tbuckley/cabot-search huggingface dataset:
A prospective cohort study in colorectal cancer assessing the relationship between post-surgery detection of methylated <i>BCAT1</i> or <i>IKZF1</i> ctDNA and risk for residual disease and survival.
Authors: David Murray, Graeme P. Young, Susanne Kartin Pedersen, Philippa Rabbitt, Susan E Byrne, Kathryn J Cornthwaite, Amitesh Roy, Christos Karapetis, Erin L. Symonds
Journal: Journal of Clinical Oncology (2018)

3596 Background: The methylated ctDNA biomarkers BCAT1 and IKZF1 are common events in colorectal cancer (CRC), play a role in its development and drugs targeting BCAT1 are available. As these biomarkers disappear from blood after surgery in most patients, a prospective study was conducted to assess the relationship between their persistence post-surgery and presence of and risk for residual disease as well as survival. Methods: ctDNA status using these biomarkers was determined within 12 mo of initial surgical resection. Detection of either marker was related by logistic regression and survival analysis (Cox proportional hazards) to pathologically-determined presence or risk of residual disease (“RD”, margins involved, metastases present or nature of node involvement) and to recurrence-free survival. Results: 172 CRC patients were tested for the biomarkers and then followed for a median 37.1mo (IQR 22.6-49.8) during which 23 experienced recurrence and 10 died from CRC. 28 (16%) were ctDNA positive post-surgery. Univariate analysis showed that a positive result was more likely if any of three markers of RD was present (OR 7.7, 95% CI: 2.3-25.0 p = 0.001); while increasing number of lymph nodes (OR 8.3, 95% CI: 1.8-37.7 p = 0.004) and involved peritoneum (OR 3.8, 95% CI: 1.6-9.2 p = 0.003) where also associated with a positive result. Multivariate modelling with adjustment for treatment status at time of venesection indicated that features of RD was an independent predictor of post-surgery ctDNA status: cases with 3 features (margins or apical node involved, distant metastases) were 5.3 times (95% CI: 1.5-18.4, p-value = 0.008) more likely to be positive. Modelling recurrence-free survival showed that post-surgery ctDNA positivity was associated with an increased risk of recurrence (HR 3.8, 1.5-9.5, p = 0.004). Conclusions: CRC cases positive for these ctDNA biomarkers within 12 months of surgery are at increased risk of residual disease and subsequently for recurrence. This has implications for adjuvant therapy and monitoring of cases; randomised studies are now indicated to determine if such can provide survival benefit. Clinical trial information: 12611000318987.
Randomized All-Comers Evaluation of a Permanent Polymer Zotarolimus-Eluting Stent Versus a Polymer-Free Amphilimus-Eluting Stent
Authors: Rik Rozemeijer, Mera Stein, Michiel Voskuil, Rutger van den Bor, Peter Frambach, Bruno Pereira, Stefan Koudstaal, Geert E. Leenders, Leo Timmers, Saskia Z. Rittersma, Adriaan O. Kraaijeveld, Pierfrancesco Agostoni, Kit C. Roes, Pieter A. Doevendans, Pieter R. Stella
Journal: Circulation (2018)

Polymer-free amphilimus-eluting stents (PF-AES) represent a novel elution technology in the current era of drug-eluting stents. The clinical safety and efficacy of PF-AES as compared with latest-generation permanent-polymer zotarolimus-eluting stents (PP-ZES) have not yet been investigated in a large randomized trial.In this physician-initiated, prospective, multicenter, randomized, noninferiority trial, an all-comers population requiring percutaneous coronary intervention was enrolled across 3 European sites. Randomization (1:1 ratio) to PP-ZES or PF-AES was performed after stratification for troponin status and diabetes mellitus. In both treatment arms, troponin-positive patients were planned for 12-month dual antiplatelet therapy, whereas troponin-negative patients were planned for 1-month dual antiplatelet therapy. Outcome assessors were blinded to the allocated treatment. The device-oriented primary end point of target-lesion failure was defined as cardiac death, target-vessel myocardial infarction, or target-lesion revascularization at 12-months as analyzed by modified intention-to-treat (80% power, and a 3.5% noninferiority margin).In total, 1502 patients were randomized and 1491 treated with the assigned stent and available for follow-up. The primary end point occurred in 42 (5.6%) of the 744 patients receiving PP-ZES versus 46 (6.2%) of the 747 patients receiving PF-AES. PF-AES were clinically noninferior to PP-ZES (risk difference, 0.5%; upper limit 1-sided 95% confidence interval, 2.6%; Pnoninferiority=0.0086). Cardiac death occurred in 10 (1.3%) versus 10 patients (1.3%; P value for difference, 1.00), target-vessel myocardial infarction occurred in 18 (2.4%) versus 17 patients (2.3%; P value for difference, 0.87), and target-lesion revascularization occurred in 22 (2.9%) versus 20 patients (2.6%; P value for difference, 0.75) for PF-AES as compared with PP-ZES. Overall, definite or probable stent thrombosis occurred in 1.0%.PF-AES were noninferior to PP-ZES regarding target-lesion failure at 12 months. Findings regarding the secondary end point and prespecified subgroups were generally consistent with that of the primary end point.URL: https://www.clinicaltrials.gov . Unique identifier: NCT02328898.
Phase I study of recombinant interleukin-15 in combination with checkpoint inhibitors nivolumab and ipilimumab in subjects with refractory cancers.
Authors: Geraldine Helen O'Sullivan Coyne, Kevin Conlon, Naoko Takebe, Howard Streicher, Mary Flanagan Quinn, Ashley Bruns, Tony Navas, Ralph E. Parchment, Larry Rubinstein, Elad Sharon, James H. Doroshow, Thomas A. Waldmann, Alice P. Chen
Journal: Journal of Clinical Oncology (2018)

