tbuckley/cabot-search huggingface dataset:
NSABP B-59/GBG 96-GeparDouze: A randomized double-blind phase III clinical trial of neoadjuvant chemotherapy (NAC) with atezolizumab or placebo in Patients (pts) with triple negative breast cancer (TNBC) followed by adjuvant atezolizumab or placebo.
Authors: Charles E. Geyer, Sibylle Loibl, Priya Rastogi, Sabine Seiler, Joseph P. Costantino, Namrata Vijayvergia, Patricia Cortazar, Peter C. Lucas, Carsten Denkert, Eleftherios P. Mamounas, Christian Jackisch, Norman Wolmark
Journal: Journal of Clinical Oncology (2018)

TPS603 Background: TNBC is associated with higher percentages of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC), and women with a pCR have a favorable prognosis. However, Liedtke (2008) and Loibl (2017) found that women with residual disease have a substantially higher risk of recurrence than women with other subtypes of breast cancer. Additionally, Adams (2017) and Schmid (2017) found that therapeutic blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy. Methods: Design This is a phase III, double blind, placebo-control trial evaluating neoadjuvant atezolizumab with NAC followed by adjuvant atezolizumab in TNBC. Pts are stratified by region (North America; Europe), tumor size (1.1-3.0cm; > 3.0cm), AC/EC schedule (q2w; q3w), and nodal status (positive; negative), then randomized 1:1 to receive atezolizumab/placebo 1200 mg IV every 3 wks concurrently with both sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses with every 3-wk carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 wks (per investigator discretion) for 4 cycles. Following surgery, pts resume atezolizumab/placebo 1200 mg IV every 3 wks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Eligibility criteria Centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. LVEF > 55% and no significant cardiac history. Statistical methods Co-primary endpoints are event-free survival (EFS) and pCR breast/nodes. Secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. Trial is an academic collaboration between NSABP and GBG with support from Genentech/Roche. NCT03281954 Support: Genentech/Roche Clinical trial information: NCT03281954.
Oxidative stress inhibits human p53 by site-specific glutathionylation at cysteines 124, 141, and 182 and disruption of dimerization
Authors: Chinavenmeni S. Velu, Suryakant K. Niture, Catalin E. Doneanu, Nagarajan Pattabiraman, Kalkunte S. Srivenugopal
Journal: Cancer Research (2006)

3360   Several lines of evidence indicate that the sequence-specific DNA binding activity of human p53 is highly prone to oxidative inactivation, and the redox modulators such as the Ref-1/ thioredoxins can reactivate and stimulate p53 transactivating function in cells. However, the cellular mechanisms including covalent modifications, if any, those protect and modulate the p53 protein during the recurring episodes of oxidative and nitrosative stresses, which often underlie the processes of carcinogenesis, malignant progression, and different disease states, remain unknown. Here, we show for the first time, that p53 is subjected to a new and reversible posttranslational modification, namely, glutathionylation (S-thiolation, which involves disulfide formation between reactive cysteines in proteins and low MW thiols) under oxidative stress. Using biotinylated GSH or GSSG as probes, we detected rapid thiol incorporation into the purified recombinant p53 protein and the extent of glutathionylation increased with higher GSSG/GSH ratios. The modified p53 had significantly decreased ability to bind its consensus DNA sequence. Reciprocal immunoprecipitations and a GST-overlay assay showed that cellular p53 was marginally glutathionylated under steady-state conditions, however, the modification levels increased markedly in cells treated with DNA-damaging or oxidizing agents, in parallel with the kinetics of p53 accumulation seen after these treatments. In-gel trypsinization and peptide identification by electrospray tandem mass spectrometry revealed Cys-124, Cys-141 and Cys-182 as the sites of glutathionation. Biotinylated maleimide also reacted rapidly with p53 to form an adduct with cys141, implying this to be the most reactive cysteine on protein surface. Computer-assisted molecular modeling using the crystal structure of p53-DNA complex showed that disulfide formation is compatible with either cys 124 or cys 141 alone, but, not together, and glutathionation of either sites would lead to a destabilization of the dimeric state and hinder p53 association with DNA. Protein crosslinking by glutaraldehyde followed by SDS-PAGE confirmed the inability of glutathionated p53 to form dimeric and tetrameric states. Glutathionylation of reactive cysteines is emerging as a central mechanism by which changes in the intracellular redox state may be transduced into a functional cellular response. We conclude that S-thiolation is a novel negative regulatory mechanism that protects the essential thiols of p53 from irreversible oxidation, and is a part of the posttranslational signaling cascade that control p53’s biological activities. The process may also control the levels of functionally-active p53 after DNA damage response (supported by RO1 CA 97343 grant to KSS).
Ribociclib (RIBO) + letrozole (LET) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) with no prior endocrine therapy (ET) for ABC: Preliminary results from the phase 3b CompLEEment-1 trial.
Authors: Michelino DeLaurentiis, Patrick Neven, Guy Heinrich Maria Jerusalem, Thomas Denis Bachelot, William Jacot, Susan Faye Dent, Marco Colleoni, Aleix Prat, Miguel Martin, Alistair E. Ring, Paul H. Cottu, Janice M. Lu, Hamdy A. Azim, Katie Zhou, Jiwen Wu, Juan Pablo Zarate, Claudio Zamagni
Journal: Journal of Clinical Oncology (2018)

