC (38-120/450-1200 mg/m2) q2w x4 followed after 1 wk rest by docetaxel (60-100mg/m2) q2w x4. GAIN-2 will compare toxicity and efficacy of an idd regimen (EnPC) vs a dd regimen with modification of single doses depending on individual hematological and non-hematological toxicities. Primary objective is invasive disease-free survival (IDFS). Secondary objectives are survival by other definitions, compliance, safety, side effects of taxanes and subgroup analyses (by 0-3, 4-9 or 10+ involved nodes and Ki-67). Efficacy analyses are planned 60 mths after end of accrual, safety interim analyses after 200 and 900 pts have completed CT. It was assumed that dtEC-dtD will achieve a 5-yr IDFS of 75% and ddEnPC will improve IDFS to 79% (HR 0.819) with a power of 80% (α=0.05, ß= 0.2).GAIN-2 is registered under NCT01690702 Results: 75pts were recruited since 1 st Oct 2012. Recruitment (in total 2886 pts) is planned for 36 mths in 80-100 sites in Germany. Run-in safety data to be presented. Conclusion: GAIN-2 will compare the efficacy of adjuvant iddEnPC and dtEC-dtD in pts with early N + BC. Clinical trial information: NCT01690702.
The DART Study: A phase 2 randomized double-blind study of dalantercept plus axitinib versus placebo plus axitinib in advanced clear cell renal cell carcinoma (RCC).
Authors: Martin Henner Voss, Elizabeth R. Plimack, Brian I. Rini, Michael B. Atkins, Robert Alter, Rupal Satish Bhatt, J. Thaddeus Beck, Musa Mutyaba, Kristen M. Pappas, Dawn Wilson, Xiaosha Zhang, Matthew L. Sherman, Shuchi Sumant Pandya
Journal: Journal of Clinical Oncology (2015)

TPS4583 Background: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis involved in blood vessel maturation and stabilization. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in dual angiogenic blockade and augmented inhibition of tumor growth in RCC xenograft models. Dalantercept is an ALK1 receptor-fusion protein that acts as a ligand trap by binding to ligands, bone morphogenetic proteins (BMP) 9 and 10. Part 1 of this study evaluated the safety, tolerability, and preliminary activity of escalating dose levels of dalantercept (0.6, 0.9, and 1.2 mg/kg) plus standard doses of axitinib (5 mg PO BID) every 3 weeks in patients with advanced RCC who received at least one prior VEGFR TKI and no more than 3 prior tx. 29 pts were enrolled in Part 1 and the combination was associated with an acceptable safety profile and preliminary activity (25% RR, preliminary median PFS of 8.3 months for all dose levels combined). The mPFS for the 0.9mg/kg dose level has not been reached. AEs ( > 30%) regardless of attribution: fatigue, diarrhea, dysphonia, peripheral edema, nausea, decreased appetite, epistaxis, hypertension, arthralgia, creatinine rise, cough, and hand-foot rash. There were no grade 4/5 related adverse events. The 0.9 mg/kg dose level was selected for Part 2. Methods: Part 2 is a multi-center Phase 2 study and is actively accruing patients across approximately 50 sites in the US. In Part 2, 130 patients will be randomized 1:1 to dalantercept plus axitinib or placebo plus axitinib in a double-blinded fashion. Key eligibility: predominantly clear cell RCC; ECOG 0-1; 1 prior VEGFR TKI. 1 prior mTOR inhibitor and any number of prior immune therapies are also permitted. An independent DMC will evaluate safety data during the study. The primary endpoint is PFS. Secondary endpoints include: ORR by RECIST v1.1, OS, pharmacokinetic assessments, and pharmacodynamic evaluations of ALK1 pathway and other angiogenesis markers in serum and archived tumor specimens. Clinical trial information: NCT01727336.
Final results of a phase II trial of weekly nab-paclitaxel with GM-CSF as chemoimmunotherapy for platinum-resistant epithelial ovarian cancer.
Authors: Ron E. Swensen, Barbara Ann Goff, Jennifer Childs, Doreen Higgins, Theodore Gooley, Patricia A Fintak, Barbara Buening, Mary L. Disis
Journal: Journal of Clinical Oncology (2012)