TPS3128 Background: Interleukin-15 is a stimulatory cytokine. Recombinant human IL-15 (rhIL-15), a nonglycosylated single-chain peptide, increased circulating CD8+T-cells, NK cells and inflammatory cytokines in clinical trials (Conlon et al, 2015. JCO). Simultaneous in vivo administration of IL-15 with anti-CTLA-4 and anti-PD-L1 is associated with increased levels of tumor antigen-specific CD8+T cells and T-cell tumor lytic activity, increased antigen-specific IFN-γ release, decreased tumor growth, and improved mouse survival; as well as inhibition of suppressive functions of CD4+CD25+ and CD8+CD122+ regulatory T-cells (Yu et al, Proc Natl Acad Sci. 2012). Therefore we postulate the combination of checkpoint inhibitors+rhIL-15, which act on different stages of T-cell activation, will enhance anti-tumor immune responses through T-cell expansion, differentiation, and cytotoxic activity. Methods: Open label phase I trial of the rhIL-15+ipilimumab+nivolumab combination following a 3+3 design, with safety lead-in doublets of rhIL-15+nivolumab (Cohort A) or rhIL-15+ipilimumab (Cohort B). Estimated enrollment: 45 patients (pts). 42-day cycles: rhIL-15 administered subcutaneously on days 1-8 and 22-29 for the first 4 cycles only; nivolumab intravenously (IV) day 8, 22 and 36; ipilimumab IV day 1. Pts must be ≥18 years of age, have histologically confirmed solid tumors that have progressed on standard of care therapy, ECOG PS ≤2. Pts with treated brain metastasis with stable disease ≥4 weeks without requiring steroids/anti-seizure medication, and who do not response on any 2/3 agents, are eligible. Exclusion criteria include grade3 immune related adverse events during prior checkpoint inhibitor treatment, active/chronic autoimmune disease, systemic steroid use or HIV/hepatitis infection. Currently, cohort A has enrolled 1 of 3 planned pts. Assessment of intrinsic apoptosis biomarkers, PD-L1 levels, T-cell phenotypic markers, markers of T-cell activation/inhibition (Zap70 pY493/pY580 SHP2), cell enumeration, proximity of tumor cells to T cells at the maximally tolerated dose using a validated/quantitative immunofluorescence assay, is planned. Clinical trial information: NCT03388632.
Response to neoadjuvant chemoradiation in rectal cancer: Experience from the national cancer institute of Peru.
Authors: Johanny F Muro, Karin Veliz, Mike M Maldonado, Claudio J. Flores, Paola Catherine Montenegro
Journal: Journal of Clinical Oncology (2017)

