tbuckley/cabot-search huggingface dataset:
Dynamic monitoring and predictive value of circulating tumor cells in EGFR mutant advanced NSCLC patients treated with first-line EGFR-TKIs.
Authors: ChunXia Su, Tao Jiang, Jing Zhao, Chao Zhao, Xuefei Li, Jiqiao Shen, Caicun Zhou
Journal: Journal of Clinical Oncology (2018)

e21045 Background: There is a need to develop a convenient alternative to CT scanning to monitor EGFR tyrosine kinase inhibitors (TKIs) treatment in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Here, we proposed a non-invasive, folate receptor (FR)-based circulating tumor cell (CTC) assay counts to predict and dynamically monitor the therapeutic response to first-line EGFR-TKIs. Methods: Eligible patients were enrolled and three milliliter (mL) of blood were obtained prior to initial treatment, after one month, and follow-up every two months hereafter. CTCs were isolated based on negative enrichment by immunomagnetic beads and detected by a ligand-targeted polymerase chain reaction (LT-PCR) method. Results: 232 patients with EGFR mutations treated with first-line EGFR-TKIs were included. The objective response rate (ORR) of patients with low baseline CTC level ( < 20.5 FU/3 mL) were significantly higher than those with high baseline CTC level (≥20.5 FU/3 mL) (55.8% vs 38.5%, P = 0.030). The disease control rate (DCR) was comparable between two groups (P = 0.310). Moreover, patients with low baseline CTC level had a significantly longer progression-free survival (PFS) than those with high baseline CTC level (HR = 0.50, P < 0.001). This difference remained significant after multivariate analysis (P = 0.003). At baseline, CTC counts were similar among patients with partial response (PR), stable disease (SD) and progression disease (PD). At the first evaluation, significant decrease in CTC value was associated with PR (P = 0.020), but not with SD (P = 0.569). For patients with PR at first evaluation, change in CTC value was correlated with both PR (P = 0.042) and SD/PD (P = 0.032) groups at the second evaluation. Conclusions: The current evidences suggest that FR-positive CTCs can be used for both the dynamic monitoring and prediction of outcome in EGFR-mutant NSCLC patients treated with EGFR-TKIs, which could serve as an alternative or supplement to CT scanning.
PD.2.01 Characterization of T790M According to Primary EGFR Mutation in Post EGFR-TKI Progression NSCLC in Brazil
Authors: C. Ferreira, M. Zalis, M. Custodio, G. Montenegro, M. Zukin, C. Mathias, C. Haddad, E. Mascarenhas, L. Araujo, T. Montella, B. Da Silva, C. Bustamante, A. Muras, M. Reis
Journal: Journal of Thoracic Oncology (2018)
A phase III, double-blind, randomized study of pamiparib versus placebo as maintenance therapy in patients with inoperable, locally advanced, or metastatic gastric cancer (GC) that responded to platinum-based first-line chemotherapy.
Authors: Fortunato Ciardiello, Yung-Jue Bang, Johanna C. Bendell, Andres Cervantes, Rainer Karl Brachmann, Yuting Zhang, Mitch Raponi, Heinrich Farin, Shen Lin
Journal: Journal of Clinical Oncology (2019)

TPS173 Background: Gastric cancer is the fifth most common cancer, and is the third leading cause of cancer deaths worldwide. In patients with locally advanced or metastatic GC, fluoropyrimidine- and platinum-based combination chemotherapy is first-line standard of care. Despite refinement in chemotherapy regimens, outcomes are poor and survival after first-line treatment remains low. A subset of GCs exhibit platinum sensitivity and genomic instability that is characteristic of homologous recombination deficiency (HRD). Poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) are involved in DNA damage repair, and their inhibition is cytotoxic for cells with HRD. Pamiparib is a selective PARP1/2 inhibitor that crosses the blood-brain barrier, has shown potent DNA–PARP trapping, and has demonstrated antitumor activity in preclinical models. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg oral twice daily (BID) was established as the recommended dose. Methods: This ongoing, global, double-blind, placebo-controlled, randomized, multicenter phase III study (NCT03427814) is designed to compare the efficacy, safety, and tolerability of pamiparib vs placebo as maintenance therapy in ~540 patients with advanced GC who have responded to first-line, platinum-based chemotherapy. Patients who are ≤ 8 weeks after their last dose of first-line platinum based chemotherapy will be randomized 1:1 to receive either pamiparib 60 mg BID or placebo in 28-day cycles. Patient randomization will be stratified by genomic loss of heterozygosity status (ie, high vs low), region, and ECOG status. Radiologic assessments will be centrally evaluated per RECIST every 8 weeks after first dose. The primary endpoint is progression-free survival; key secondary endpoints include safety/tolerability, overall survival, objective response rates, time and duration of response, and time to second subsequent treatment. Correlative biomarker analyses in tumor tissues and blood will be performed. Clinical trial information: NCT03427814.
Phase II study to evaluate the efficacy and safety of rilotumumab and bevacizumab (BEV) in subjects with recurrent malignant glioma (MG).
Authors: Mary Lou Affronti, Annick Desjardins, Henry S. Friedman, Katherine B. Peters, James E Herndon II, Frances McSherry, Eric S Lipp, Alise Brickhouse, Woody C Massey, Elizabeth Miller, Sprague Cheshire, Christina Cone, Katherine H Kalinowski, Jung-Young Kim, Harry H Lay, Victoria Poillucci, Cindy Southerland, Jill Tetterton, James J Vredenburgh
Journal: Journal of Clinical Oncology (2012)

