tbuckley/cabot-search huggingface dataset:
EGFR with L858R and H870R double mutations showed reduced sensitivity to Gefitinib
Authors: Issan Tam, Lai Leung, Lap Chung, Maria Wong
Journal: Cancer Research (2007)

LB-329   Tyrosine kinase inhibitor (TKI) treatment directed against epidermal growth factor receptor (EGFR) can lead to dramatic shrinkage of lung cancers that harbor common EGFR mutations such as L858R or exon 19 deletions. The T790M second mutation can confer TKI resistance but the effects of other types of double mutation, which can occur in up to 10% of lung cancers, are unclear. This study analyzed a double EGFR mutation (L858R+H870R) found in the leptomeningeal metastasis of a male Chinese patient whose primary lung cancer showed initial response to TKI. The functional role of the novel H870R mutation and its effect on L858R in terms of phosphorylation and TKI-induced apoptosis were examined in transfection studies. Vectors expressing full length EGFR cDNA with mutants L858R, H870R and L858R+H870R were constructed by site directed mutagenesis and transfected into COS7 cells. Vectors expressing wild type (WT) EGFR, delE746_A750 and the empty expression vector were used for comparison.  Cells in regular cultures were analyzed for survival by Hoechst staining. Compared to untreated cells, 512nM gefitinib increased apoptosis in L858R- (3.951 fold) and L858R+H870R- (2.334 fold) mutant cells, but not H870R- (1.154 fold) mutant cells, suggesting that H870R is not sensitive to gefitinib-induced apoptosis. Sensitivity to gefitinib is the highest in L858R but it is reduced in combined L858R+H870R mutation.  >To further explore the correlation between phosphorylation profiles and gefitinib sensitivity, serum starved cells were treated with gefitinib in serial dilutions followed by EGF stimulation. The phosphorylation status of EGFR Y869 (Y845), Y1016 (Y992), Y1110 (Y1086) and Y1197 (Y1173) were investigated by western blot analysis. Differential phosphorylation profiles were observed. For pY1016, pY1110 and pY1197, L858R was the most sensitive to gefitinib inhibition. H870R and H870R+L858R showed lower sensitivity, requiring 16-32 folds higher concentration of gefitinib to effect similar degrees of inhibition at these sites. For pY869, a reversed pattern was observed with H870R and H870R+L858R showing similar sensitivity to gefitinib inhibition, while L858R showed relative resistance, requiring 16 fold higher concentration for the same effect.  >In the EGFR TK domain, Y869 is important for keeping EGFR in an active conformation by van der Waals interaction with K860 and H-bond with E872. For H870R, the linear and basic side chain of arginine has replaced the ring structure of histidine, increasing the negative charges near Y869. The close proximity of H870R to Y869 may affect the H-bond between Y869 and E872, as well as phosphate-transfer along the signaling pathway and response to TKI. In summary, our results suggested that the presence of H870R could reduce the gefitinib sensitivity of L858R.
Association of plasminogen-activator inhibitor 1 (PAI-1) 4G/5G gene polymorphism with survival and chemotherapy-related vascular toxicity in non-seminomatous testicular cancer (TC)
Authors: de Esther Haas, N. Zwart, C. Meijer, Hendrika Boezen, Albert Suurmeijer, J. van der Meer, Harald Hoekstra, F. E. van Leeuwen, D. T. Sleijffer, Jourik Gietema
Journal: Journal of Clinical Oncology (2009)

