tbuckley/cabot-search huggingface dataset:
Detection and HER2 expression of circulating tumor cells in advanced gastric cancer patients.
Authors: Satoshi Matsusaka, Keisho Chin, Mariko Ogura, Mitsukuni Suenaga, Eiji Shinozaki, Nobuyuki Mizunuma, Takeshi Sano, Toshiharu Yamaguchi, Noriko Yamamoto, Yuichi Ishikawa, Yuji Mishima, Yasuhito Terui, Kiyohiko Hatake
Journal: Journal of Clinical Oncology (2012)

10541 Background: This study was aimed at detecting and HER2-expressiong circulating tumor cells (CTC) in peripheral blood of chemo-naïve or chemo-resistant patients with advanced gastric cancer. Methods: All patients were enrolled using institutional review board-approved protocols at the Cancer Institute Hospital in the Japanese Foundation for Cancer Research and provided informed consent. The study population consisted of patients of age 18 years or older with histologically proven advanced gastric cancer. A total of 140 patients with advanced gastric cancer were enrolled into a prospective study. We used CellSearch system for detection and HER2 expression for CTC. Results: We detected ≥1 CTC/7.5ml in 80 of 140 patients (57.1%). HER2-positive CTC were observed in 19 of 80 CTC-positive patients (23.8%), including 6 patients with HSR2-negative primary tumors. 21 patients with HER2-positive primary tumors administered trastuzumab in combination with chemotherapy (Xeloda+cisplatin; 15, weekly Paclitaxel; 5). We detected ≥1 CTC/7.5ml at the baseline in 11 of 20 patients with trastuzumab treatment. HER2-positive CTCs were observed in 6 of 11 CTC-positive patients (54.5%). Patients with HER2-positive CTC at the baseline were shorter PFS than those with HER2-negative CTC at the baseline. Conclusions: HER2 expression on CTC was associated with chemo-resistance. Information on the HER2 status of CTC might be helpful for stratification of HER2-directed therapies.
CALGB 30601: A phase II study of dasatinib (D) in patients (pts) with previously treated malignant mesothelioma (MM).
Authors: A. Dudek, H. Pang, R. A. Kratzke, G. A. Otterson, E. E. Vokes, H. L. Kindler
Journal: Journal of Clinical Oncology (2010)

7037 Background: SRC is commonly over-expressed in MM. D is a potent inhibitor of SRC family kinases, EphA2 and PDGFRβ. There are no approved therapies for MM pts who progress on pemetrexed. We therefore conducted a phase II trial of D in MM pts who had received 1 prior pemetrexed-based regimen. Methods: Single arm phase II. Eligible pts had unresectable MM, PS 0-1, measurable disease, and no symptomatic effusions. Primary endpoint: Progression-free survival (PFS) at 24 weeks (wks). D 70 mg BID was given orally. CT scans were obtained every 2 months. Pre- and posttreatment plasma VEGF, PDGFβ, and serum CSF-1 and mesothelin-related protein were collected. Tumor was evaluated for expression of EphA2 and PDGFRβ. Results: 46 pts enrolled at 12 sites 9/07-8/09, 35 are evaluable for PFS, 22 for response, and 46 for toxicity. Pt characteristics: Male 72%; median age 68 (range 35, 81); PS 0 41%; epithelial histology 72%, pleural 76%. Median cycles given 2 (range 1-8). The starting dose was reduced to 50 mg BID after the first 23 pts enrolled because 50% of the first 12 pts enrolled had AE ≥ grade 3. Grade 3/4 toxicities (% pts): anemia 2%, fatigue 11%, pleural effusion 9%, pericardial effusion 2%, pneumonitis 2%, hypoxia 2%, nausea 4%, hyponatremia 7%, hypophosphatemia 2%.There were 3 grade 5 toxicities: 1 ARDS, 1 respiratory failure, 1 unknown. Efficacy: 24-week PFS rate 15% (95% CI 6%, 29%), median PFS 8.3 wks (7.7, 10.3), median overall survival 20.7 wks (11.4, 28.3), partial response 0%; stable disease 20%. Conclusions: Dasatinib is inactive in previously-treated MM; the 70 mg dose is poorly tolerated. Further data on biologic correlates will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Correlation of molecular markers including mutations with clinical outcomes in advanced non small cell lung cancer (NSCLC) patients (pts) treated with gefitinib, chemotherapy or chemotherapy and gefitinib in IDEAL and INTACT clinical trials
Authors: T. J. Lynch, D. Bell, D. Haber, D. Johnson, G. Giaccone, M. Fukuoka, M. Kris, R. Herbst, A. Krebs, J. Ochs
Journal: Journal of Clinical Oncology (2005)