5082^ Background: Ovarian cancer patients with an anti-tumor immune response have a prolonged survival, suggesting that augmenting anti-tumor immunity may be therapeutic. We hypothesized that weekly nab paclitaxel (nabP) followed by GM-CSF may enhance anti tumor immunity and prolong time to progression (TTP). Methods: Eligible subjects had platinum resistant ovarian, primary peritoneal or fallopian tube cancer, and an elevated CA125. Conditional power estimate after 11 subjects showed 22 subjects had 80% power to show a response rate (RR) &gt;21% if the true study RR is 35%. Study end points were RR and TTP. Progression (DP) was doubling of CA125 above the nadir. Complete response (CR) was a decline of CA125 below institutional normal. Partial response (PR) was a decline of &gt;50% from baseline. Stable disease (SD) was all other scenarios. Subjects received nabP, 100mg/m 2 days 1,8,15 followed by GM-CSF 250mcg days 16-26 of a 28 day cycle until progression or 6 cycles were complete. Responding subjects received up to 6 more cycles of GM-CSF on days 14-28. Results: 21 subjects received at least one dose of study medications. Median age was 61 (30-91) and had a median of 3 (1-13) prior regimens. Among those completing the study, the median TTP was 132 days vs. 272 days on the prior platinum regimen. 9/21 (43%) had a PR and 4/21 (19%) had a CR. Subjects with a response had a median TTP of 140 days. Assay of serial T-lymphocyte counts against CEA, MUC1, CA125 and tt and influenza controls are planned. Conclusions: Weekly nabP with GM-CSF had manageable toxicity and induced a high response rate (62% by CA125) in patients with platinum resistant ovarian cancer, however this regimen did not prolong the TTP beyond the TTP observed in the prior platinum regimen.
Long-term aspirin use and intratumoral gene expression in prostate cancer.
Authors: Konrad Hermann Stopsack, Ericka M. Ebot, Mary K Downer, Jennifer R. Rider, Lorelei Mucci
Journal: Journal of Clinical Oncology (2017)

106 Background: Pharmacoepidemiologic studies suggest prognostic benefits of aspirin in prostate cancer. We hypothesized that prostate cancer tissue from regular aspirin users at cancer diagnosis compared to nonusers is characterized by specific transcriptional changes. Methods: We analyzed tumor whole-transcriptome data from men diagnosed with prostate cancer during prospective follow up of the Physicians Health Study 1 (PHS1, n 1 = 150), initially a randomized-controlled trial of aspirin for prevention of cardiovascular disease and cancer. We compared the expression of putative aspirin target genes ( PTGS2, CTNNB1, MYC, AXIN2, PTGER3) between regular aspirin users ( ≥ 3 x 324 mg/week) and non-users at cancer diagnosis. We used Gene Set Enrichment Analysis to identify Gene Ontology biological process gene sets (total, 3609) associated with aspirin use. Leading edge genes of ≥ 3 functionally related gene sets were summarized in a meta-gene score. Results were validated among prostate cancer patients from the Health-Professionals Follow-up Study (HPFS, n 2 = 254; aspirin use, ≥ 2 x/week). Results: Regular aspirin use was common (65% in PHS1; 45% in HPFS) and not associated with age, stage, and Gleason grade. In PHS1, none of the predefined genes were associated with aspirin use (all p &gt; 0.05). 26 gene sets were downregulated in aspirin users at a false discovery rate (FDR) &lt; 0.25 (9 at FDR &lt; 0.05). 11 gene sets were clustered functionally around ribosome function and protein translation. A “ribosome” score of 96 genes was higher in aspirin users compared to nonusers (difference, 35.5 standard deviations [SD]; p = 0.0001). There was no dose-dependency for cumulative duration of aspirin use before cancer diagnosis ( p trend = 0.17) or time since stopping use among non-users at diagnosis ( p = 0.32). In HPFS, neither the pre-defined target genes (all p &gt; 0.18) nor the score were associated with aspirin use (difference, –9.8 SD; p = 0.18). Conclusions: Although RNA acetylation and resulting intratumoral gene expression changes due to aspirin use may be biologically plausible, we were unable to corroborate this association in two-long term prospective studies. Short-term trials might assess if aspirin has direct effects on tumor gene expression.
A sugar engineered non-fucosylated anti-CD40 antibody, SEA-CD40, with enhanced immune stimulatory activity alone and in combination with immune checkpoint inhibitors.
Authors: Shyra Jane Gardai, Angela Epp, Germein Linares, Loir Westendorf, May Kung Sutherland, Haley Neff-LaFord, Jonathan Gregor Drachman, Stanford Peng, Che-Leung Law
Journal: Journal of Clinical Oncology (2015)