5083 Background: High PAI-1 expression by tumor has been associated with poor prognosis in different cancer types, while high systemic PAI-1 levels may increase the risk of vascular thrombosis. We investigated whether the 4G/5G del/ins polymorphism in the PAI-1 promoter (rs1799889; 4G might lead to higher transcription), is associated with differences in survival and prevalence of cardiovascular events in TC. METHODS: Data were collected on survival and cardiovascular events (venous thromboembolism [VTE] and coronary heart disease [CHD]) of TC patients treated with standard platinum based chemotherapy from 1977-2004. PAI-1 genotype was determined from non-tumor genomic DNA by a Taqman SNP assay. Genotypes were compared for survival (Kaplan-Meier curves + log-rank and Cox-regression analysis), disease outcome (logistic regression) and prevalence of VTE and CHD (χ(2)-test). RESULTS: Data are available for 324 patients with median follow-up of 10 yrs (range 0-28). The 3 genotypes 4G/4G (n = 84), 4G/5G (n = 164), and 5G/5G (n = 76) do not differ in age and initial chemotherapy regime. However, the 4G/4G variant shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared to 4G/5G + 5G/5G (24% vs 10%; p = 0.003), as well as a decreased TC related survival compared to 4G/5G + 5G/5G (83% vs 94%; p = 0.001) with a hazard ratio of 2.68 for TC related death (95%CI 1.26-5.72; adjusted for IGCCC p = 0.011). In addition, the 4G/4G variant shows an odds ratio of 3.35 for refractory TC and early relapses (<2 yrs) (95% CI 1.48-7.58; p = 0.004). The 3 genotypes do not differ significantly in prevalence of VTE (4G/4G 11.9%, 4G/5G 8.5%, 5G/5G 7.9%; p = 0.616) and CHD during/after chemotherapy (4G/4G 6.0%; 4G/5G 4.9%; 5G/5G 2.6%; p = 0.594). CONCLUSIONS: The 4G/4G variant of the PAI-1 4G/5G gene polymorphism is associated with IGCCC poor prognosis, reduced survival and higher prevalence of refractory disease and early relapses. No effect on vascular toxicity was found. The 4G/4G variant of the PAI-1 gene may be an unfavorable prognostic factor as well as an unfavorable predictive factor for response to chemotherapy in patients with TC. No significant financial relationships to disclose.
Preplanned first-step analysis of LET-LOB neoadjuvant study: A double-blind randomized phase IIb trial of letrozole (L) plus lapatinib (Lp) or placebo (P) in postmenopausal HER2-ve, HR+ve operable breast cancer
Authors: A. Frassoldati, V. Guarneri, A. Bottini, K. Cagossi, L. Cavanna, G. Bisagni, R. D'Amico, F. Piacentini, C. Oliva, P. Conte
Journal: Journal of Clinical Oncology (2009)

570 Background: In HR+ve BC, the simultaneous blockade of ER and HER-related pathways could prevent the hormone-resistance due to activation of EGFR-family signalling, as shows the high activity of the combination of letrozole and lapatinib in HR+ve/HER2+ve advanced BC. The LET-LOB trial evaluates the clinical and biological effects of the combined inhibitory strategy with letrozole + lapatinib in untreated ER+ve/HER2-ve BC patients suitable for hormonal neoadjuvant therapy. Methods: Postmenopausal women with stage II-IIIa, HR+ve/HER2-ve BC are randomized to L (2.5 mg/d) + Lp (1500 mg/d) or L + P, given continuously for 24 weeks before surgery. Primary end point is the clinical RR (with ultrasonography, US); secondary endpoints are the pathological RR, the safety, and HR/EGFR-related biomarker evaluation. According to the “two step Simon's design” of the study, at least 20 cORs (8 in L+P and 12 in L+Lp) must be observed in the first 43 patients; then, additional 48 patients will be recruited to demonstrate a 40% increase in cOR with L+Lp, assuming a cOR of 50% with L+P. Results: Since April 2007, 39/55 randomized patients completed the preoperative treatment. Median age was 68 yrs. At diagnosis, mean US tumor size was 3 cm. All patients were HER2-ve, and either ER+ve or PR+ve (both +ve: 76%). After 3 and 6 months of therapy, a 29% and 41% reduction from baseline mean US longest tumor diameter was observed. No change in mean LVEF has been reported at the 3- and 6-month evaluations. 5 episodes of G3 toxicity have occured (skin rash, 1; liver function parameters, 4). So far 31 women underwent surgery (conservative in 65 %). The efficacy results according to the first step Simon's analysis will be performed by the IDMC on march 2009, and will be presented at the meeting along with updated clinical and safety data. Conclusions: Preliminary blinded results suggest that the combination of L+Lp in ER+ve/HER2-ve operable BC is feasible, without early cardiac events or other severe toxicities, and associated with clear tumor downstaging. Biological correlative studies will clarify the relationship between the double inhibition strategy and the clinical response. Supported by GlaxoSmithKline. [Table: see text]
Abstract 13480: Noninvasive Spatial and Temporal Tracking of Multilayered Cell Sheet on Infarcted Heart Using Reporter Gene Imaging
Authors: Kentaro Otani, Tsutomu Zeniya, Hidekazu Kawashima, Hajime Fukuda, Yoshiko Hashikawa, Tetsuaki Moriguchi, Masayuki Inubushi, Hidehiro Iida, Kenichi Yamahara
Journal: Circulation (2013)