e15157 Background: Preoperative Chemoradiation (CRT) in rectal cancer has benefit in local control. 50 - 60% of cases are down-staged and 20% achieve a pathologic complete response (pCR). Despite the fact that there is no a clear benefit in long-term outcomes, response to preoperative treatment could have a prognostic value. Our objectives were to determine the pCR and down-staging (DS) rates after neoadjuvant CRT, as well as disease free survival (DFS), overall survival (OS) and prognostic factors associated with these outcomes Methods: Patients with rectal cancer treated with preoperativefluoropyrimidine based CRT at the National Cancer Institute of Peru (INEN) from 2007 to 2012 were evaluated. OS and DFS were calculated according to Kaplan-Meyer method. The survival curves were compared using the Log-rank or Breslow test. Multivariate analysis was performed with Cox regression Results: 282 patients were included, median age was 62 years (range 18-93), female: male ratio (1:1). Clinical stages were as follows: I, 13.8%; II, 32.3% and III, 52.9%. Median follow up was 5 years. Patients received capecitabine and 5-FU during radiotherapy in 75.5% and 24.5% of cases respectively. Sphincter preserving surgery was possible in 46% of cases. In patients who underwent surgery, DS and pCR rates were 52% and 10.8%, respectively. Patients who achieved pCR were predominant female and had CEA less of 5 ng/mL. In multivariate analysis, clinical stage, DS, type of fluoropyrimidine (capecitabine) and surgery were associated with OS. 5 year DFS and OS was 54.9% and 60.5% respectively in patient that underwent surgery Conclusions: DS rate achieved at our institution is within the range reported by the literature and is associated with an improvement in OS. Our pCR rate was lower than what has been reported, this might be related to great proportion of patients with advanced clinical stage (EC III) in our study. This patient could have benefit with totally neoadjuvant Chemoradiation.
TCT-448 Impact of Clinical Indication / Risk Strata on Outcomes in Patients Supported with Impella Microaxial Heart Pumps
Authors: Eisha Wali, Paul Larsen, Joseph Venturini, Linda Lee, Taishi Hirai, Jonathan Rosenberg, Margaret Lee, Jonathan Paul, John Blair, Roderick Tung, Atman Shah, Sandeep Nathan
Journal: Journal of the American College of Cardiology (2018)
Non-randomized phase II study to assess the efficacy of pembrolizumab (Pem) plus radiotherapy (RT) or ablation in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) patients.
Authors: Neil Howard Segal, Nancy E. Kemeny, Andrea Cercek, Diane Lauren Reidy, Pamela Joan Raasch, Peter Warren, Anastasia E. Hrabovsky, Naomi Campbell, Jinru Shia, Karyn A. Goodman, Joseph Patrick Erinjeri, Stephen Barnett Solomon, Yoshiya Yamada, Leonard Saltz
Journal: Journal of Clinical Oncology (2016)

3539 Background: Pem alone is not active in pMMR mCRC. RT or tumor ablation alone does not result in objective systemic benefit. However, these local modalities can induce systemic immunity (abscopal effect) that can be augmented by checkpoint blockade in clinical and preclinical models. The PD-1 pathway is an important immune checkpoint to inhibit antitumor responses. A Phase II study to evaluate the safety and abscopal effect of Pem after RT or ablation in pts with pMMR mCRC is ongoing (NCT02437071).Methods: Pts with histologically/cytologically confirmed, unresectable/recurrent mCRC, who have received ≥ 2 standard therapies, underwent palliative RT (cohort 1) or ablation (cohort 2) and received 200 mg pembrolizumab Q3W for up to 24 months. The primary objective is Overall Response Rate (ORR) according to RECIST v1.1 in a non-targeted lesion. Nine pts are enrolled in stage 1 in each cohort; 15 additional pts are enrolled in stage 2 following 1 observed response in a Simon two-stage design. Correlative studies include PDL-1 status and immune correlates.Results: As of 14 Jan 2016, 26 pts [mean age 55 (range 18-80); 62% male; ECOG 0/1: (12%/88%)] received a median of 4 doses of Pem (range 1-10). While drug-related AEs were reported in 73% of pts, all were either grade 1 or 2; the most frequent were fatigue (23%), rash (15%), and nausea (15%). 19 pts were evaluable for response. Interim ORR is 9% (1 of 11) in the RT cohort. No responses were observed in the ablation cohort. Updated data will be presented.Conclusions: Pem after RT or ablation is feasible with a tolerable safety profile, with one patient achieving a PR in non-irradiated lesions after RT (abscopal effect). Accrual to the RT + Pem arm continues. Clinical trial information: NCT02437071.
Pritumumab binding to glioma cells induces ADCC and inhibits tumor growth.
Authors: Santosh Kesari, Ivan Babic, Rajesh Mukthavaram, Pengfei Jiang, Natsuko Nomura, Sandeep C. Pingle, Tiffany Juarez, Junbao Yang, Venkata Yenugonda, Elmar Nurmemmedov, Mark Charles Glassy
Journal: Journal of Clinical Oncology (2017)