1056 Background: CDK4/6 inhibitor RIBO has been approved for use in combination with LET for the treatment of HR+, HER2– ABC in postmenopausal women with no prior therapy for advanced disease, based on the significantly prolonged PFS versus placebo + LET observed in the pivotal phase 3 MONALEESA-2 trial (Hortobagyi et al. NEJM 2016). Here, we report baseline characteristics and early safety results for the first 1,000 pts enrolled in CompLEEment-1, an open-label, phase 3b trial evaluating RIBO+LET as first-line therapy in an expanded pt population. Methods: Pts (N≈3,000) with HR+, HER2– ABC, ≤1 line of prior chemotherapy, and no prior ET for ABC received RIBO (600 mg/day, 3 wk on/1 wk off) + LET (2.5 mg/day); men and premenopausal women received concomitant goserelin (3.6 mg subcutaneous implant every 28 days). The primary outcome was safety and tolerability. A pre-planned interim analysis was conducted ~12 months after first pt first visit. Results: Demographics and baseline characteristics for the first 1,007 pts enrolled in the study were captured in the database snapshot (January 17, 2018) and are summarized in Table 1. Details on safety results from the interim database lock (February 2018) will be presented. Conclusions: Initial population characteristics from CompLEEment-1 demonstrate a diverse group of pts, more reflective of those seen in a real-world setting. NCT02941926 Clinical trial information: NCT02941926.Demographics Median age, y 60 Pre/postmenopausal/male, % 15/83/2 ECOG PS 0/1/2, % 63/34/3 Disease history Histologic grade 1/2/3/4, % 9/39/19/1* Stage at initial diagnosis I/II/III/IV, % 15/30/19/33* Median time from initial diagnosis, mo 57 Current extent of disease, % Bone 72 Bone only 29 CNS 1 Visceral 55 Lung 22 Liver 39 Skin 3 Lymph nodes 27 Number of metastatic sites, % 0-2 68 3-5 32 Prior (neo)adjuvant medication, % 57 Chemotherapy for advanced disease, % 19 Setting at last therapy, % (Neo)adjuvant 50 Advanced disease 18 *Remaining cases unknown/unavailable
Moving to an active lifestyle? A systematic review of the effects of residential relocation on walking, physical activity and travel behaviour
Authors: Ding Ding, Binh Nguyen, Vincent Learnihan, Adrian E Bauman, Rachel Davey, Bin Jalaludin, Klaus Gebel
Journal: British Journal of Sports Medicine (2018)

