tbuckley/cabot-search huggingface dataset:
An economic analysis of National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10, a randomized trial of adjuvant vinorelbine plus cisplatin versus observation in early stage non-small cell lung cancer (NSCLC)
Authors: R. Ng, N. Mittmann, M. Florescu, F. A. Shepherd, A. Salvarrey, L. Seymour, T. Winton, B. Evans, N. Leighl
Journal: Journal of Clinical Oncology (2006)

7155 Background: NCIC CTG JBR.10 is among the landmark trials to establish 3rd generation platinum-based adjuvant chemotherapy as standard of care after complete resection of stages IB-II NSCLC, improving 5-year survival by 15% and median survival by 21 months (p 0.04). The cost-effectiveness of adjuvant chemotherapy from the perspective of Canada’s public health care system was undertaken in a retrospective analysis based on the JBR.10 study population. Methods: Direct medical resource utilization data, from prospective trial data of patients enrolled onto the BR.10 trial at the 5 largest accruing Canadian centres, were identified and collected retrospectively. Direct medical costs included treatment, hospitalization and procedures. Data were captured from the time of randomization until death or study closure (April, 2004). Non-medical direct and indirect costs were not included. Available costs are presented both with and without discounting at 5% per year. Costs (2005 $CAN) were obtained from provincial sources. Average costs per treatment arm (adjuvant chemotherapy vs. observation) were calculated. Basic demographic statistics were calculated. Results: Utilization data were collected from 172 patients (36% of the trial population), 83 randomized to observation and 89 to chemotherapy. Preliminary results are available for the non-drug related costs of direct medical care including hospitalization and procedures. The mean cost of treatment for patients in the observation arm is $15,323 (25–75% IQR $1,933-$17,831), and $18,701 (25–75% IQR $2,873-$18,781) for patients in the adjuvant chemotherapy arm (2005 $CAN). Conclusion: Non-drug related costs are only slightly higher in patients treated with adjuvant chemotherapy in the NCIC BR.10 trial, despite substantially longer survival for this group of patients. These preliminary results will be updated and cost effectiveness data will be available in May 2006. No significant financial relationships to disclose.
<i>BRCA1</i> and <i>BRCA2</i> mutational spectrum of an Asian population.
Authors: M. K. Chan, J. M. Chan, P. Ang, W. Lee, Y. Ho, G. Ho, A. S. Lee
Journal: Journal of Clinical Oncology (2010)

e12003 Background: Although mutations in the BRCA1 and BRCA2 genes are identified in about 5%-10% of breast cancer cases, prevalence rates among Asian patients have been less well documented. In our previous study involving 90 Asian breast cancer patients with known family history, the prevalence rates for deleterious mutations in these genes were 6.7% and 8.9% respectively. To further understand the mutational spectrum of BRCA genes we extended our analysis to a new cohort of patients in this study. Methods: Ninety-five Asian subjects with mainly early-onset breast cancers (85.3%) with no reported family history of breast and/or ovarian cancer, and 14.7% with familial breast cancer, were analyzed by full sequencing of all exons and intron-exon junctions of BRCA1 and BRCA2. Results: Among 6 BRCA1 mutations identified, 2 and 4 were mapped to intervening sequences (IVS) and coding regions respectively. Of the latter, 3 were missense mutations while 1 was a synonymous alteration. Biocomputational prediction of functional effect using PolyPhen suggested that all the missense mutations were benign. The IVS mutations were of unknown biological effect. All 9 BRCA1 polymorphisms identified were documented in the Breast Cancer Information Core (BIC) database, of which 7 were unlikely to be of clinical impact and 2 had unknown clinical effects. Of the 6 BRCA2 mutations identified, 2 were mapped to IVS and 4 to coding regions. In the coding regions, 3 mutations were synonymous alterations while one (I2490T) was a missense mutation predicted by PolyPhen to be possibly damaging. Ten BRCA2 polymorphisms were identified, of which 8 had no clinical importance and 2 had unknown clinical effects as curated in BIC. One polymorphism (N991D) was predicted by PolyPhen to be possibly damaging. Conclusions: Observations from this study suggest a diversity of BRCA mutational spectrum within subpopulations of patients with distinct pedigree risks. A reduced role for BRCA involvement in young Asian Chinese breast cancer patients without family history is suggested. This study underscores the importance of genetic association studies of more common, moderate penetrance susceptibility factors to understand breast cancer risk in this cohort. No significant financial relationships to disclose.
Two-month cisplatin-epirubicin-paclitaxel (PET) weekly administration for the treatment of large operable breast cancer. SICOG 0105 phase II study
Authors: G. Frasci, G. D'Aiuto, P. Comella, R. Thomas, M. Rinaldo, M. Di Bonito, R. Rubulotta, S. Bonagura, M. Licenziato, G. Comella
Journal: Journal of Clinical Oncology (2004)