Background and aim: Transplantation of stem cell sheet is a promising strategy for the treatment of ischemic heart disease. The reporter gene imaging allows the noninvasive and serial observation of cell dynamics in vivo. The aim of this study was to investigate the feasibility of temporal and serial tracking of cell sheets on the infarcted heart using SPECT with human sodium/iodide symporter (hNIS) as a reporter gene. Methods: Cell sheets were generated from mouse embryonic fibroblasts (MEF) derived from mice overexpressing hNIS (hNIS-Tg) (3х106 cells/sheet) using temperature-responsive dishes. Myocardial infarction was produced by ligating the left anterior descending coronary artery in F344 athymic rats. Two weeks after surgery, triple-layer cell sheets were transplated onto the infarct area (Day 0). Serial SPECT imaging was acquired after the injection of 99mTc-pertechnetate (380-660 MBq) using small animal SPECT/CT system (NanoSPECT/CT; Bioscan) at Day 1, 4, 7, 10 and 15. The histological analysis wa...
Phase IB study of eribulin mesylate in combination with carboplatin in patients with advanced solid tumors.
Authors: U. Swami, D. P. Petrylak, H. Raftopoulos, D. E. Shuster, G. Wang, V. Kumar, G. Martinez, S. Goel, J. Aisner
Journal: Journal of Clinical Oncology (2010)

2589 Background: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, has clinical activity as monotherapy in breast cancer and other solid tumors. This phase I, open-label, dose-finding study determined the maximum tolerated dose (MTD) for eribulin in combination with carboplatin. Methods: Patients with advanced solid tumors whose prior standard therapy failed were enrolled. Carboplatin was administered by 30-min IV infusion and eribulin by 2- to 5-min IV bolus, separated by 1 h. In stage 1, eribulin mesylate (0.7, 0.9, 1.1, and 1.4 mg/m2) was dose escalated with carboplatin AUC5 in a 3+3 design in two schedules differing by the order of administration. In stage 2, eribulin mesylate (1.1 and 1.4 mg/m2) was dose escalated with carboplatin AUC6 using the preferred schedule from stage 1. In both stages, the MTD was defined as the highest dose where <2/6 patients had dose-limiting toxicities (DLTs). The safety, efficacy, and pharmacokinetics (PK) of eribulin were also assessed. Results: 52 patients (27 females, 25 males) with a median age of 60 years (range: 38-80 years) were treated. In stage 1, a DLT (diarrhea) was experienced in 1/5 patients at 1.4 mg/m2 in the carboplatin-first schedule and in 0/3 patients in the eribulin-first schedule, defining the MTD as 1.4 mg/m2 (same as the monotherapy dose) with eribulin given first. In stage 2, eribulin was given first and DLTs occurred in 1/6 patients (febrile neutropenia) at 1.1 mg/m2 and in 2/3 patients (febrile neutropenia, neutropenia) at 1.4 mg/m2, defining the MTD as 1.1 mg/m2. PK analyses for both agents suggest the absence of any PK interaction. Most frequent AEs (%) across doses/cycles were neutropenia (52; 40 grade 3/4), thrombocytopenia (29; 13 grade 3/4), fatigue (58; 4 grade 3/4), and nausea (40; 0 grade 3/4). Two partial responses by RECIST were observed in prostate cancer and one complete response in tonsillar cancer. Conclusions: Combination of eribulin with carboplatin was tolerated and showed preliminary activity. An extension arm with the combination at recommended phase II doses (eribulin mesylate 1.1 mg/m2, carboplatin AUC6) is enrolling patients with chemo-naive, advanced non-small cell lung cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai, K and L Consulting Services Eisai Eisai
Personal views: My cancer and the magic bullet
Authors: Caroline Richmond
Journal: BMJ (1998)

In June the first treatment for cancer that uses monoclonal antibodies was licensed. By a miracle of chance, it was designed for my particular subtype of cancer, and it has brought me complete remission. The odds against this happening are enormous. I’m as pleased as Punch, and so is my oncologist.