Objective To synthesise the literature on the effects of neighbourhood environmental change through residential relocation on physical activity, walking and travel behaviour. Design Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number CRD42017077681 ). Data sources Electronic databases for peer-reviewed and grey literature were systematically searched to March 2017, followed by forward and backward citation tracking. Eligibility criteria A study was eligible for inclusion if it (1) measured changes in neighbourhood built environment attributes as a result of residential relocation (either prospectively or retrospectively); (2) included a measure of physical activity, walking, cycling or travel modal change as an outcome; (3) was quantitative and (4) included an English abstract or summary. Results A total of 23 studies was included in the review. Among the eight retrospective longitudinal studies, there was good evidence for the relationship between relocation and walking (consistency score (CS)&gt;90%). For the 15 prospective longitudinal studies, the evidence for the effects of environmental change/relocation on physical activity or walking was weak to moderate (CS mostly &lt;45%), even weaker for effects on other outcomes, including physical activity, cycling, public transport use and driving. Results from risk of bias analyses support the robustness of the findings. Conclusion The results are encouraging for the retrospective longitudinal relocation studies, but weaker evidence exists for the methodologically stronger prospective longitudinal relocation studies. The evidence base is currently limited, and continued longitudinal research should extend the plethora of cross-sectional studies to build higher-quality evidence.
Abstract 13168: High Morbidities in Hospitalized Adolescents With Both Single and Biventricle Congenital Heart Disease
Authors: Aparna Kulkarni, Patricia Zybert, Shelby Kutty, Richard Neugebauer, Brett Anderson
Journal: Circulation (2016)

Introduction: Quality of life in adolescents with single ventricle (SV) is known to be significantly impaired. In this study, we sought to quantify inpatient morbidities for single ventricle (SV) versus biventricle (BV) adolescents using data from the Pediatric Health Information System (PHIS). Methods: The PHIS database was queried for all admissions in adolescents aged 12-18 years (1/1/2004–12/31/2013) coded for CHD. Patients were categorized as SV or BV based on their primary and secondary ICD-9 diagnostic and/or procedure codes. Patient characteristics, diagnoses, procedures, vital status and standardized costs were examined. Results: 4,267 adolescents were admitted to 42 children’s hospitals over 10 years, accounting for 8,512 hospitalizations. Among patients, 24.6% were SV, 64.1% BV and 11.3% unclassifiable. Among hospitalizations, 29.5% were SV patients, 56.1% were BV patients, and 14.4% were unclassifiable. SV patients were more likely to have multiple hospitalizations than BV patients [51.0% vs 37.9%, p ≤ 0.001]. Mean age for adolescent admissions were similar for SV and BV hospitalizations [mean (SD) 15.0 (1.9) years vs 14.8 (1.9)]. Median lengths of stays (LOS) for BV hospitalizations were 2 days, [IQR 1-5] and 2 days [IQR 1-4] for SV hospitalizations, with a higher proportion of patients with LOS&gt;2 days in the BV group [46.9%] than SV group [38.5%, p&lt;0.001]. BV hospitalizations were more likely to entail ICU stays [36.6% vs 26.1%, p ≤0.001], to require mechanical ventilation [20.2% vs 8.8%, p ≤0.001] and had higher median total costs [$14,500, IQR $4140-$40,900 vs $8250, IQR $2,440-$23,300, p≤0.001]. There were no differences between SV and BV hospitalizations in use of one or more electrophysiological studies [16.4% vs 18.2%, p=0.062] or reporting of one or more tachyarrhythmias [7.5% vs 7.0%, p=0.505]. Procedure codes for pacemaker/intracardiac defibrillator were higher among SV hospitalizations [6.1% vs 4.1%, p≤0.001], as was an associated diagnosis of heart transplantation [2.3% vs 0.5%, p≤0.001]. Conclusions: Adolescents with CHD requiring hospitalizations are resource intensive irrespective of their CHD classification.
Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: MONALEESA-3
Authors: Dennis J. Slamon, Patrick Neven, Stephen Chia, Peter A. Fasching, Michelino De Laurentiis, Seock-Ah Im, Katarina Petrakova, Giulia Val Bianchi, Francisco J. Esteva, Miguel Martín, Arnd Nusch, Gabe S. Sonke, Luis De la Cruz-Merino, J. Thaddeus Beck, Xavier Pivot, Gena Vidam, Yingbo Wang, Karen Rodriguez Lorenc, Michelle Miller, Tetiana Taran, Guy Jerusalem
Journal: Journal of Clinical Oncology (2018)