601 Purpose: The present study was aimed at defining the antitumor activity of 8 PET weekly cycles with G-CSF support in patients with large operable breast cancer. Methods: Breast cancer (T2-T3 N0–1) patients received 8 weekly cycles of cisplatin 30 mg/sqm, epirubicin 50 mg/sqm, paclitaxel 120 mg/sqm, with G-CSF (5 microgr./kg days 3–5) support. Results: To date 47 patients (T2/T3=19/28; N0/N+=8/39) have been enrolled. Forty patients have completed the planned chemotherapy plan, and are evaluable for clinical and pathological response. Twenty Complete (50%), 19 Partial (48%), and 1 Minor Responses have been recorded, giving a 98% response rate [95% confidence interval, 84–100%]. Breast-sparing surgery was performed in 24/40 patients (in 15 radical mastectomy had been planned at diagnosis). At pathological assessment, 20 patients (50%) showed absence of residual disease in breast and 19 (48%) had negative axilla. In 14 women both breast and axilla were found disease-free (35%). At a 33-month median follow-up (range; 1–45), only 4 relapses, and one death have occurred. Grade 3–4 neutropenia, and anemia occurred in 27% and 5% of patients, respectively. Emesis, diarrhea, and mucositis were the main non-hematologic toxicities; however, they were severe in less than 10% of patients. Peripheral neuropathy was frequent, but never severe. Conclusions: A Two-month weekly treatment with PET represents a well tolerated and highly effective approach in large operable breast cancer patients. It is worth-noting that in spite of the short duration of chemotherapy more than one-third of patients achieved a complete eradication of the tumor in both breast and axilla. The accrual is still ongoing (planned sample size being 50 patients), and we expect that final results will be available at the time of the meeting. No significant financial relationships to disclose.
Gene expression profiling of microdissected stroma from normal ovary and ovarian tumors reveals altered expression of genes implicated in adhesion and angiogenesis
Authors: Goli Samimi, Tomas Bonome, Mike Radonovich, Cindy Pise-Masison, John Brady, Sue Ghosh, Shu-wing Ng, Samuel Mok, Michael Birrer
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2960 

Cross-talk between epithelial and stromal cells is required to maintain the normal function of the ovary. However, the mechanisms underlying signaling between tumor-associated stroma and adjacent ovarian epithelial tumor cells remain unclear. The aim of this study was to investigate alterations in gene expression that occur in tumor-derived versus normal stroma. We analyzed fifty-one microdissected serous tumor and 10 normal stromal isolates. Following two-cycle cDNA synthesis and IVT labeling, the samples were profiled with Affymetrix U133 2.0 Plus microarrays. The resulting signal intensities were normalized and assessed for quality. BRB-ArrayTools software was used to complete downstream analyses. Unsupervised hierarchical clustering employing a euclidean distance metric with average linkage described relationships between tumor-derived and normal stroma, while supervised class comparison identified differentially regulated genes distinguishing tumor from normal stroma. Relative gene expression in each sample was confirmed by real-time PCR. Putative co-regulated signaling pathways were compiled from the expression data using a protein interaction database derived from PathwayExpert software. Unsupervised hierarchical clustering analysis utilizing 9,741 filtered probe sets clearly distinguished tumor-derived from normal stroma. Supervised class comparison analysis identified 2,703 (p<0.001) differentially regulated probe sets in tumor versus normal stroma. Permutation analysis ensured that the resulting gene list contained no more than 10 false discoveries at a 95% confidence interval. To validate the array based expression data, 9 differentially expressed genes were selected for real-time PCR analysis across all of the stromal samples. CYR61, CTGF, THBS1, MXRA5, SPP1, LTBP2, TGFBR1 and COLL11A1 were all significantly up-regulated in tumor-derived stroma by 2.1- to 34.3-fold over normal (89% validation rate). Analysis of the entire differentially regulated gene list identified co-regulated pathways implicated in adhesion and angiogenesis in the tumor associated stromal isolates. Previous work on two members of the adhesion pathway, CYR61 and CTGF, has demonstrated up-regulation of the proteins in breast, pancreatic, and ovarian cancer. Our study is the first to measure gene expression in microdissected stromal ovarian cancer samples, thereby allowing us to identify discrete signaling events directly attributable to this component of the tumor. We have demonstrated that otherwise normal stroma undergoes changes in gene expression in response to the epithelial tumor microenvironment. Ultimately, signaling events affecting cell adhesion and angiogenesis identified here may support epithelial tumor cell expansion and survival.
Ablation of Histidine triad nucleotide-binding protein-1 (Hint1) increases sensitivity to hepatocellular carcinoma
Authors: Juliette Martin, Anne-Christine Piguet, Monika Ledermann, Bettina Saar, Ludwig Wilkens, Gisele Ferrand, Haiyang Li, I.Bernard Weinstein, Jean-Francois Dufour
Journal: Cancer Research (2008)

2239   Background and aim: HINT1 is a nucleotide binding protein with adenosine-5’ phosphoraminidate hydrolase activity. In vitro studies revealed that Hint1 1) up-regulates p53 and the pro-apoptotic factor Bax and 2) inhibits T-cell factor/beta-catenin-mediated transcription of Wnt target genes. In vivo, mice with an homozygous-deletion of Hint1 spontaneously develop more tumors than control mice after 2 years. The aim of this study was to investigate the susceptibility of Hint1-/- mice to hepatocarcinogenesis.  Methods: Hint1-/- and C57BL6 mice (2 weeks old) were subjected to a diethylnitrosamine/phenobarbital tumour-induction protocol: 1 intraperitoneal injection of diethylnitrosamine; 2 weeks later, drinking water supplemented with 0.05% phenobarbital. Animals were harvested 10, 20 and 30 weeks after injection (10/group). The number and volume of tumors were determined in vivo by MR imaging using Primovist® contrast then livers were dissected. The histology was analyzed by H&E staining. The expression of glutamine synthase, a marker for activation of the Wnt pathway was analysed by immunohistochemistry.  Results: After 20 weeks, MR imaging and liver dissection confirmed hepatic tumors in 30% of control and 70% of Hint1-/- mice but no tumors after 10 weeks in either group. The tumors were more numerous in the Hint1-/- group (1.6/mouse) than in controls (0.6/mouse). After 30 weeks, all animals developed tumors, which were more numerous in the Hint1-/- group (11.25 nodules/ mouse) than in controls (8.25 nodules/mouse) and larger in Hint1-/- mice (89.14 mm3 at 20 weeks and 178 mm3 at 30 weeks) than in controls (
Association between anaplastic lymphoma kinase rearrangements (rALK) and the clinical activity of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in patients with non-small cell lung cancer (NSCLC).
Authors: L. V. Sequist, R. B. Natale, N. N. Senzer, R. Martins, R. Lilenbaum, J. E. Gray, D. R. Borger, G. Paez, D. S. Grayzel, S. N. Gettinger
Journal: Journal of Clinical Oncology (2010)

7517 Background: Oncogenic ALK gene rearrangements (rALK) recently have been identified in approximately 3-5% of all NSCLC, particularly in non-smoking patients (pts) with epidermal growth factor receptor (EGFR) wild-type tumors. IPI-504 is a potent, water-soluble heat shock protein 90 (Hsp90) inhibitor that is being evaluated in a clinical study of patients with NSCLC, stratified by EGFR status. In preclinical models, ALK is a client protein of the Hsp90 chaperone; therefore, a retrospective analysis of the ALK status of pts in this trial was conducted. Methods: A nonrandomized phase II trial investigating the safety and antitumor activity of IPI-504 as a single agent was performed. Eligible pts had advanced NSCLC that progressed after treatment with at least one tyrosine kinase inhibitor. The primary endpoint was response rate, assessed via central, independent radiology review. rALK was assessed centrally with a fluorescent in situ hybridization (FISH) break-apart assay. Results: 76 pts were enrolled. 15 pts had tissue available for analysis of the ALK gene. See Table below. Conclusions: rALK may be a useful biomarker predicting response to therapy with IPI-504. These clinical data are the first to suggest that NSCLC pts with rALK may preferentially respond to Hsp90 inhibition. Validation is ongoing in a prospective extension of this clinical trial. Clinical activity based on molecular characterization N ORR CBR Overall 76 5 (6.6%) 20 (26.3%) EGFR mutant 24 1 (4.2%) 8 (33.4%) EGFR wild type 42 4 (9.5%) 12 (28.5%) EGFR unknown 10 0 0 Known ALK fusion status 15 3 (20%) 6 (40%) rALK positive 3 2 (66.7%) 3 (100%) rALK negative 12 1 (8.3%) 3 (25%) Abbreviations: ORR, overall response rate (all partial responses); CBR, clinical benefit rate (partial response or stable disease maintained for at least 12 weeks). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Infinity Infinity Infinity
Benefit of Intensified Therapy for Patients With Local or Regional Embryonal Rhabdomyosarcoma: Results From the Intergroup Rhabdomyosarcoma Study IV
Authors: K. Scott Baker, James R. Anderson, Michael P. Link, Holcombe E. Grier, Stephen J. Qualman, Harold M. Maurer, John C. Breneman, Eugene S. Wiener, William M. Crist
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To compare failure-free survival (FFS) and survival for patients with local or regional embryonal rhabdomyosarcoma treated on the Intergroup Rhabdomyosarcoma Study (IRS)–IV with that of comparable patients treated on IRS-III. PATIENTS AND METHODS: Patients were retrospectively classified as low- or intermediate-risk. Low-risk patients were defined as those with primary tumors at favorable sites, completely resected or microscopic residual, or orbit/eyelid primaries with gross residual disease and tumors less than 5 cm at unfavorable sites but completely resected. Intermediate-risk patients were all other patients with local or regional tumors. RESULTS: Three-year FFS improved from 72% on IRS-III to 78% on IRS-IV for patients with intermediate-risk embryonal rhabdomyosarcoma (P = .02). Subset analysis revealed two groups that benefited most from IRS-IV therapy. FFS at 3 years for patients with resectable node-positive or unresectable (group III) embryonal rhabdomyosarcoma arising at certain favorable sites (head and neck [not orbit/eyelid or parameningeal] and genitourinary [not bladder or prostate]) improved from 72% on IRS-III to 92% on IRS-IV (P = .01). Similarly, 3-year FFS for patients with completely resected tumor or with only microscopic disease remaining (group I or II) at unfavorable sites improved from 71% on IRS-III to 86% on IRS-IV (P = .04). Only patients with unresectable embryonal rhabdomyosarcoma (group III) at unfavorable sites had no improvement in outcome on IRS-IV (3-year FFS for IRS-III and IRS-IV, 72% and 75%, respectively; P = .31). CONCLUSION: IRS-IV therapy benefited certain subgroups of patients with intermediate-risk embryonal rhabdomyosarcoma. A doubling of the intensity of cyclophosphamide (or ifosfamide equivalent) dosing per cycle between IRS-III and IRS-IV is thought to be a key contributing factor for this improvement.
Prolonged Response to Trastuzumab in a Patient With HER2-Nonamplified Breast Cancer With Elevated HER2 Dimerization Harboring an<i>ERBB2</i>S310F Mutation
Authors: Saranya Chumsri, Jodi Weidler, Siraj Ali, Sohail Balasubramanian, Gerald Wallweber, Lisa DeFazio-Eli, Ahmed Chenna, Weidong Huang, Angela DeRidder, Lindsay Goicocheal, Edith A. Perez
Journal: Journal of the National Comprehensive Cancer Network (2015)

In the current genomic era, increasing evidence demonstrates that approximately 2% of HER2-negative breast cancers, by current standard testings, harbor activating mutations of ERBB2. However, whether patients with HER2-negative breast cancer with activating mutations of ERBB2 also experience response to anti-HER2 therapies remains unclear. This case report describes a patient with HER2-nonamplified heavily pretreated breast cancer who experienced prolonged response to trastuzumab in combination with pertuzumab and fulvestrant. Further molecular analysis demonstrated that her tumors had an elevated HER2 dimerization that corresponded to ERBB2 S310F mutation. Located in the extracellular domain of the HER2 protein, this mutation was reported to promote noncovalent dimerization that results in the activation of the downstream signaling pathways. This case highlights the fact that HER2-targeted therapy may be valuable in patients harboring an ERBB2 S310F mutation.
Characteristics of a phase II study that predict for a positive phase III trial—A study of 383 clinical trials
Authors: S. M. Ueda, V. E. Sugiyama, C. Stave, J. Y. Shin, B. J. Monk, D. S. Kapp, B. I. Sikic, K. Osann, J. K. Chan
Journal: Journal of Clinical Oncology (2007)