7006 Background: Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase leads to major responses in ≤19% of pts; symptoms improve in nearly half (IDEAL I & 2). When combined with systemic chemotherapy, no therapeutic gain was seen compared to chemotherapy alone (INTACT I & II). Somatic activating mutations in the EGFR-TK domain (exons 18–21) have been found in pts with a dramatic, rapid response to gefitinib (Lynch et al, Paez et al, Pao, et al). Methods: Tumor samples were obtained from patients enrolled on the IDEAL studies (monotherapy for previously treated patients) and INTACT studies (randomized trials of chemotherapy +/- gefitinib in untreated advanced stage patients). Using standard sequencing protocols we sequenced exons 18–21 of EGFR TK domain. Selected samples were analyzed for ras and p53 mutations. Correlations were made between mutational status, therapies and outcome measures including tumor response and survival. Results: Among 416 IDEAL patients, 119 had available tumor sample, 78 were fully evaluable and validated for exons 18–21. Fourteen mutations were detected (11 deletion, 3 point mutations). Of the 14 pts with mutations: adenocarcinoma (12), women (8), smokers or former smokers (9), and objective responses (6). Among 2130 INTACT patients, there were 672 available tumor samples. Of 312 evaluable samples to date, 32 mutations have been detected (22 deletion, 10 point mutations). Of the 32 pts with mutations: adenocarcinoma (25), men (17), never smokers (9); 15/23 had objective responses to treatment (9 inevaluable). EGFR, ras and p53 mutation status will be correlated wtih treatment received (chemotherapy, chemotherapy + gefitinib, or gefitinib alone). Clinical outcomes including progression free and overall survival by mutation status will also be presented. Conclusions: Prospective studies examining the role of mutational status and other biomarkers with clinical outcome including response and survival are underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca, Bristol-Myers Squibb, Genentech, Ligand, Roche Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, Roche Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, Genta, NCI, Roche AstraZeneca
The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth
Authors: S. L. Smiley, D. O. Henry, M. K. Wong
Journal: Journal of Clinical Oncology (2006)

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin &gt; tinzaparin &gt; enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.
A phase I/II study of oxaliplatin, docetaxel, and capecitabine in advanced carcinoma of the esophagus and stomach
Authors: D. L. Evans, T. Miner, T. Ng, P. Akerman, D. Harrington, D. Martel, C. Maia, D. Benton, N. Saba, H. Safran
Journal: Journal of Clinical Oncology (2006)

14046 Background: The Brown University Oncology Group has attempted to modify the regimen of docetaxel, cisplatin and fluorouracil (DCF) to reduce toxicity, simplify administration and maintain efficacy. We have a completed a phase I/II study of weekly doxetaxel, carboplatin and capecitabine for patients with advanced esophagogastric cancer (Safran et al, Am J Clin Oncol, 2006). In this phase I study we have substituted oxaliplatin for carboplatin to determine the maximum tolerated dose (MTD) of weekly docetaxel and oxaliplatin with capecitabine. Methods: Patients with metastatic esophageal and gastric cancers received docetaxel and oxaliplatin on days 1 and 8 and capecitabine in divided doses, twice daily, on days 1–10, with each cycle repeated every 21 days. Patients were treated at 4 dose levels as shown in the table. Results: Fourteen patients have been enrolled. The median age was 58.5 years. Eight patients had esophageal cancer and six had gastric cancer. Grade 3/4 dose limiting toxicities (DLTs) of diarrhea, nausea, and febrile neutropenia occurred in three of four patients at dose level 3. An intermediate dose level was added (2A), reducing the capecitabine dose. Conclusion: Oxaliplatin 50 mg/m 2 and docetaxel 35 mg/m 2 day 1 and 8 with capecitabine 750 mg/m 2 BID × 10 days in 21 day cycles may represent a promising, easily administered regimen for metastatic esophageal and gastric cancer. Enrollment continues at dose level 2A. [Table: see text] [Table: see text]
Outpatient intraperitoneal chemotherapy for ovarian cancer chemotherapy—A comparison of reimbursement for intraperitoneal versus intravenous therapy
Authors: J. C. Schink, T. Bamlett-Sherman, L. M. Anastos
Journal: Journal of Clinical Oncology (2007)

16027 Background: The GOG 172 trial produced compelling evidence that IP chemotherapy produced superior outcomes to IV chemotherapy for women with advanced ovarian cancer (AOC). In January 2006 these results were published along with an NCI Clinical Alert documenting the improved overall survival resulting from IP treatment. However, broad adoption of IP chemotherapy may hinge in part on adequate reimbursement, thus requiring support from governmental and third party payors. This analysis is designed to compare reimbursement for outpatient IP versus IV chemotherapy, assuming that the net effect might affect overall adoption of this important new therapy. Methods: A prospective trial of outpatient IP chemotherapy was initiated 1/2006 for women with AOC. A group of 28 AOC patients received 119 IP treatments between 1/2006 and 10/2006. Reimbursement for these treatments, net of related costs, was compared with that for standard IV chemotherapy. The IP regimen includes: aprepitant, palonosetron and dexamethasone on day 1; followed by docetaxel 70 mg/M2 then amifostine 910 mg/M2 (all IV) then cisplatin 100 mg/M2 IP; concluding with paclitaxel 60 mg/M2 IP on day 8. The IV regimen was carboplatin AUC 5 and taxane (paclitaxel 175 mg/M2 or docetaxel 70 mg/M2). The nursing administration codes for IP were 96445 on days 1 and 8; by comparison, the codes for IV were 96413 for infusions up to 1h, and 96415 for each additional hour. Data on precertification, total drug and administration charges, drug costs, and reimbursement were assimilated and used to compare reimbursement net of select costs. Results: Reimbursement for IP code 96445 was significantly higher than for IV codes 96413 and 96415, with the respective mean billed $2,469 for IP vs $834 for IV. Reimbursement rates for 96445 ranged from 25% to 100% (median 97%, mean 87%). Mean total charges for IP regimen was 1.28 times higher than for IV regimen, and reimbursement rates were comparable. Conclusions: IP chemotherapy for AOC is more effort intense and requires more chemotherapy drug and supportive care medications, resulting in higher charges and higher net revenue when administered on an outpatient basis. No significant financial relationships to disclose.
Analysis of IGF1R gene copy number by silver in situ hybridization (SISH) in non-small cell lung cancer (NSCLC)
Authors: M. W. Wynes, S. Singh, R. Dziadziuszko, K. Dziadziuszko, K. Jaskiewicz, J. Jassem, N. Aumen, F. R. Hirsch
Journal: Journal of Clinical Oncology (2009)

7525 Background: IGF1R is a potential biomarker for predicting outcome of NSCLC patients (pts) treated with therapeutics targeting the IGF1R signaling pathway. SISH can be expeditiously analyzed on a bright field microscope given that the morphology of the tissue is observed concurrent to the scoring of discrete gene signals. Methods: An experimental SISH probe designed by Ventana Medical Systems (Tucson, AZ) was used to evaluate IGF1R gene copy number on a tissue microarray containing triplicate samples from 189 pts surgically treated for NSCLC (median follow-up 4 years and 5-year survival probability of 40%). Valid results, at least one core with sufficient tumor content for assessment, were obtained for 166 patients. There were 128 males; 93 squamous cell carcinomas (SCC), 47 adenocarcinomas, 5 large cell carcinomas and 21 other histologies. The pathological stages were I: 68, II: 37 and III/IV: 60. The mean number of IGF1R gene copies/nuclei/core was determined by a board certified pathologist counting 50 nuclei in each core. The mean number of IGF1R gene copies/nuclei/patient was determined by using, within the triplicates, the core with the highest gene copy number/nuclei. Results: The mean number of IGF1R gene copies/nuclei per patient was 2.26 (range: 1.12 - 7.56; standard deviation 0.81). The median copy number was 2.11. The pts were divided into two groups, those with 2.1 genes/nuclei or less and those with greater than 2.1 genes/nuclei. There was no statistical difference related to gender (p=0.422) or between pathological stages, (p=0.221). However, there was a highly significant difference between the two categories when considering histological pattern. Among patients with SCC, 66.3% had high copy number compared to 33.7 % in non-SCC histologies (p=0.008). Analysis of overall survival comparing pts with low vs. high IGF1R gene copy number revealed no statistical difference in the median survival: 1.5 yrs (95% CI 0–3.7 yrs) vs. 3.3 yrs (2.0–4.5 yrs) or the 3-year survival: 46% (35–57%) vs. 52% (41–63%). Conclusions: IGF1R gene copy number detected by SISH is higher in SCC than in other histologies of NSCLC, but does not associate with gender, pathological stage or survival. IGF1R SISH should be further explored as a predictive biomarker for IGF1R therapeutics. [Table: see text]
Regulation of the EGFR-E2F3a axis by the interferon regulatory factor (IRFs) and by promoter methylation of miR-34a in ovarian cancer
Authors: D. Reimer, M. Hubalek, S. Riedle, S. Skvortsov, M. Erdel, E. Mueller-Holzner, C. Marth, P. Altevogt, A. G. Zeimet
Journal: Journal of Clinical Oncology (2009)

e16522 Background: Although, EGFR targeting has reached “bedside” in various tumor entities, including ovarian cancer, the essential role of E2F3a in EGFR mediated proliferation remained uncovered. Recently, we outlined the clinical relevance of E2F3a in ovarian cancer. Now we were able to elucidate the pathway between EGFR activation and E2F3a induction. Methods: Promoter mapping of E2F family members was assessed using the JASPER software. E2F3a protein was assessed by immunoblot analyses in siRNA based IRF-1, IRF-2 knockdown HOC-7 cells. Cell growth was determined by MTT assays after siRNA based knockdown of E2F3a. Expression of E2F3a regulating miR-34a, miR-210 and miR-20a were assessed by RT-PCR in 130 ovarian cancer patients and methylation status of the E2F3a promoter and of miRNA promoters were estimated using Methyllight. 6p22 amplification status of patients was determined by FISH analyses. Results: Promoter mapping of E2F family members revealed that IRF-1 and IRF-2 are potential intermediate components of the herein described EGFR-E2F3a axis. As evidenced by knock-down of IRF-1, IRF-2 or both, the ratio between the two mutually antagonistic IRF-1 and IRF-2 was found to be substantial for EGF induced E2F3a up-regulation. E2F3a knock-down yielded a complete abolishment of EGF induced cancer cell proliferation. Although, activated EGFR status showed a highly significant correlation with E2F3a expression, a subgroup of patients presented high E2F3a mRNA levels without EGFR activation. Within this subgroup promoter methylation of miRNA-34a, that regulates E2F3a, was revealed to represent an alternative mechanism of E2F3a regulation in ovarian cancer, whereas promoter methylation of E2F3a itself was not relevant in E2F3a control. Unlike in prostate or bladder cancer 6p22 amplification was not found to be relevant for E2F3a up-regulation in ovarian cancer. Conclusions: Our present data point to the substantial role of the ratio between IRF-1 and IRF-2 in EGFR mediated E2F3a induction. Furthermore, in vivo regulation of E2F3a involves methylation and thereby silencing of miR-34a. Targeting of the herein described molecular pathway, downstream EGFR, could represent an appealing therapeutic approach in ovarian cancer. No significant financial relationships to disclose.
Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia
Authors: B. C. Medeiros, J. R. Gotlib, S. E. Coutre, C. Jones, S. A. Khan, R. Rajwanshi, R. Rajwanshi, J. Zehnder, J. Zehnder
Journal: Journal of Clinical Oncology (2009)

7052 Background: High treatment-related mortality and low response rates often discourage elderly patients with acute myeloid leukemia from receiving treatment. Previous data demonstrate that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Protracted exposure to low doses of temozolomide can significantly inhibit AGAT enzymatic activity. Methods: Phase II clinical trial of tailored temozolomide therapy to high-risk AML patients according to AGAT methylation promoter status. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200 mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) received protracted doses of temozolomide (100 mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Patients who achieved CR were given up to 5 consolidation treatments. Results: Fifteen patients have completed treatment to date. The median age was 78 (68–83) and nine were male. De novo AML was diagnosed in eight patients and five patients had s-AML. Nine patients had a normal karyotype and three patients had a complex karyotype. Two patients had only a NPM1 mutation and one had NPM1 mut /FLT3-ITD. In 13 patients, the AGAT promoter was found to be unmethylated. AGAT protein was present in 5/11 patients. All patients had an intact mismatch repair pathway. Thirteen patients had HCT-CI scores of 0–2. Six patients (6/13) achieved a complete remission (CR) after 1 cycle of therapy (1/2 for patients with methylated and 5/11 for patients with unmethylated AGAT promoter). Nonhematologic toxicities were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Three patients remain in CR with a median duration of 22 weeks (14–36 weeks). Seven patients have died from disease progression, while two patients died of neutropenic sepsis (early deaths). With a median follow-up of 38 weeks (10–48), the median overall survival for the entire population is 12 weeks (3.5 - 38) weeks (responders 26.5 weeks). Conclusions: These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status. [Table: see text]
Open-configuration magnetic resonance (MR) guided microwave thermocoagulation treatment for breast tumors: Preliminary report of hepatic metastases and resected breast tumors
Authors: H. Abe, T. Shimizu, S. Naka, H. Shiomi, K. Demura, K. Murakami, Y. Kurumi, S. Morikawa, T. Tani
Journal: Journal of Clinical Oncology (2007)

11095 Background: Minimally invasive therapies such as radiofrequency ablation, focused ultrasound surgery, and cryotherapy for early stage primary breast cancers may be appropriate in carefully selected patients. In this study, open-configuration magnetic resonance (MR)-guided microwave thermocoagulation treatment was used for breast tumors, and the efficacy of this treatment was assessed. Methods: We used MR-guided microwave thermocoagulation treatment on eight patients with metastatic liver tumors from breast cancer. A 0.5 T open-configuration MR system and a microwave coagulator were used. Near-real-time MR images and real-time temperature images were collected and displayed on the monitor. Secondly, it was examined whether the description of breast tumors was possible with open- configuration MR device, and simulated a tumor puncture while imaging a real-time MR image. The resected breast tumor was punctured while confirming the tumor with open-configuration MR system, and microwave thermocoagulation was enforced. Tumor tissue viability after microwave thermocoagulation was assessed by hematoxylin and eosin and NADH vital staining. Results: The visibility of the tumor by MR imaging was not disturbed throughout the procedure. In 8 patients, 11 hepatic metastases were treated by MR-guided microwave thermocoagulation treatment successfully without any major adverse event. Five of the 8 patients are alive with new metastatic foci with a mean observation period of 25.9 months (range 1 - 43 months). It was able to be confirmed that viability of the tumor had disappeared by the microwave thermocoagulation in resected breast tumors. Conclusions: This technique is feasible and safe to treatment of breast tumor with real-time observation. Open-configuration MR-guided microwave thermocoagulation therapy appears to be a feasible method with advantages to add to the growing list for nonsurgical ablation therapy of early stage primary breast cancer and should be investigated in further comparative studies. No significant financial relationships to disclose.