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
Locally Advanced Rectal Cancer
Authors: Alessandro Fichera
Journal: JAMA Surgery (2018)

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Palliative radiotherapy (RT) to the breast using a novel hypofractionated radiotherapy regime: Results of the HYPORT phase I/II study (CTRI/2015/12/006407).
Authors: Sanjoy Chatterjee, Rosina Ahmed, Santam Chakraborty, Soumitra Datta, Sandip Ganguly, Joydeep Ghosh, Jayanta Das, Mandira Saha, Avipsa Das, Indu Arun, Soumendranath Ray
Journal: Journal of Clinical Oncology (2018)

e12613 Background: Trials of breast surgery in metastatic breast cancer (MBC) have failed to improve outcomes. RT to the breast could provide local palliation with a hypothetical benefit to progression free survival. Prospective studies have not comprehensively addressed this issue. Hypofractionated 40 Gy 15 fraction (EQD2 45.4 Gy3) dose of adjuvant RT is non-inferior to protracted regimes. We report the safety & efficacy of a shortened, more convenient, biologically equivalent (EQD2 45.5 Gy3) 10 fraction (2 week) hypofractionated RT to breast. Methods: Thirty MBC patients with symptomatic breast lesions provided consent for palliative breast and SCF RT (35 Gy 10 fractions, 2 weeks) with in vivo dosimetry for RT quality assurance. All patients underwent a regional FDG PETCT and breast biopsies pre and within 6 hours post RT for translational studies. Primary objective was to assess the toxicity of the novel regime, with secondary objectives exploring the symptomatic, quality of life (FACT-B), psychological distress (PHQ4) and metabolic improvement post RT ( at 1 & 3 months). Results: Median age was 54 years, one of 30 patients withdrew consent, with 79.3% undergoing biobanking biopsies and all patients completed quality assured RT. Pain and ulceration at baseline was reported by 40% and 60% patients respectively. Grade 2 acute dermatitis was found in 6% with no grade 3/4 toxicities. At 1 month pain score reduced by ≥ 2 points in 92% patients. Ulceration healed in 42% patients at 3 months. A clinically meaningful improvement in the FACT-TOI score at treatment completion (change ≥ 5) was seen in 9 of the 28 respondents (32%). Among the 11 patients with moderate-severe psychological distress at presentation, an improvement in the PHQ4 was observed in 55% post RT. None of the patients had local metabolic progression at 3 months. The estimated 1 year survival was 55% (95% CI:36% - 84%). Conclusions: This novel RT regime is safe and effective in palliating local symptoms. None of the patients had metabolic progression whilst a substantial clinical improvement was noted in quality of life and psychological distress. A follow up study is exploring a 5 fraction regime in a similar cohort. Clinical trial information: CTRI/2015/12/006407.
Persistence of circulating tumor cells in high risk early breast cancer patients five years after adjuvant chemotherapy and late recurrence: Results from the adjuvant SUCCESS A trial.
Authors: Wolfgang Janni, Brigitte Kathrin Rack, Peter A. Fasching, Lothar Haeberle, Hans Tesch, Ralf Lorenz, Fabienne Schochter, Marie Tzschaschel, Amelie De Gregorio, Tanja N. Fehm, Volkmar Müller, Andreas Schneeweiss, Werner Lichtenegger, Matthias W. Beckmann, Christoph Scholz, Klaus Pantel, Thomas W. P. Friedl
Journal: Journal of Clinical Oncology (2018)