3074 Background: SEA-CD40 is a non-fucosylated, humanized IgG1 monoclonal antibody directed against human CD40. It is derived from dacetuzumab, a humanized IgG1 previously developed for B-lineage malignancies. Antibody glycosylation is essential for Fc receptor-mediated activity and nonfucosylated antibodies may show improved efficacy via increased binding to FcγRIIIa (CD16). Methods: Enhanced functionality of SEA-CD40 was determined through FcγRIIIa binding, immune activation, and induction of antigen-specific T-cells Results: While SEA-CD40 and the parent antibody dacetuzumab bind to CD40 with similar affinity, the non-fucosylated SEA-CD40 has a higher affinity for both low (158F) and high (158V) affinity FcγRIIIa. The consequence of enhanced SEA-CD40/FcγRIIIa binding is potent ADCC activity and improved agonistic signaling to antigen presenting cells (APCs). SEA-CD40 treatment of human PBMCs elicits a robust immune response consisting of proinflammatory cytokine production, APC maturation and up-regulation of co-stimulatory receptors on APCs with activity at antibody concentrations as low as 10 ng/ml. Utilizing a surrogate antibody against mouse CD40, the immune stimulatory properties of nonfucosylated anti-CD40 were confirmed in vivo in syngeneic tumor models. SEA-CD40 induction of antigen specific T-cells was assessed using human peripheral blood mononuclear cells (PBMCs) exposed to the M1 influenza antigen. SEA-CD40 stimulated the expansion of influenza specific T-cells and elevated their production of IFNγ. Likewise, SEA-CD40 also stimulated T-cell proliferation and IFNγ production in PBMCs from melanoma, pancreatic, or breast cancer patients in response to a mixture of the tumor-associated antigens MAGE-A1/A3. Interestingly, antigen-specific T-cell responses to both the influenza and tumor antigens were enhanced in the presence of blocking antibodies to CTLA4 or PD1. Conclusions: These observations demonstrate the potential of combining the non-fucosylated agonistic SEA-CD40 with immune check point inhibitors to generate more effective adaptive antitumor immune responses.
Challenges in enrolling to metastatic castration-resistant prostate cancer (mCRPC) studies that require androgen receptor splice variant (AR-V) positivity.
Authors: Michael Thomas Schweizer, Kathleen Haugk, Heather H. Cheng, Jessica L Maes, Ruth F Dumpit, Peter Nelson, Robert B. Montgomery, Stephen R Plymate, Evan Y. Yu
Journal: Journal of Clinical Oncology (2017)

264 Background: AR-Vs are truncated androgen receptor (AR) isoforms that lack the ligand-binding domain (LBD) and are associated with resistance to drugs targeting the ligand-AR LBD interaction (e.g. abiraterone [Abi], enzalutamide [Enza]). Preclinical studies have shown that niclosamide, an anthelminticsdrug, is able to overcome AR-V mediated drug resistance. Methods: We are conducting a Phase I dose-escalation study testing high-dose niclosamide in combination with the FDA-approved dose of Enza. Niclosamide is given three-times-daily by mouth at one of the following dose-levels: 500, 1000 or 1500 mg. All patients are required to have mCRPC, have received prior Abi, and have detectable AR-V transcripts in circulating tumor cells (CTC) as determined using the AdnaTest ProstateCancerSelect/ProstateCancerDetect assay. Patients are permitted to start Enza prior to the addition of niclosamide. The primary objective is to assess safety. Niclosamide’s pharmacokinetic profile will also be determined. Results: From December 2015 to October 2016 we screened 14 patients. All patients previously progressed on Enza, with 13/14 patients demonstrating a rising PSA on Enza at screening. Two had previously documented AR-Vs as determined from prior transcript profiling studies; however, only one of these patients was AR-V positive (AR-V5-6) at the time of study enrollment. Of the 12 patients without prior evidence of AR-V, none were found to be AR-V+. All patients (14/14) were positive for actin and 10/14 were positive for full-length AR using the AdnaTest. To date, one patient has completed treatment with high-dose niclosamide. No study drug-related adverse events have been observed. Conclusions: Rates of AR-V positivity have been lower than expected in our cohort of patients that have progressed on Abi and Enza – challenging study accrual. Multicenter studies are needed to confirm rates of AR-V positivity in mCRPC populations. Furthermore, in order to ensure enrollment expectations are met, novel biomarkers (e.g. AR-V status as determined using AdnaTest) should undergo pre-study confirmatory testing within institutions prior to use as enrollment criteria. Clinical trial information: NCT02532114.
Adult Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation, Fludarabine, and Thiotepa Conditioning
Authors: Sarah Anand, Samantha Thomas, Kelly Corbet, Cristina Gasparetto, Richard Lopez, Gwynn D. Long, Ashley K. Morris, David A. Rizzieri, Stefanie Sarantopoulos, Keith M Sullivan, Anthony D. Sung, Nelson J. Chao, Mitchell E. Horwitz
Journal: Blood (2016)