tbuckley/cabot-search huggingface dataset:
A prospective study on the effect of endoxifen concentration and CYP2D6 phenotypes on clinical outcome in early stage breast cancer patients receiving adjuvant tamoxifen.
Authors: Anabel Beatriz Sanchez-Spitman, Vincent O. Dezentjé, Jesse J Swen, Dirk Jan A.R. Moes, Erdogan Batman, Carolien H. Smorenburg, Lynn Jongen, Maartje Los, Patrick Neven, Hans Gelderblom, Henk-jan Guchelaar
Journal: Journal of Clinical Oncology (2018)

523 Background: It has been postulated that endoxifen levels are better predictors of tamoxifen efficacy than CYP2D6 phenotype. Although in a retrospective study an endoxifen threshold of 5.9 ng/ml for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM study (NTR1509) is to associate endoxifen levels and, CYP2D6 phenotypes with clinical outcome in early stage breast cancer patients receiving tamoxifen. Methods: Breast cancer patients who were receiving adjuvant tamoxifen were included. Blood samples were used for CYP2D6 genotyping and endoxifen levels by Amplichip and high-performance liquid chromatography-tandem mass spectrometry assay, respectively. Endoxifen levels and CYP2D6 phenotypes were associated with relapse-free survival (RFS) by using Cox-regression analysis. Patients who changed to an aromatase inhibitor, were censored at the time of switch. Results: A total of 667 pre and post-menopausal patients were enrolled. No association was found between endoxifen serum levels used as a continuous variable and RFS (Adjusted Harzard Ratio (HR): 0.991, 95 % CI: 0.946-1.038, p-value: 0.691). Categorizing endoxifen levels in quartiles, or using 5.9 ng/ml as threshold did not alter these results. In addition, no association was observed between CYP2D6 phenotypes and RFS(Adjusted HR: 0.929, 95 % CI 0.525-1.642, p-value 0.799). Conclusions: This first prospective clinical study shows no association between endoxifen levels and CYP2D6 phenotypes with RFS in early breast cancer patients using adjuvant tamoxifen. These results do not support the use of therapeutic drug monitoring based on endoxifen levels or CYP2D6 genotyping. Associations between Endoxifen levels and CYP2D6 phenotypes with RFS. Clinical trial information: NTR1509. Multivariable analysis HR 95 % CI p Endoxifen 0.991 0.946-1038 0.691 Threshold (ng/ml): < 5.9 1.000 Reference > 5.9 1.538 0.719-3.290 0.267 Quartiles (ng/ml): Q1 ( < 6.6) 1.000 Reference Q2 (6,6-10,3) 1.986 0.909-4.340 0.085 Q3 (10,3-14,1) 1.331 0.580-3.059 0.500 Q4 ( > 14.1) 0.950 0.399-2.262 0.907 CYP2D6 phenotypes UM/EM 1.00 Reference hetEM/IM/PM 0.929 0.525-1.642 0.799
A retrospective study of raltitrexed combined with S-1 as salvage treatment for patients with metastatic colorectal cancer after failure of standard chemotherapy.
Authors: Weijian Guo, Zhenhua Wu, Mingzhu Huang, Xiaowei Zhang
Journal: Journal of Clinical Oncology (2017)

e15066 Background: The FOLFOX regimen consisting of fluorouracil (5-FU) and oxaliplatin, and the FOLFIRI regimen consisting of 5-FU and irinotecan serve as either first- or second-line treatment for metastatic colorectal cancer (mCRC), and there is no third-line chemotherapy regimen after failure of 5-FU, oxaliplatin, and irinotecan. Studies have shown that raltitrexed or S-1 has no complete cross-resistance with 5-FU and may be used for mCRC after failure of 5-FU. In the present study, we retrospectively analyzed the efficacy and safety of raltitrexed combined with S-1 in the treatment of mCRC after failure of conventional chemotherapy. Methods: Eighteen patients with mCRC treated with raltitrexed combined with S-1 after failure of fluorouracil, oxaliplatin and irinotecan between February 2014 and August 2016 were included in this study. Raltitrexed (3 mg/m 2 ) intravenous infusion was given on the first day, and the administration of S-1 (daily dose according to body surface area (BSA): 100 mg/day when BSA ≥1.25 m 2 to &lt; 1.5 m 2 ; 120 mg/day when BSA≥1.5 m 2 ) continued for 2 weeks, and stopped for one week. The regimen was repeated every 3 weeks. Tumor response was evaluated according to RECIST 1.1 criteria. Toxicity was graded according to NCI-CTC 4.0 version. Results: Among 18 patients, 2 had PR, 8 had SD, and 8 had PD. The ORR (objective response rate) was 11.1%, and the DCR (disease control rate) was 55.6%. The median PFS (progression free survival) and OS (overall survival) were 2.5 months and 7.0 months respectively. Adverse reactions included fatigue, abnormal liver enzymes, neutropenia, stomatitis, pyrexia, arrhythmia, hypertension, diarrhea, nausea and most of these were grade 1-2. Only one patient had grade 3 neutropenia and grade 3 diarrhea. Conclusions: The combination of raltitrexed and S-1, both of which targeting TS, preliminarily showed promising effects for metastatic colorectal cancer after failure of standard chemotherapyand may be used as third-line treatment regimen.
Analysis of protein-altering variants in telomerase genes and their association with MUC5B common variant status in patients with idiopathic pulmonary fibrosis: a candidate gene sequencing study
Authors: Amy Dressen, Alexander R Abbas, Christopher Cabanski, Janina Reeder, Thirumalai R Ramalingam, Margaret Neighbors, Tushar R Bhangale, Matthew J Brauer, Julie Hunkapiller, Jens Reeder, Kiran Mukhyala, Karen Cuenco, Jennifer Tom, Amy Cowgill, Jan Vogel, William F Forrest, Harold R Collard, Paul J Wolters, Jonathan A Kropski, Lisa H Lancaster, Timothy S Blackwell, Joseph R Arron, Brian L Yaspan
Journal: The Lancet Respiratory Medicine (2018)
Overcoming suvivorship care planning implementation challenges through decentralization.
Authors: Carol A. Rosenberg, Thomas A. Hensing, Bruce Brockstein, Linda Green, Anisha Patel, Nadia Still, Debra Wujcik, Laura DiGiovanni, Carrie Tilley, Carrie Tompkins Stricker
Journal: Journal of Clinical Oncology (2018)

38 Background: To meet Commission on Cancer accreditation requirements, cancer programs must implement processes to monitor the dissemination of survivorship care plans (SCP) for patients with Stages I-III cancers who were treated with curative intent and completed active therapy. Challenges of SCP delivery across disease sites include lack of designated/trained staff, time burden, knowledge of current evidence-based guidelines, and sustainability. We describe the challenges NorthShore University HealthSystem Kellogg Cancer Center (NKCC) and their Living in the Future (LIFE) Cancer Survivorship Program faced in meeting this standard and how evolving the SCP delivery process has resulted in a sustainable model. Methods: LIFE implemented a technology-based SCP tool using a centralized consultative model led by a nurse practitioner (NP) with specialized survivorship training. Physicians referred eligible patients to the survivorship clinic for an education visit where they received a SCP from the NP. Since the centralized model was dependent on one person for delivery, a more sustainable model was needed. NKCC transitioned to a decentralized process, moving SCP creation and delivery responsibility to all oncology care providers (OCPs). Although not all OCPs had specialized survivorship training, care quality was supported by automated SCP creation based on evidence-based care recommendations embedded in the technology. Results: To date, 143 evidence-based SCPs have been delivered since tool implementation in April 2017. During the centralized model (April 25– June 30) 67 SCPs were created by the lead LIFE NP; 76 were created during the decentralized process while the lead NP was on leave (July 3 – Oct 1). By using a technology-based SCP, OCPs incorporated SCP delivery into their workflow and no longer had to refer patients to a separate clinic. Conclusions: This project demonstrates the feasibility of a sustainable, decentralized process using a technology-based SCP as an option for augmenting centralized SCP delivery. A comparable number of patients received a SCP during both processes with an equivalent number of SCPs being delivered via the decentralized model by OCPs supported by evidence-based technology.
Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
Authors: Rikke B. Holmgaard, David A. Schaer, Yanxia Li, Stephen P. Castaneda, Mary Y. Murphy, Xiaohong Xu, Ivan Inigo, Julie Dobkin, Jason R. Manro, Philip W. Iversen, David Surguladze, Gerald E. Hall, Ruslan D. Novosiadly, Karim A. Benhadji, Gregory D. Plowman, Michael Kalos, Kyla E. Driscoll
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. <h3>Results</h3> In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. <h3>Conclusions</h3> Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.
HER2-enriched subtype and ERBB2 mRNA as predictors of pathological complete response following trastuzumab and lapatinib without chemotherapy in early-stage HER2-positive breast cancer: A combined analysis of TBCRC006/023 and PAMELA trials.
Authors: Aleix Prat, Carmine De Angelis, TomÃ¡s Pascual, Carolina Gutierrez, Antonio Llombart-Cussac, Tao Wang, Javier Cortes, Brent Neil Rexer, Jamunarani Veeraraghavan, Andres Forero-Torres, Antonio C. Wolff, Serafin Morales, Ian E. Krop, Anne Clarisse Pavlick, Begona Bermejo, Susan G. Hilsenbeck, Mafalda Oliveira, Rachel Schiff, C. Kent Osborne, Mothaffar F. Rimawi
Journal: Journal of Clinical Oncology (2018)

509 Background: HER2-Enriched (HER2-E) intrinsic subtype within HER2-positive breast cancer is characterized by high expression of ERBB2 and related genes. Here we retrospectively evaluated the value of the HER2-E subtype and ERBB2 mRNA expression alone to predict pathological complete response (pCR) in tumor samples from PAMELA and TBCRC 006/023 trials. Methods: All patients had HER2-positive early breast cancer and were treated with neoadjuvant lapatinib and trastuzumab. Patients with hormone receptor-positive tumors were also treated with letrozole or tamoxifen. In PAMELA (NCT01973660), 151 patients were treated for 18 weeks. TBCRC 006 (NCT00548184) treated 66 patients for 12 weeks and TBCRC 023 (NCT00999804) randomized 97 patients to 12 vs. 24 weeks of treatment. pCR was defined as no residual invasive carcinoma in the breast. Baseline intrinsic subtypes and ERBB2 mRNA expression were determined using the nCounter-based PAM50 predictor. ERBB2 expression was dichotomized as low (lowest 1/3) vs high (highest 1/3) as used in PAMELA. Results: Two-hundred and sixty-five tumors (84.4%) were profiled; 65.7% were classified as HER2-E. pCR was more likely to occur if HER2-E (35.1% vs. 9.9%; odds ratio [OR] = 4.92; 95% CI 2.31-10.50; P < 0.001) or ERBB2-high (36.1% vs. 8.2%; OR = 6.51; 95% CI 2.96-14.31; P < 0.001). HER2-E subtype represented 84.0% and 46.0% of ERBB2-high and ERBB2-low groups, respectively. Rates of pCR in HER2-E/ERBB2-high, nonHER2-E/ERBB2-high, HER2-E/ERBB2-low, and nonHER2-E/ERBB2-low groups were 45.0%, 16.1%, 10.8%, and 6.7%, respectively. Finally, the HER2-E/ERBB2-high group independently predicted pCR (adjusted OR = 6.0; 95% CI [3.1-11.8]; P< 0.001). Conclusions: Combining HER2-E subtype and ERBB2 mRNA levels better identifies anti-HER2 sensitivity than each variable alone in HER2-positive breast cancer. The combined biomarker identified nearly 50% of patients with pCR to an all-biologic regimen, and if validated may provide a means for rational therapeutic de-escalation.
Abstract 17294: Serum B-type Natriuretic Peptide at the Time of Ventricular Tachycardia Ablation Correlates With Myocardial Substrate
Authors: Ricardo M Lugo, Sushan Yang, Asad Al Aboud, Marcia Blair, Kelsey Tomasek, Yan Ru Su, Deepak Gupta, Benjamin Shoemaker, Quinn Wells, Arvindh Kanagasundram
Journal: Circulation (2016)

Introduction:  Elevated serum B-type Natriuretic Peptide (BNP) has been shown to independently predict an increased risk of ventricular arrhythmias.   Hypothesis:  Serum BNP levels positively correlate with the burden of left ventricular (LV) myocardial scar.   Methods:  We studied 36 consecutive patients (mean age 67.8 years, 94% male, 72% ischemic etiology) enrolled in the Vanderbilt Ventricular Tachycardia Ablation Registry who underwent catheter ablation for substrate-mediated monomorphic ventricular tachycardia between 2014-2016. Serum BNP was measured from central venous blood collected at the time of venous access prior to starting the ablation procedure. LV endocardial scar area (cm 2 ) was quantified from CARTO3 electroanatomic mapping, with scar defined by bipolar electrogram amplitude    Results:  Larger scar area was significantly associated with higher BNP levels (Pearson’s rho = 0.53, p = 0.0009, Figure 1). The association between scar area and BNP levels persisted even after accounting for the LV volume (r = 0.356, p = 0.042). In a multi-variable adjusted linear regression analysis including age and LV ejection fraction (LVEF), each 1 cm 2  increase in scar area was associated with a 5.0 pg/mL higher BNP level (95% CI 0.2 - 9.8, p = 0.043). This relationship was similar when using LV volume in place of LVEF (p = 0.047).   Conclusions:  Larger LV scar burden is one pathophysiologic mechanism by which serum BNP levels may be a biomarker for the prediction of a patient’s individual risk for ventricular arrhythmias.
Treatment and outcomes in older women with DCIS: SEER-Medicare 2007-2013.
Authors: Mary Chen Schroeder, Chen Huang, Karen Marie Winkfield, Akiko Chiba, Lacey R. McNally, Alexandra Thomas
Journal: Journal of Clinical Oncology (2018)

547 Background: Ductal carcinoma in situ (DCIS) is a low-risk precursor lesion for which hormonal therapy (HT) has been shown in clinical trials to lower risk of subsequent (subs) breast cancer (bc) but not improve overall survival (OS). We report population-based uptake of HT and outcomes by type of local therapy. Methods: SEER-Medicare data identified women (wm) with no comorbidity, ages 66+ and diagnosed 2007-2013 with DCIS as first cancer. Wm were required to have Medicare Parts A, B & D at diagnosis. Treatments were identified with Medicare claims (2007-2014): surgery within 6 months and HT within one year of diagnosis. Outcome and survival analyses included 2007-2009 diagnoses, for adequate follow up. Subs breast events were identified: any bc and ipsilateral invasive bc (ips ibc). Local therapy included NONE, lumpectomy (BCS), BCS with radiation (w/XRT), and mastectomy (MAST). Results: 4,098 wm with DCIS were studied. 40.7% of wm received HT: 26.7% Tamoxifen, 14.0% an aromatase inhibitor. HT use varied by local therapy [BCS (32.8%), BCS w/XRT (52.0%), MAST (28.0%), NONE (19.6%), p < 0.01] but not race [white (40.4%), black (46.3%), other (38.7%), p = 0.13]. More wm ages 66-74 received HT than wm aged 75+ (45.9% v 32.7%, p < 0.01). Outcomes for the full cohort are shown (Table). For wm ages 66-74 outcomes did not differ between those having NONE v any local therapy [5yr OS (95.7% v 96.9%, p = 0.71), subs bc (0% v 4.2%, p = 0.31), subs ips ibc (0% v 1.0%, p = 0.64)]. On multivariate Cox model of wm 66-74, HT was associated with better OS (HR = 0.60, CI: 0.40-0.9992, p = 0.0497) but not marital status or age (66-69 v 70-74, HR = 1.56, p = 0.10); blacks had worse OS than whites (HR = 2.45, p = 0.01). Conclusions: In this large population-based cohort of older wm with DCIS, about half received HT. Wm who received HT had fewer subs bc and superior survival. OS for wm who elected NONE was inferior to those undergoing local therapy, though this was not significant for wm ages 66-74. These findings suggest opportunities remain to improve outcomes for wm with DCIS. NONE (N = 44) BCS (N = 408) BCS w/XRT (N = 834) MAST (N = 393) p* No HT HT No HT HT No HT HT No HT HT Subs bc (%) 2.9 0 11.2 5.3 3.8 2.4 7.6 0.9 < 0.01 Subs ips ibc (%) 2.9 0 6.1 3.1 0.7 0.2 0.4 0 0.02 5yr OS (%) 80.0 66.7 89.2 92.4 94.7 95.9 90.2 92.3 0.03 * No HT v HT
Spatial Organisation of Lactotroph Cells in Pituitary Tissue Facilitates Co-Ordination of Prolactin Gene Transcription Dynamics
Authors: K Featherstone, K Hey, H Momiji, A V McNamara, A L Patist, D Spiller, H C Christian, A S McNeilly, J Mullins, B Finkenstadt, D Rand, M R White, Davis
Journal: Endocrine Reviews (2014)
Abstract 20786: Progesterone Metabolites Alter Activation Gating of the Human Ether-a-go-go-Related Gene (hERG)-Related Current
Authors: Christian Egly, Tyler Shugg, Chris W Stamatkin, Avinash S Patil, James E Tisdale, Brian R Overholser
Journal: Circulation (2016)

Introduction:  Progesterone (P4) at high concentrations, such as those achieved during pregnancy, may decrease the function of the voltage-gated potassium channel encoded by the human ether-a-go-go-related gene (hERG). Reductions in hERG-related current have been linked to maternal and fetal QT interval prolongation, a risk factor for arrhythmias and miscarriage. Cytochrome P450 (CYP) 3A activity is enhanced during pregnancy, is present in the fetal liver, and forms the 16α-P4 and 6β-P4 metabolites. Our objective was to assess the ability of P4 and its metabolites, formed via CYP3A isoenzymes, to alter hERG-related current.   Methods:  Whole-cell, voltage-clamp experiments were performed on HEK293 cells stably expressing hERG. Acute effects were assessed by applying 10 nM, 100 nM and 1 μM of P4, 16α-P4, 6β-P4, or dimethylsulfoxide (DMSO; control) in pipette solution. Long-term effects were assessed by treating cells with P4, 16α-P4, 6β-P4, or DMSO for 24 hours. Activation gating was assessed by fitting a Boltzmann function to normalized currents.   Results:  Acute application of P4 or metabolites (n=9 per group) did not reduce hERG-related current or alter activation gating (p>0.05). Long-term P4 exposure significantly reduced hERG-related current at -100 mV (maximal inward current) from a mean ± SD of -45.4 ± 14.7 pA/pF (n=19) to -30.6 ± 16.9 (n=17; p=0.03). P4 metabolites did not decrease hERG-related current following 24-hour exposure. However, a depolarizing shift in activation gating was observed (Figure) with mean ± SD voltage at half maximal activation (V 50 ) with 16α-P4 of 3.9 ± 0.29 mV (n=18) and 6β-P4 of 1.3 ± 0.99 (n=21) versus control of -4.8 ± 1.1 (n=19) and P4   of -3.2 ± 0.71 (n=17); p   Conclusions:  P4 decreases hERG-related current at high concentrations during prolonged exposure. The P4 metabolites formed via CYP3A cause an inhibitory shift of hERG activation gating. These effects could contribute to the QT interval variability during pregnancy.
A phase I study of DKN-01 (D), an anti-DKK1 monoclonal antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) for first-line therapy with advanced biliary tract cancer (BTC).
Authors: Jennifer Rachel Eads, Stacey Stein, Anthony B. El-Khoueiry, Gulam Abbas Manji, Thomas Adam Abrams, Alok A. Khorana, Rebecca A. Miksad, Devalingam Mahalingam, Cynthia A. Sirard, Andrew X. Zhu, Lipika Goyal
Journal: Journal of Clinical Oncology (2017)

4075 Background: DKK1 is a secreted modulator of Wnt signaling often expressed in tumors, including BTC. DKK1 expression in BTC is associated with advanced stage and shorter survival. Depletion of DKK1 has efficacy in BTC xenograft models, inhibits cell invasion, and decreases MMP9 and VEGF-C expression, known promoters of metastasis and angiogenesis. D is a humanized monoclonal antibody against DKK1. This study evaluated the safety and efficacy of D in combination with GC in pts with advanced BTC. Methods: In Part A, pts received D at either 150 or 300 mg (and 300 mg D in Part B expansion) with 1000 mg/m2 G and 25 mg/m2 C on days 1 and 8 of each 21-day cycle. Response assessed every 2 cycles using RECISTv1.1. Results: 27 pts were enrolled; 4 dosed at 150 mg and 23 dosed at 300 mg. Median age: 65; Female: 74%; White: 85%. Gallbladder cancer 37%, intrahepatic cholangiocarcinoma 59%. 3 pts had prior G: 2 pts with adjuvant G; 1 pt with 2 prior regimens. Median number of cycles with D: 8 (range 1, 17). Median duration on study 6.8 mos; 8 pts still on therapy. No dose limiting toxicities or D-related serious adverse events have been observed. 24 pts (89%) had grade 3/4 treatment emergent adverse events (TEAEs); events in ≥ 3 pts include: neutropenia (n = 19), leukopenia (n = 9), thrombocytopenia (n = 9), hyperbilirubinemia (n = 6), anemia (n = 5), AST/ALT elevation (n = 4), and ALP elevation, bacteremia, hypertension, and hyponatremia (n = 3 each). The MTD of D + GC was 300 mg. At the MTD; 7 pts had a confirmed partial response (PR), 14 pts had stable disease &gt; 6 weeks, and 1 pt had progressive disease. Both overall and MTD median PFS were 9.4 mos (95% CI 4.6, NE); median overall survival and duration of response were not reached. Conclusions: The addition of D (300 mg) to GC demonstrated a preliminary PFS of 9.4 mos and disease control rate of 96% with a 32% PR rate in pts with BTC. D + GC is well tolerated with no new emerging safety trends. Clinical trial information: NCT02375880.