6604 Background: To identify the characteristics of a phase II study that predict for a subsequent positive phase III trial. Methods: All phase II studies and subsequent phase III clinical trials on biologics in advanced cancers published from 1985 to 2005 were extracted. Chi-square test and logistic regression models were used for analyses. Results: 383 phase III clinical trials and their preceding phase II studies were identified. 183 (47.8%) phase III trials were “positive” and 200 (52.2%) were negative. 220 trials (57.4%) used biologics alone and 162 (42.3%) used a combination of biologics and chemotherapy. Over the study periods 1985–1990, 1991–1995, 1996–2000, 2001–2005, the percentage of phase II studies that led to positive phase III trials increased from 37.7% to 33.3% to 56.0% to 76.8% (p&lt;0.001). The interval between the publication of phase II and III studies, 0.5–5, 6–10, 11–15, and 16–20 years were also associated with the success of phase III trial, 55.6%, 42.2%, 32.6%, and 10.0%, respectively (p&lt;0.001). Phase II studies from multiple rather than single institutions were more likely to have a successful trial (60.4% vs. 39.4%; p&lt;0.001). The percent of successful trials from pharmaceutical companies was significantly higher compared to academic, cooperative groups, and research institutes (89.5% vs. 44.2%, 45.2%, 46.3%; p=0.002). The publication of the phase II studies in journals with an impact factor of 8 or greater compared to those less than 8 was also predictive (44.1% vs. 58.0%; p=0.024). Phase II studies with a lower attrition rate were also associated with a positive phase III trial (61.1% vs. 41.8%; p=0.025). On multivariable analysis, all factors, except for journal impact factor, were independent predictive factors for a positive phase III trial. Conclusions: In phase II biologic studies, characteristics such as larger number of patients, more recent year of study, multiple vs. single institution participation, shorter time period between publication of phase II to phase III trial, and lower rate of attrition were predictive factors of success in a phase III trial. Investigators need to be cognizant of these phase II study characteristics before designing phase III trials. No significant financial relationships to disclose.
Utilization of phospho-GSK3b as a cellular and in vivo pharmacodynamic marker to evaluate the activity of AKT pathway inhibitors
Authors: Sandaruwan Geeganage, Zhao Hai Lu, Albert Dee, Lillian Sams, Tao Wang, Sophie Boguslawski, Sajan Joseph, Mei Lai
Journal: Cancer Research (2007)

288   The PI3 Kinase/AKT pathway plays a critical role in cell survival signaling and the activation of this pathway has been linked to tumorigenesis. Upregulation of AKT (PKB) and PI3 Kinase is seen in many tumor types and the negative regulator of this pathway PTEN is deleted in a number of tumor types. Therefore, this pathway remains an attractive target for cancer drug discovery. Glycogen Synthase Kinase-beta (GSK3b) is characterized to be phosphorylated at its Ser 9 site by AKT. Phosphorylation of GSK3b by AKT results in inactivation of the kinase activity of GSK3b and downstream activation of glycogen synthesis and metabolic events leading to and promoting cell proliferation. Therefore, phosphorylation of GSK3b at the Ser 9 site can be utilized as a pharmacodynamic marker for evaluating the in vivo PK/PD effects of AKT/PI3K inhibitors. We developed a novel in cell ELISA to measure the phosphorylation of GSK3b in U87MG cells. In order to link cellular target inhibition to in vivo target inhibition, we utilized a commercially available sandwich ELISA to measure the in vivo activity of PI3 Kinase/AKT pathway inhibitors quantitating the phosphorylation level of GSK3b in native U87MG glioblastoma cells. We treated these cells and mice bearing U87MG xenografts with the PI3 Kinase inhibitor wortmannin and an Isoquinoline Sulfonamide (IS) AKT inhibitor. The ELISA analysis showed that PI3 Kinase inhibitor Wortmannin and IS AKT inhibitor inhibits GSK3b phosphorylation U87MG cells potently in vitro and in vivo. The inhibition correlates well with the inhibition of phosphorylation of other known AKT substrates such as phospho-Forkhead and phospho-TSC2. In vivo pGSK3b inhibition shows excellent correlation with serum exposure of compound. These results show that phospho-GSK3b can be utilized as a in vitro and in vivo PD marker to develop inhibitors of AKT and PI3 Kinase as potential targeted cancer therapeutic agents.