Rituximab costs £6000 for a course, is for low grade B cell follicular relapsed or chemoresistant stage III or IV non-Hodgkin’s lymphoma, halves the size of tumours in only 48% of patients given it, of whom only one in eight gets a complete remission. I was one of these patients. So, statistically, the chances of it being for my type of (incurable) cancer, and of me being given it (considering the cost to the NHS) and getting a full remission, are slender. Having just read Innumeracy by the mathematician John Allen Paulos (he uses his middle name to avoid being taken for the Pope) I feel I should quantify the odds. If, say, 7% of all cancer patients have a lymphoma, or to put it another way are lymphomaniacs, and 80% of those are non-Hodgkin’s, and 85% of those are B cell, and 60% are low grade, and 40% of those are follicular, and 30% of those are chemoresistant or relapsed ... the odds of getting a full remission are around 1 in 10 000.
Is Multiple Myeloma a Chronic Disease? A Population Based Study Comparing 1843 Patients to a Matched Swedish Population.
Authors: Hareth Nahi, Johan Liwing, Anders Aldrin, Johan Andreasson, Cecilie Blimark, Kristina Carlson, Jon Enestig, Max Flogegård, Karin Forsberg, Astrid Gruber, Peter Johansson, Helene Kviele, Birgitta Lauri, Ulf-Henrik Mellqvist, Per Näsman, Agneta Swedin, Magnus Svensson, Katarina Uttervall, Johan Aschan
Journal: Blood (2012)
Outcomes differences in tumors &lt; 1 cm by age and breast cancer subtype.
Authors: J. K. Litton, H. Chen, E. A. Mittendorf, F. Meric-Bernstam, M. Chavez-Mac Gregor, W. A. Woodward, A. Sahin, R. L. Theriault, G. N. Hortobagyi, A. M. Gonzalez-Angulo
Journal: Journal of Clinical Oncology (2010)

580 Background: Women with small breast cancers are often counseled that risk of recurrence is low and no chemotherapy is recommended. However, some biologic factors such as HER2+ increase recurrence after small tumors. The purpose of this work was to evaluate the risk of recurrence of patients with tumors ≤ 1 cm by age and by tumor subtype. Methods: From 1990 to 2002, 1,012 patients with a T1a,bN0M0 breast cancer were diagnosed at our institution and did not receive chemotherapy or trastuzumab. Patients were categorized by breast cancer subtype: hormone receptor-positive and HER2-negative (HR+), HER2-positive (HER2+), or triple receptor-negative (TN). Patients and tumor characteristics were compared using the chi-square test or Wilcoxon's rank sum test. Recurrence estimates used the Kaplan-Meier method and compared between groups using the log-rank statistic. Cox proportional hazards models were used to determine associations of breast cancer subtypes and age at diagnosis with recurrence risk. Results: Recurrence-free survival (RFS) rates by age are in the Table. Women ≤ 50 years old with either HER2+ or HR+ tumors had a significantly worse outcome than older women. Multivariable models using age as a continuous variable and adjusting for T-stage, hormone therapy, grade and tumor subtype demonstrate that patients ≤50 years had an increased risk of distant-RFS (DRFS) as compared to patients ≥ 50. Patients ≤35 had 2.60 (95% CI = 1.05, 6.46, p =0.04) times greater risk of DRFS vs. patients >50. Patients with TN breast cancer had 2.08 (95% CI = 1.04, 4.17, p =0.039) times greater risk of DRFS than HR+ disease patients. Conclusions: For patients diagnosed with T1abN0 breast cancer, both age at diagnosis and breast cancer subtype were significantly associated with outcome. With age as a categorical variable and adjusted by other patient and tumor characteristics, patients ≤ 35 had worse RFS and DRFS and use of systemic therapy may need to be reconsidered. RFS Age N events 5-year estimate (%) 95% confidence interval (%) P value HER2 positive ≤35 5 42.9 18.2, 100 35-50 15 70.5 57.2, 86.9 > 50 12 87.7 78.9, 97.4 0.0027 HR positive ≤35 3 88.9 75.5, 100 35-50 27 90.3 86.1, 94.7 >50 35 96.2 94.6, 97.9 0.0030 TN ≤35 4 75.0 50.3, 100 35-50 14 79.5 68.3, 92.4 > 50 20 88.6 82.1, 95.5 0.146 No significant financial relationships to disclose.
Improvement in liver histology after 3 years of E1 therapeutic vaccination in 23 patients with chronic hepatitis C
Authors: Frederik Nevens, Yves Horsmans, T. Roskams, H. Van Vlierberghe, D. Sprengers, A Elewaut, V. Desmet, G Leroux-Roels, A de Brauwer, E Depla, S. Dincq, C. Vander Stichele, F. Hulstaert, G. Maertens
Journal: Hepatology (2004)
Preliminary phase II results of oxaliplatin, 5-FU, and leucovorin in advanced biliary tract cancer.
Authors: S. Lee, H. Kim, S. Kim, C. Kim, S. Bae, K. Lee, J. Yun, D. Hong, H. Park
Journal: Journal of Clinical Oncology (2010)