e14004 Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a regional draining lymph node of a patient with cervical carcinoma. This antibody binds ectodomain vimentin on the surface of tumor cells and has demonstrated some benefit to glioblastoma patients in limited clinical trials. We wanted to determine if pritumumab inhibits glioma growth in vivo and if binding to glioma cells induces cell-mediated immunity. Methods: Pritumumab was used in flow cytometry experiments with several glioma cell lines and patient-derived neurosphere lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay was used with glioma target cells. Xenograft studies were performed in mice with and without intact B- and NK- cells. Results: We performed flow cytometry using pritumumab antibody and demonstrate binding of pritumumab to the surface of glioma cells and patient-derived glioma initiating cells. We observed significant induction of ADCC by pritumumab binding to glioma cells. Xenograft studies demonstrated pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Intact cell-mediated immunity was necessary for pritumumab’s anti-tumor effect. Analysis of a blood brain barrier model showed significant binding of pritumumab in brain tumor areas and minimal distribution in normal brain tissues suggesting the antibody can cross the blood brain barrier. Conclusions: Our data demonstratepritumumab binds glioma cells in vitro and can induce ADCC. In addition, pritumumab can limit the growth of xenograft glioma tumors in vivo only in the presence of intact cell-mediated immunity. Together these data suggest pritumumab is suitable for development as an anti-tumor therapeutic.
Integrated analysis of mRNA and miRNA to unravel novel mechanisms of sunitinib long term response in mRCC.
Authors: Javier Puente, Nuria Lainez, Marta Dueñas, María José Méndez-Vidal, Emilio Esteban, Daniel E. Castellano, Laura Basterrechea, María José Juan Fita, L. M. Antón Aparicio, Urbano Anido, Julio Jose Lambea- Sorrosal, Begoña Perez-Valderrama, Sergio Vazquez-Estevez, Cristina Suárez, Xavier Garcia del Muro, Enrique Gallardo Diaz, Pablo Maroto, Luz Samaniego, Beatriz Suárez, Jesus Paramio
Journal: Journal of Clinical Oncology (2016)

e16080 Background: Normal and pathological angiogenesis is under the control of various developmental genetic programs, including Notch and Hedgehog pathways. More recently, miRNAs have emerged as key regulators of these processes. Sunitinib (SU), represents a widely used therapy for metastatic renal cell carcinoma patients. However, there is a significant proportion of patients who show no clinical benefit. Accordingly, the determination of potential biomarkers of response to this treatment is needed in order to appropriately select those patients that will benefit from the therapy. Methods: Retrospective, observational and multicenter study of pts treated with SU under clinical practice. Two groups were included: pts with metastatic renal carcinoma (RCC) who achieved progression free survival (PFS) ≥ 22 months (LR), and pts who showed progressive disease at first radiological evaluation (PR). The objectives were to compare the clinical and molecular characteristics at tumor level in LR vs. PR pts. Expression levels of miRNAs and mRNAs were monitored by RTqPCR. To determine their ability to discriminate the two populations we sequentially performed unpaired tTest, ROC analyses and Kaplan Meyer distributions with LogRank test. In all the cases, a p ≤ 0.05 was considered significant. Results: A total of 123 pts in 16 centers were included, 97 were identified as LR and 26 as PR. So far, 52 tumor samples have been analyzed, 39 of LR (75%) and 13 of PR (25%). The analysis of the expression of 14 different genes (selected from previous studies) showed that increased levels of HEYL, a Notch pathway effector, and SUFU1, which acts as Hedgehog signaling repressor, characterize the LR population. In addition, among the 13 miRNAs analyzed (selected on the basis of their activity on angiogenesis, signal transduction, EMT and stemness) the increased levels of hsa-miR-27b, of hsa-miR-23b and of hsa-miR-628 were associated with the LR population as well. Conclusions: Our data indicate that the activation of Notch positively correlated with LR to SU. Importantly, the elevated expression of miRNAs indicated the existence of cooperative effects, and suggested the involvement of target genes responsible for resistance to SU in mRCC.
RETROSPHER. ERBB2 amplification detection in the plasma at diagnosis for early high-risk HER2-positive breast cancer
Authors: R. Sabatier, S. Garnier, N. Carbuccia, A. Guille, C. Tarpin, A. Goncalves, D. Birnbaum
Journal: Annals of Oncology (2018)

Background: Despite recent advances, early high-risk HER2-positive breast cancers (BC) have a risk of relapse close to 20%, with no validated prognostic biomarker. Circulating tumour DNA has been described to have a prognostic value for some early BC. Most published studies monitored mutations previously identified on tumour tissue. An alternate way to monitor plasma from patients with HER2-positive BC might be to look for ERBB2/HER2 amplification. Methods: We selected 40 HER2-positive high-risk early BC (cT ≥ 2 and/or N+ and/or residual disease after neoadjuvant chemotherapy) included in our institutional BC-BIO-IPC 2009-005 prospective program (NCT01521676). Plasma samples were collected at diagnosis and cell-free DNA (cfDNA) was isolated using the Qiagen EZ1 ccfDNA Midi kits. We then used commercial kits (BioRad) for ERBB2 and TERT (reference gene), and looked for ERBB2 amplification by digital PCR (BioRad QX200). Results: After DNA isolation from 1.5 to 2ml of plasma, cfDNA was eluted in 55µl of buffer. The median cfDNA concentration was 0.08 ng/μl (range <0.05 - 0.306, Qubit), with 25 cases having a concentration below 0.1 ng/μl. Median concentration was 4.68 ng/μl for metastatic cases. After droplet generation, 25 samples had enough droplets to allow the reading and analysis of ERBB2 amplification results. Of these samples, 52% were amplified, the others being equivocal. None of these samples were classified as "non-ERBB2 amplified". All controls were accurately classified. Except for age (p = 0.05, T-test), identification of circulating ERBB2 amplification did not correlate to usual clinicopathological features, including survival (but relapse (12%) and deaths (8%) rates were low in this set). However, it tended to be correlated to cfDNA concentration (p = 0.06, T-test). Conclusions: ERBB2 amplification detection in plasma is feasible and can be observed for more than 50% of patients with early high-risk HER2-positive BC. If confirmed, these results may lead to propose plasma ERBB2 amplification monitoring at diagnosis and during follow-up, to optimize the systemic management in case of persistence or increase of ERBB2 amplification during or after standard treatments. Clinical trial identification: NCT01521676. Legal entity responsible for the study: Institut Paoli Calmettes. Funding: Novartis. Disclosure: R. Sabatier: This work has been partly funded by Novartis. All other authors have declared no conflicts of interest.
Compliance with biweekly SOX combination chemotherapy versus triweekly SOX as a first-line therapy for elderly patients with advanced gastric cancer.
Authors: Shu Zhang
Journal: Journal of Clinical Oncology (2018)

e16075 Background: Although the triweekly S-1 and oxaliplatin (SOX3) combination chemotherapy has yielded significant improvements in PFS, OS and RR, the high toxicities limit the use in elderly patients with advanced gastric cancer (AGC). We evaluated the efficacy and toxicity of biweekly SOX2 and SOX3 regimens for the treatment of elderly AGC patients. Methods: A total of 47 elderly patients (aged ≥ 65 years) with ECOG PS 0-1 and pathologically proven unresectable metastatic or recurrent AGC were randomized to receive either SOX2 (S-1 80mg/m2, day1-10 and oxaliplatin 85 mg/m2, q2w or SOX3 (S-1 80 mg/m2, day1-14 and oxaliplatin 130 mg/m2, q3w). Results: Forty-seven elderly AGC patients were enrolled (24 in SOX2 arm; 23 in SOX3 arm) from March 2013 to May 2016 in this study. The median patient age was 69 years (range, 65–78 years). The results showed that the response rates (RR) were 58.3% (14/24) and 52.2% (12/23) (p = 0.722), and disease control rates (DCR) were 87.5% and 82.6% (p = 0.701) in SOX2 and SOX3 arms, respectively. The PFS and OS were 6.6 months (95%CI 4.36-8.84) vs 7.3 months (95% CI 3.53-11.13) (p = 0.489) and 16.4 (95%CI 12.10-20.70) vs. 15.9 (95%CI 11.80-20.00) (p = 0.116) from the start of the chemotherapy in SOX2 and SOX3 arms, respectively. The grade 3/4 toxicities included leukopenia (0% vs. 13.0%); neutropenia (8.3% vs. 26.1%); anemia (12.5% vs. 17.4%), thrombocytopenia (8.3% vs. 13.0%) , vomiting (0% vs. 17.4%), diarrhea (0.0% vs. 8.7%), hyperbilirubinemia (4.2% vs. 13.0%), neurotoxicity (4.2% vs. 8.7%) in SOX2 and SOX3 arms, respectively, showing a low toxicities of SOX2 regimen comparing to SOX3 regimens. Conclusions: This study suggested that the biweekly SOX2 combination chemotherapy had well tolerated with a better compliance and non-inferior efficacy to triweekly SOX3 as a first-line therapy for elderly advanced gastric cancer.