2074^ Background: Prognosis of recurrent MG remains poor with a median survival of 3-9 months. Few evidence based treatments are available and response rates have been &lt; 20% with 6 month progression–free survival (PFS) of &lt; 9-16%. Poor prognosis is linked to the MG’s ability to induce vascular proliferation and invasion. MG’s have an abundance of neo-vascularization and high levels of vascular endothelial growth factor (VEGF). BEV, an antibody to VEGF, is the most active agent tested for recurrent MG with an overall response rate of 21.2%. Rilotumumab is a human monoclonal antibody that blocks human hepatocyte growth factor (HGF) and its receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity inducing angiogenesis and expression of additional angiogenic autocrine factors such as VEGF. The novel combination of rilotumumab (C-Met inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and tumor proliferation may demonstrate synergistic tumor growth inhibition. Methods: A two-stage design is used to assess radiographic response rate with &gt; 3 responses required for the first stage. Secondary endpoints were PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve MGs received rilotumumab at 20 mg/kg in combination with BEV at 10 mg/kg every two weeks ≥ 28 days after the last surgical procedure. A brain MRI was obtained after each 6-week cycle. Results: 15 of the 19 patients required for the first stage have been accrued. 10(67%) were male and ≥ 50 years. 73% received ≥ 2 prior regimens and 46% had ≥ 2 prior progressions. Best tumor response included 1(7%) complete response, 2 (13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive disease with 20% (3/15) non-evaluable due to early termination secondary to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month PFS of 25.4% (95% CI: 6.4, 50.5) and 6-month OS of 68.3% (95% CI: 34, 87.1). Toxicities are listed below. Maximum average weight increase over all cycles was 6.3 % (SD ± 6.09). Conclusions: Rilotumumab in combination with BEV is an active regimen in MG. Toxicity will need to be closely monitored. [Table: see text]
TCT-95 A simplified formula to calculate fractional flow reserve in sequential lesions circumventing the measurement of coronary wedge pressure during balloon inflation: the APIS-S pilot study
Authors: Carlos Cortes, Ignacio Amat-Santos, Wojtek Wojakowski, Felipe Navarro Del Amo, Karl Mischke, Borja Ibanez, Juan Luis Gutiérrez-Chico
Journal: Journal of the American College of Cardiology (2018)
Utility values among patients (pts) with metastatic renal cell carcinoma (mRCC) receiving first-line treatment with pazopanib (PZ) and sunitinib (SU).
Authors: May Hagiwara, Jinhee Park, Thomas E. Delea
Journal: Journal of Clinical Oncology (2016)

e21068 Background: A large randomized non-inferiority trial (COMPARZ) demonstrated comparable efficacy but better tolerability and health-related quality of life (HRQOL) with PZ vs SU in treatment-naïve pts with mRCC. Preference-based measures of HRQOL (utilities) were not assessed in the trial, however. The objective of this study was to estimate utilities for pts receiving PZ and SU using data on adverse events (AEs) observed in COMPARZ. Methods: Two analyses were conducted. First, a regression model relating AEs to utilities was estimated using data from the VEG105192 trial, a phase 3 randomized controlled trial of PZ vs. placebo in mRCC pts. The dependent variable in this regression was the EQ-5D utility index value. Independent variables were age, sex, performance status, prior treatment, treatment group, and AEs experienced on the day of each assessment. AEs were characterized by (1) grade and (2) whether the AE was observed more frequently in SU vs. PZ pts in COMPARZ. Using the estimated regression model, utilities were estimated for each day of pre-progression follow-up for all pts in COMPARZ based on baseline characteristics and AEs present on each day. Mean utilities during PFS were then calculated for each treatment group using Kaplan-Meier methods. Confidence intervals were obtained by bootstrapping. In a secondary analysis, mean utilities for PZ and SU in COMPARZ were calculated by combining AE data from COMPARZ with estimated utilities for AEs from published studies. Results: With utilities based on the regression model derived from VEG105192, mean (95%CI) utilities during PFS were 0.709 (0.67, 0.75) for PZ and 0.683 (0.64, 0.73) for SU (difference = 0.026 (0.004, 0.050)). With utilities based on published estimates, mean (95%CI) utilities during PFS were 0.739 (0.73, 0.75) for PZ and 0.708 (0.70, 0.72) for SU (difference = 0.030 (0.016, 0.044)). Conclusions: Differences in the AE profiles of PZ and SU may yield differences in mean utility values. These findings, which are consistent with results of analyses of HRQOL in COMPARZ and patient preferences in the PISCES trial, may have important implications for the relative cost-effectiveness of PZ and SU. Clinical trial information: NCT00720941.
CD133-redirected chimeric antigen receptor engineered autologous T-cell treatment in patients with advanced and metastatic malignancies.
Authors: Yao Wang, Meixia Chen, Zhiqiang Wu, Chuan Tong, Jianhua Huang, Haiyan Lv, Hanren Dai, Kaichao Feng, Yelei Guo, Yang Liu, Qingming Yang, WeiDong Han
Journal: Journal of Clinical Oncology (2017)

3042 Background: Expressed by cancer stem cells of various epithelial cell origins, CD133 is an attractive therapeutic target for cancers. Autologous chimeric antigen receptor-modified T cells directed CD133 (CART-133) were firstly tested in this clinical trial. We aimed to determine the safety dosage, toxicity and biological activity of CART-133 in epithelium-derived solid tumors. Methods: The initially enrolled 8 patients with sorafenib-refractory hepatocellular carcinoma (HCC), treated by CART-133 monotherapy, were assigned into 3 dose cohorts (1, 0.5-1.5×10 5 /kg; 2, 5-10×10 5 /kg; 3, 1-2×10 6 /kg). For the additional 16 patients (6 HCCs, 7 pancreatic carcinomas, 2 colorectal carcinomas, and 1 cholangiocarcinoma), all non-HCCs were conditioned by regimen (Nab-pacitaxel/cyclophosphamide or anti-PD1 antibody) before cell infusions. Results: For the initial 8 HCCs, 1 from cohort 2 occurred hemoglobin/platelet decline and direct hyperbilirubinemia (Grade 3), 4 from cohort 2/3 reported delayed low fever, nausea accompanied with elevation of CRP and serum cytokines. The 4-6 week persistence of relatively higher CAR copy numbers and its reverse relationship with the count of CD133 + cells harboring pro-metastatic epithelial progenitor cells in peripheral blood led to the determination of acceptable cell infusion dose from 0.5 to 2×10 6 /kg and reinfusion cycle in 24 patients. Similar toxicities ( ≤ Grade 3) were observed in 15 cases. The cholangiocarcinoma patient who uniquely received 1 cycle of CART-133 infusion after anti-PD1, developed Grade 3 skin/mucosal vasculature damage, blood three-lineage decline and cytokine release syndrome, whereas, obtained a 4.5 month-lasting partial remission. Although no marked reduction of tumor volume was observed in most patients, 21 out of 23 patients had an 8-22 week progression-free survival, 2 patients without bulky tumor burden attained 8/10-month ongoing stable disease by the cut-off data (Jan 1, 2017). Conclusions: This trial showed the feasibility, controllable toxicities and effective biological activity of CART-133 transfer for the treatment of late-stage tumor patients. Clinical trial information: NCT02541370.
Abstract 9815: Nadolol Seems to Be Superior to Selective Beta Blockers in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: Is a Smaller Arrhythmic Window Part of the Explanation?
Authors: Ida Skrinde Leren, Jørg Saberniak, Eman Majid, Trine F Haland, Thor Edvardsen, Kristina H Haugaa
Journal: Circulation (2015)