515 Background: Recent data suggest that circulating tumor cells (CTCs) are of prognostic relevance in early as well as metastatic breast cancer. However, there is a lack of data on the prognostic impact of CTCs to predict late recurrences during long-term follow-up, especially in patients with hormone receptor positive tumors. Methods: The SUCCESS A trial is a randomized Phase III study, in which patients with high-risk early breast cancer were first randomized to 3 cycles of epirubicin-fluorouracil-cyclophosphamide followed by either 3 cycles of docetaxel or 3 cycles of gemcitabine-docetaxel, followed by a second randomization to 2 vs. 5 years of zoledronate treatment. Presence of CTCs 5 years after chemotherapy was assessed using the CellSearch System (Janssen Diagnostics, LLC), and CTC positivity was defined as ≥ 1 CTC in 7.5 ml whole blood. Recurrence-free survival (RFS) was analyzed by univariable and multivariable Cox regressions. Survival time was measured as of the date of blood sampling for CTC assessment. Results: Follow-up data for patients with known CTC status 5 years after chemotherapy were available for 206 (5.5%) of 3754 randomized patients (median time interval of CTC assessment 62.4 months since randomization). The CTC status was positive in 16 (7.8%) patients (range 1 – 53 CTCs). Median follow-up time after CTC assessment was 360 days (range 1 – 911 days). Overall, 13 late recurrences were observed; 11 in 153 hormone receptor positive patients and 2 in 53 hormone receptor negative patients. In hormone receptor positive patients, CTC status was a significant prognostic factor for RFS in univariable (hazard ratio [HR] 5.14, 95% confidence interval [CI] 1.47 – 18.03, p = 0.011) and in multivariable cox regressions adjusted for age, tumor stage, nodal stage, grade, histological type, and HER2 status (HR 5.95, 95%CI 1.14 – 31.16, p = 0.035). Conclusions: The presence of CTCs 5 years after chemotherapy was associated with decreased RFS, suggesting that persisting CTCs during long term follow-up independently predict late recurrences in hormone receptor positive patients. Extended follow-up data will be presented at the meeting. Clinical trial information: NCT02181101.
Palbociclib after CDK and endocrine therapy (PACE): A randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+/HER2- metastatic breast cancer.
Authors: Erica L. Mayer, Seth Andrew Wander, Meredith M. Regan, Angela DeMichele, Andres Forero-Torres, Mothaffar F. Rimawi, Cynthia X. Ma, Massimo Cristofanilli, Carey K. Anders, Cynthia Huang Bartlett, Eric P. Winer, Harold J. Burstein
Journal: Journal of Clinical Oncology (2018)

TPS1104 Background: CDK4/6 inhibition (CDK4/6i) has a well-established role in the management of hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC). The addition of a CDK4/6i to endocrine therapy (ET) in HR+/HER2- MBC leads to prolongation of progression-free survival in the first-line and pre-treated settings. Mechanisms of resistance to CDK4/6i are not well described, and it is not known if continuation of CDK4/6i with subsequent lines of ET improves outcomes over ET alone. Further, preclinical data suggest combination therapy with ET, CDK4/6i, and anti-PDL1 may provide synergistic efficacy. The PACE trial was designed to determine optimal subsequent line of therapy in patients (pts) with HR+ /HER2- MBC that has progressed despite prior CDK4/6 inhibition and endocrine therapy. Methods: PACE is a multicenter phase II trial randomizing pts 1:2:1 to Arm A: fulvestrant alone (with option for palbociclib monotherapy crossover at time of progression); Arm B: fulvestrant and palbociclib; or Arm C: fulvestrant, palbociclib, and avelumab. The primary objective is to evaluate progression-free survival (PFS) with the combination of fulvestrant and palbociclib vs. fulvestrant alone; secondary objectives include overall response (OR) and PFS comparisons for other arms; assessment of outcomes in predefined molecular subgroups including ESR mutation, PI3K mutation, loss of Rb; safety and tolerability; and comparing OR by RECIST vs irRECIST. Extensive analysis of tissue, ctDNA, and CTC for markers of response and resistance to therapy is planned. Eligible pts have HR+/HER2- MBC, with prior response to and subsequent progression on CDK4/6i and ET, defined as at least 6 months of prior treatment, with confirmed subsequent progression, and no more than one prior P dose reduction for toxicity. Pts may have had 1-2 prior ET, and 0-1 prior lines of chemotherapy. A sample size of 220 patients is planned. NCT03147287.