e14507 Background: There is no standard palliative chemotherapy regimen in biliary tract cancers (BTC). Fluoropyrimidine or gemcitabine, with or without platinum, are most frequently used. The purpose of this prospective multicenter phase II study was to evaluate the efficacy and safety of FOLFOX-6 (5-FU/LV plus oxaliplatin) combination chemotherapy in patients with advanced BTC. Methods: Eligible criteria included pathologically or cytologically confirmed biliary adenocarcinoma, unresectable or metastatic BTCs with at least one measurable lesion, no previous palliative chemotherapy, age ≥ 18, performance status ≤ 2, adequate organ function and no clinically significant cardiovascular disease. Enrollment of 40 patients was planned. Patients received FOLFOX-6 (oxaliplatin 85 mg/m2 and folinic acid 400 mg/m2 on day 1 follwed by a 5-FU bolus 400 mg/m2 and 46-h infusion 2,400 mg/m2 every 2 weeks) until progression of disease or unacceptable toxicities. Results: 35 patients were enrolled in this phase II study since May 2008. Medain age was 60 years (range 35-80), male/female = 18/17, ECOG performance status 0/1/2 = 18/14/3. The primary tumor site was 7 patients in gallbladders, 21 patients in intrahepatic cholangiocarcinoma, and 7 patients in extrahepatic cholangiocarcinoma. 30 patients showed metastatic disease at baseline. Treatment related grade 3/4 toxicities included (number of pts): diarrhea (1), neutropenia (6), anemia (1), thrombocytopenia (2), nausea (1). Overall response rate was 26.7% and overall disease control rate was 63.3%. The median TTP was 4.03 months (95%CI, 3.75-5.68 months) and the overall survival was 10.77 months (95%CI, 7.92-13.62 months). No treatment related deaths occurred during the study. Conclusions: This preliminary analysis suggests that FOLFOX-6 would be an effective and well-tolerated chemotherapy regimen for Korean patients with advanced BTC. No significant financial relationships to disclose.
Health related quality of life (HRQOL) evaluated with the EORTC C30 questionnaire in first line therapy of elderly patients with chronic lymphocytic leukemia (CLL): Results of a phase III trial of the German CLL Study Group (GCLLSG)
Authors: B. F. Eichhorst, R. Busch, M. Hallek
Journal: Journal of Clinical Oncology (2006)