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable arrhythmogenic disease, and typically presents as syncope or sudden cardiac death during exercise. Beta blockers are first choice therapy but little is known about antiarrhythmic effects of different beta blockers in CPVT. Nadolol has shown superior antiarrhythmic effect in other cardiomyopathies. Hypothesis: We hypothesized that nadolol is superior to selective beta blockers in arrhythmia protection in CPVT patients. Methods: We included 34 CPVT patients (age 34±19 yrs, 44% female, 88% RYR2 mutation positive). We serially performed 2 bicycle exercise tests in each patient; 1)&gt;6 weeks on maximum tolerated dose of selective beta blockers. 2)&gt;6 weeks on maximum tolerated dose of nadolol. We recorded resting and maximum heart rate (HR), HR at first arrhythmia and the most severe arrhythmia occurring. Arrhythmic window was defined as the difference between maximum HR and HR at first arrhythmia. Severity of arrhythmias was scored as arrhythmic score: no arrhythmias (0point), single ventricular extra systoles (1point), bigemini (2points), couplets (3points) and nonsustained VT (4points). Results: Resting HR was similar on nadolol and selective beta blockers (54±10bpm vs. 56±14bpm, p=0.50), while maximum heart rate was lower on nadolol (122±21bpm vs. 139±24bpm, p&lt;0.01). First arrhythmias occurred at similar HR at both exercise tests (113±21bpm vs. 113±19bpm, p=1.0). Consequently, arrhythmic window was smaller during nadolol treatment (17±10bpm vs. 32±26bpm, p=0.03) (Figure) and also the arrhythmic score was lower than on selective beta blockers (1.1±1.2 vs. 2.4±0.9, p&lt;0.01). Conclusion: Arrhythmic score was lower on nadolol compared to selective beta blockers. Also, arrhythmic window, representing the span of heart rates where arrhythmias may occur and progress in severity, was smaller. This suggests that nadolol should be the beta blocker of choice in CPVT patients.
Safety, toxicity and activity of multi-kinase inhibitor vandetanib in combination with everolimus in advanced solid tumors.
Authors: Tina Cascone, Kenneth R. Hess, Sarina Anne Piha-Paul, David S. Hong, Ishwaria Mohan Subbiah, Tarak Bhatt, Siqing Fu, Aung Naing, Filip Janku, Daniel D. Karp, Funda Meric-Bernstam, John Heymach, Vivek Subbiah
Journal: Journal of Clinical Oncology (2016)

9073 Background: RET gene aberrations have been identified in several types of cancer, including lung, thyroid, colon and breast cancers. Inhibition of RET signaling in preclinical tumor models using vandetanib (VAN), a TKI that targets VEGFR2/EGFR and RET, in combination with everolimus (EV), an mTOR inhibitor, was found to overcome intrinsic and /or acquired tumor resistance to either agent alone, suggesting the combined therapy warrants investigation in patients. Methods: A “3+3” dose escalation and expansion trial was designed to determine the safety, maximum tolerated dose , recommended Phase II dose (RP2D), dose-limiting toxicities (DLTs) and activity of VAN+EV in advanced/refractory solid tumors. Tumor responses were assessed by RECIST. The molecular correlates of clinical response were analyzed by next generation sequencing (NGS) and/or FISH if available. Results: Among the 96 pts treated to date, median age was 56 years (18-82 yrs) and 43 pts (45%) were male. Most common diagnoses were sarcoma (20), renal cell carcinoma (RCC, 14), thyroid cancer (9; 3 MTC), and NSCLC (15). Forty-eight pts had ≥ 3 metastatic sites of disease. Most common AE’s were G1-G3 diarrhea (44, 68%), G1-G3 fatigue (44, 46%), G1-G3 rash (39, 41%), G1-G3 mucositis (24, 25%), G1-G3 LFT elevation (18, 19%), G1-G2 anemia (12, 13%), G1-G4 thrombocytopenia (TCP, 14, 15%). DLTs: diarrhea, fatigue, LFT elevation, TCP, and QTc prolongation. Among 47 pts with tumors harboring aberrations in the target pathways, 9 pts tested RET fusion+ and 4 had RET mutations. Best evaluable responses were PR (12, 13%) in sarcoma, RCC and NSCLC, and SD (42, 45%). and, of these, 9 (PR) and 21 (SD) pts had tumors with matched aberrations. Among 6 evaluable NSCLC pts with RET fusion+ by NGS, 5 pts achieved PR and 1 SD (P < 0.05, PR in RET fusion+ vs. RET–, discussed separately). Durable responses ( > 6 months) were noted in 16 pts with SD and 6 with PR. One RET M918Tmutant MTC pt responded to the combination after progressing on VAN monotherapy. Conclusions: The RP2Ds of VAN and EV are 300 mg and 10 mg. Responses were noted in pre-treated pts with refractory sarcoma, RCC, MTC, and NSCLC harboring RET aberrations. Additional testing of the combined therapy is warranted. Clinical trial information: NCT01582191.
Donor-derived MDS/AML in families with germline GATA2 mutation
Authors: Pallavi Galera, Amy P. Hsu, Weixin Wang, Stephenie Droll, Rui Chen, Jason R. Schwartz, Jeffery M. Klco, Sally Arai, Luke Maese, Christa Zerbe, Mark J. Parta, Neal S. Young, Steven M. Holland, Dennis D. Hickstein, Katherine R. Calvo
Journal: Blood (2018)
Current trends and survival in patients with esophageal squamous cell carcinoma: An analysis of the National Cancer Database from 2007 to 2013.
Authors: Brandon C. Chapman, Michael J. Weyant, Patrick W Hosokawa, Douglas M Overbey, Sarah Hilton, Martin McCarter, Ana Gleisner, Barish H. Edil, Csaba Gajdos
Journal: Journal of Clinical Oncology (2017)

4032 Background: Although surgical resection is the treatment of choice for patients with esophageal squamous cell carcinoma (ESCC), some evidence suggests that definitive chemoradiation (CR) may have equivalent survival compared to surgery alone. The objective of this study was to evaluate current trends in the treatment of ESCC and its impact on overall survival (OS). Methods: Using the NCDB (2004-2013), patients with non-metastatic/loco-regional ESCC were categorized into definitive CR, neoadjuvant CR/surgery, surgery alone, and surgery/adjuvant therapy. Multivariate Cox proportional hazard models by stepwise selection were applied to estimate hazard ratios (HR) of predictors of OS. Results: We identified 11,229 patients with ESCC undergoing definitive CR (n = 8855, 78.9%), neoadjuvant therapy/surgery (n = 953, 8.5%), surgery alone (n = 1130, 10.1%), and surgery/adjuvant therapy (n = 291, 2.6%). The distance of primary tumor from incisors was comparable for all four groups. On multivariable analysis, treatment modality had the largest impact on OS followed by AJCC stage, age and annual surgical volume. Compared to neoadjuvant therapy/surgery, both surgery only (HR 1.17, 95% CI 1.04-1.32) and definitive CR (HR 1.51, 95% CI 1.37-1.66) were associated with increased long-term mortality. However, there was no difference in mortality in the surgery/adjuvant therapy group (HR 1.10, 95% CI 0.94-1.30) compared to the neoadjuvant therapy/surgery group. Patients treated at facilities performing more than 20 esophagectomies per year, regardless of whether they underwent surgical resection, had improved OS compared to facilities performing 10-19 per year (HR 1.47, 95% CI 1.29-1.68), 5-9 per year (HR 1.44, 95% CI 1.29-1.62), and &lt; 5 per year (HR 1.53, 95% CI 1.38-1.70). Conclusions: Patients receiving either neoadjuvant therapy or adjuvant therapy and esophagectomy for ESCC have improved OS compared to patients undergoing esophagectomy alone and definitive CR. These findings suggest that patients with ESCC should be considered for multimodality treatment at high-volume centers and surgery should be included in the treatment plan whenever possible.
Integrative whole-genome analysis of salivary duct carcinoma.
Authors: Sehhoon Park, Youngwook Kim, Sanghoon Song, Miran Lee, Teresa Swatloski, Hyung Lae Kim, Young-Hyeh Ko, Han-Sin Jeong, Keunchil Park
Journal: Journal of Clinical Oncology (2018)

6083 Background: Salivary duct carcinoma (SDC) is one of the most aggressive histological subtypes of salivary gland cancers. Conventional chemotherapy and radiation have shown only limited efficacy in metastatic SDC. Currently, clinically approved targeted-therapeutics are not available for treatment of this disease, mainly due to its rarity and limited understanding of the molecular mechanisms underlying its pathogenesis. Thus, we conducted multi-level genomic profiling of the SDC to delineate the genomic alterations prevalent in this disease. Methods: Whole-genome sequencing, whole exome-sequencing and transcriptome sequencing were performed on 10 discovery cohort of SDC samples. Genomic profiling was performed in additional 32 SDC samples to corroborate the findings obtained from the initial discovery cohort. Results: The cancer cohort is characterized by an average mutation burden of 85 somatic non-silent exonic mutations per tumor. The cohort displayed a mutational signature of BRCAness and APOBEC/AID. Several genes, including TP53, RB1, SMAD4, HRAS, APC, PIK3CA and GNAQ were recurrently mutated in SDC. A novel fusion gene, generated by genomic rearrangement, MYB-NHSL1, was identified. Conclusions: These findings represent an important layer in the systematic understanding of clinically meaningful genomic targets for precision medicine in SDC, a disease with a significant unmet clinical need.