7572 Background: The GCLLSG evaluated the efficacy of fludarabine (F) versus (vs.) chlorambucil (Clb) in first line therapy of older patients with advanced CLL. HRQOL was evluated by using the EORTC C30 questionnaire. Methods: Pts were randomized to receive 6 courses of F (25 mg/m²/day (d) IV for 5d; 92 pts) or 12 months (mo) of Clb (0.4–0.8 mg/kg/d PO, every 15d; 99 pts). All pts were previously untreated, aged between 65 and 79 years and in advanced stage Binet C or symptomatic Binet B or A. Primary endpoints were overall survival (OS) and progression free survival (PFS), secondary endpoint was HRQOL. The EORTC C30 questionnaire (version 2.0) was sent to all patients at baseline and after 6, 12 and 24 mo. Scores (0–100) for 15 different measures (1 global HRQOL, 5 functional, 3 symptom and 6 single item scales) were evaluated at each time point. Results: F induced significantly higher response rates and prolonged the PFS, while no significant difference in OS was observed. At baseline 130 of 191 pts (68%) completed the questionnaires followed by more than 80% at mo 6 to 24. Compliance rates were similar in both treatment arms. Between pts completing questionnaires or not no statistically significant differences in perfomance status, age, stage or response to treatment were observed. HRQOL differences in comparison to baseline values were significantly improved after F treatment in global HRQOL, role and social functioning after 12 months as shown by the table. Responders had a significantly better global HRQOL and social functioning as well. Except for an impaired physical functioning no differences in HRQOL were observed between different age groups (65–69, 70–74, 75–79). Conclusion: Elderly F treated patients with CLL showed improvement inglobal HRQOL. Elderly age groups had a similar HRQOL as younger age groups. [Table: see text] [Table: see text]
Management and outcome of venous thromboembolic events (VTEs) during sunitinib treatment
Authors: A. Rahal, C. Massard, P. Girard, J. Dômont, B. J. Escudier, A. Le Cesne, J. Soria, B. Besse
Journal: Journal of Clinical Oncology (2008)

14625 Background: Sunitinib (SU) is a multi target tyrosine kinase inhibitor approved by FDA and EMEA in Renal Cell Cancer (RCC) and Gastric intestinal stromal tumor (GIST). SU has not been reported to increase the rate of VTEs in RCC, GIST. VTEs’ management and outcome under SU treatment is unknown. We reviewed cases of VTEs in RCC, GIST and NSCLC pts treated with SU. Methods: RCC, GIST and NSCLC pts treated with SU in prospective clinical trials at Institut Gustave Roussy (IGR) were analyzed to assess the risk of VTEs rate and identify predisposing factors. SU was given at 50 mg/d 4 wks out of 6, as a 2nd or 3rd line in GIST, as maintenance therapy after 4 cycles of paclitaxel-carboplatin in NSCLC and in RCC pts after cytokine failure. Key exclusions criteria of these trials were: pts with history of thrombosis within 6 months, brain metastasis, PS WHO>1, or squamous cell lung cancer. Diagnoses of symptomatic pulmonary embolism (PE) confirmed by CT pulmonary angiography were centrally reviewed. Results: Between Aug.05 and Oct.06, 72 pts were included (21 GIST, 8 NSCLC, 43 RCC). Baseline characteristics were (RCC/GIST/NSCLC): female 23%/57%/50%, mean age 54/54/51yrs, PS 0: 84%/57%/38%, indwelling central venous catheters (ICVC) 0%/0%/100%, bone metastases: 11%/0%/75%, liver metastases: 76 %/28%/37%. None has history of previous cancer or surgery within 1 yr. Five pts (6.9%, 95%CI: 3.0–15.2%) developed symptomatic PE., 3 in NSCLC pts (37%), 1 in RCC (2%) and 1 in GIST (5%). PE occurred early aftersunitinib initiation (4 wks in 2 pts, 6 wks in 2 pts, 10 wks in 1 pt). In case of PE, SU was interrupted in NSCLC but continued in GIST and RCC pts. All 5 PE were treated with low molecular weight heparin (LMWH). In 1 pt (GIST), LMWH was discontinued after 4 months due to a grade 3 esophageal hemorrhage (peptic esophagitis) but SU was maintained for 3 additional months untill disease progression. In 1 pt (RCC), LMWH and SU were maintained for up to 24 months. Conclusions: The incidence of symptomatic PE among pts treated with SU was within the expected range for cancer patients receiving chemotherapy, but PE occurred early after SU initiation. Concomitant SU and LMWH treatment is feasible but might expose to severe hemorrhage. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology