tbuckley/cabot-search huggingface dataset:
Gene-signature-based patient selection for dasatinib therapy in metastatic breast cancer (MBC).
Authors: L. Pusztai, S. L. Moulder, J. K. Litton, V. Valero, N. T. Ueno, P. H. Morrow, K. Dotter, D. Mattair, L. C. Strauss, W. F. Symmans
Journal: Journal of Clinical Oncology (2010)

TPS130 Background: Dasatinib has modest single-agent activity in MBC. Several predictors of response have been proposed based on the known mechanism of action of this drug. The goal of this trial is to assess the positive predictive value of 3 conceptually different gene- signature-based patient selection methods. Methods: This study requires a mandatory biopsy of a metastatic lesion for gene expression analysis and employs a parallel, multi-arm, two-step, phase II design. Three markers are assessed including a cell-line derived dasatinib- sensitivity signature, a src-pathway activity signature and a summary index of all known dasatinib targets. Only marker-positive patients are treated and each marker arm is considered as a separate study with early stopping rules for futility (minimum sample size 9, maximum sample size 40/marker arm). A predictor is considered worthy of further study if the clinical benefit rate is ≥25%. Results: Twenty-five patients were accrued from July through December, 2009 to this ongoing study and 27 fine-needle aspirations (FNA) were performed (lymph nodes n=13, chest wall n=8, liver n=2, and rib, adrenal gland, skin nodule, breast n=1 each). Twenty-two samples (81%) yielded adequate tissue for molecular analysis and 91% (n=20) of these provided high- quality genomic profiles; 14 (70%) patients had a positive result for at least 1 predictor (4 were positive for 2 predictors) and are receiving therapy. The median time from biopsy to genomic prediction result was 5 days (range 3-7). There was no patient recall, hospitalization or emergency room visit due to biopsy procedure. As of December 29, 2009, no marker arm has yet met accrual goals for the first interim efficacy analysis. Conclusions: Gene- expression signature based patient selection for targeted therapy is feasible and FNA biopsies of metastatic lesions for genomic testing are safe. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.
Authors: T. Doi, N. Fuse, T. Yoshino, H. Murakami, N. Yamamoto, N. Boku, S. Otani, K. Shibayama, T. Takubo, L. Elwyn
Journal: Journal of Clinical Oncology (2011)

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]
Impact of travel distance on early diagnosis of prostate cancer (CaP) and receipt of curative treatment.
Authors: J. A. Holmes, W. R. Carpenter, Y. Wu, S. P. Hinton, M. Massing, A. P. Schenck, A. Meyer, S. B. Wheeler, P. A. Godley, R. C. Chen
Journal: Journal of Clinical Oncology (2011)

6129 Background: Patients with an elevated prostate specific antigen (PSA) level need to travel to a urologist for diagnostic biopsy; once diagnosed, travel to a urologist or radiation oncologist for curative treatment. We examined whether travel distance is associated with early diagnosis of CaP and receipt of curative treatment. Methods: North Carolina Central Cancer Registry data were linked with Medicare for 3,492 men age 65 and older and diagnosed with CaP in 2004-5. Straight-line distances from each patient to nearest urologist and nearest radiation oncologist were calculated. Linear regression was used to examine the association between distance to urologist and PSA at diagnosis while accounting for race, age, comorbidity, marital status, and urban vs. rural residence. Logistic regression was used to examine the association between distance and curative treatment: radiation therapy (RT), brachytherapy (BT), or surgery. Results: Early CaP (PSA 0-10) was more common in those living 0-10 miles vs. those living >20 miles from a urologist (69 vs. 59%, p=.04) (Table). In multivariable analysis, distance was significantly associated with higher PSA at diagnosis (β = 0.16, p<.01). In the subgroup of men with localized CaP and older than 75, in whom surgery is unlikely a treatment option, distance to nearest radiation oncologist was significantly associated with receipt of curative treatment (p<.01), especially radiation (Table). This effect remained significant on multivariable modeling (p<.01). Conclusions: Longer distance to a urologist is associated with a delay in CaP diagnosis for elderly men with elevated PSA. Distance also appears to contribute to decision-making regarding whether to pursue curative treatment in men 75 and older. Distance may represent a modifiable obstacle to health care access. Distance to urologist (miles) PSA at diagnosis (ng/mL) Distance to radiation (miles) Treatment 0-10 (%) 11-20 (%) >20 (%) RT/BT (%) Surgery (%) ADT/none (%) 0-10 69 16 15 0-10 48 2 50 11-20 68 16 16 11-20 39 2 59 > 20 59 21 20 > 20 34 3 63
Use of colorectal cancer subtypes identified through iterative clustering to predict response to therapy.
Authors: Andreas Schlicker, Garry Beran, Christine M Chresta, Gael McWalter, Alison Pritchard, Susie Weston, Sarah Runswick, Sara Davenport, Kerry Heathcote, Denis Alferez Castro, George Orphanides, Tim French, Lodewyk F A Wessels
Journal: Journal of Clinical Oncology (2012)

482 Background: Colorectal cancer (CRC) is generally stratified based on genetic and epigenetic features, such as KRAS mutation and microsatellite instability status. In order to facilitate the development of new targeted drugs and treatment regimens, it is important to redefine CRC at the molecular level by identifying subtypes that are relevant for response to targeted therapy. Methods: We applied a new unsupervised approach for iteratively stratifying tumor samples using genome-wide mRNA expression data. The resulting gene expression signatures were used to subtype CRC cell line panels and publicly available CRC tumor datasets. We employed pharmacological data on the cell line panels to link the subtypes to therapy response. Results: Starting from a gene expression dataset of 63 CRC tumor samples, we employed non-negative matrix factorization (NMF) and identified two dominant CRC subtypes. In agreement with previously published results, one of the types showed a mesenchymal and the other an epithelial-like gene expression pattern. In a second step, we applied NMF on these two dominant subtypes and further stratified them into two and three subtypes, respectively. The resulting five CRC subtypes show many differences, most notably activation of specific signaling pathways. Importantly, we recovered these five subtypes in several independent, publicly available CRC datasets. This strongly suggests that the signatures capture disease-relevant features of CRC. Furthermore, we found that the different subtypes corresponded to different cell lines in a panel of CRC cell lines. The clustered CRC cell lines displayed differential responses to a number of targeted compounds, indicating that the new CRC clusters may represent disease subtypes that of differential drug sensitivity. Conclusions: The CRC subtypes discovered using our new method offer new insights into the functional and molecular processes driving CRC. Furthermore, the evidence suggests that these subtypes may differ in activated pathway status and the response to some targeted inhibitors, indicating that targeting pathways conserved in these subtypes may provide new drug discovery opportunities.
Evaluation of phase II clinical trials of small molecule targeted inhibitors
Authors: C. C. Portera, J. E. Dancey
Journal: Journal of Clinical Oncology (2008)

14686 Background: Small molecule inhibitors, often cytostatic, pose challenges to phase (ph) II trial paradigms. Randomized ph II studies assessing rates and durations of disease stability, identification of markers for sensitivity and novel endpoints may be required for optimal evaluation. To identify how ph II studies have been conducted and to determine factors affecting trial outcome, we conducted a systemic evaluation of ph II trials of these agents. Methods: Medline search of ph II trials between 2000 to Oct 2007 was conducted. Inclusion criteria were single small molecule inhibitors of known targets, cancers excluding leukemia/lymphoma and in journals with impact factor ≥5. Publications were reviewed and following data were extracted: agent, tumor type, trial design, # patients, endpoint(s), correlative studies, clinical outcome, ph I activities, and whether agent proceeded to ph III. Results: Fifty six of 605 publications met the criteria. The 1° endpoints were response rate in 37 (66%), and progression-free or overall survival rate in 14 (25%). Seven (12.5%) did not have a clear description of statistics. Only 3 (5%) used randomized designs. Correlative studies were reported in 36 (64%). Ten evaluated small numbers of paired pre- post-treatment tumor biopsies, and 10 showed target inhibition or association of tumor characteristics with response. No studies were designed to specifically assess biomarkers as predictive markers. Two (4%) had a biomarker-defined study population. Ten (18%) met pre-determined primary endpoint goals. Among them, 3 (5%) proceeded to ph III and subsequently received FDA approval, 4 tested 2 FDA approved agents in selected patient populations with 2 follow-up ph III trials, and 3 tested novel agents in 3 tumor types without subsequent ph III trials. Conclusions: Most ph II studies of targeted agents used traditional endpoints and designs in histologically defined study populations. The success rates remain low. More studies are required to determine if randomized designs and incorporation of biomarker studies into ph II trials result in more successful ph III trials. Efforts should be made to define optimal design, study populations and biomarker studies for these agents and to improve standardized clinical trial reporting and quality of correlative studies. No significant financial relationships to disclose.
Increased Bcl-2 expression is associated with Bax promoter hypermethylation in neuroendocrine carcinoma (NEC) of the lung.
Authors: D. C. McFarland, M. Batus, L. Buckingham, J. Coon, S. Basu, M. J. Fidler, K. K. Walters, J. A. Borgia, P. D. Bonomi
Journal: Journal of Clinical Oncology (2011)

e21136 Background: Minimal advances have been made in the treatment of NECs, including small cell lung cancer (SCLC). Bcl-2 and Bax are key regulators of apoptosis. Previous studies have shown that high Bcl-2 and low Bax expression are associated with worse outcomes in NEC. The objective of our study was to quantify Bax promoter hypermethylation and correlated with Bcl-2 expression. Methods: Tissues from 150 patients treated as SCLC were stained for multiple molecular makers including Bcl-2 and Bax. Frequency and intensity of expression were measured on a scale of 0-4 (freq 0 = no expression, freq 1=1-10%, freq 2=11-35%, freq 3=36-70%, freq 4=71-100%). Methylation analysis was performed using pyrosequencing. Results: Of the original 150 tissue samples, 64 samples were analyzed for Bax methylation. Of the Bax hypermethylated samples (overall average CpG methylation >10%), 73% were Bcl-2 positive (freqXint>or=2) vs. 21% of the samples without Bax hypermethylation (Chi square p=0.002). At Bax promoter CpG site -50 (translation start=+1), methylation was 13.0% in the Bcl-2 positive vs. 7.82% for the Bcl-2 negative samples (p=0.005). Analyses of progression free and overall survival are ongoing. Conclusions: Bax hypermethylation was associated with higher Bcl-2 expression in this group of NEC patients. There results suggest that it would be reasonable to test hypomethylating agents combined with cytotoxic agents or with Bcl-2 inhibitors in NEC of the lung.
Autonomic, functional, skeletal muscle, and cardiac abnormalities are associated with increased ergoreflex sensitivity in mitochondrial disease
Authors: Alberto Giannoni, Alberto Aimo, Michelangelo Mancuso, Massimo Francesco Piepoli, Daniele Orsucci, Giovanni Donato Aquaro, Andrea Barison, Daniele De Marchi, Claudia Taddei, Matteo Cameli, Valentina Raglianti, Gabriele Siciliano, Claudio Passino, Michele Emdin
Journal: European Journal of Heart Failure (2017)
Fusion Transcript Reduction in Core Binding Factor Acute Myeloid Leukemia: Maintenance Strategy with Hypomethylating Agents
Authors: Brittany Knick Ragon, Naval Daver, Guillermo Garcia-Manero, Maro Ohanian, Alessandra Ferrajoli, Naveen Pemmaraju, Hagop M Kantarjian, Gautam Borthakur
Journal: Blood (2015)
Phase II study of the combination of oral vinorelbine (NVBo), capecitabine (X), and trastuzumab (H) in HER2-positive, metastatic breast cancer (MBC): Recent analysis of the results with a median follow-up of 44 months.
Authors: L. B. Petruzelka, V. Ganju, D. Becquart, P. F. Conte, N. Tubiana-Mathieu, M. J. Gil Gil, M. Morand, N. Vaissiere, G. Villanova, A. Chan
Journal: Journal of Clinical Oncology (2010)

1077 Background: The oral chemotherapy (CT) combination of NVBo and X has shown activity and good tolerability in MBC. H +CT is the standard treatment for HER2-positive MBC. We report the latest results from a multinational phase II study assessing the efficacy and safety of NVBo, X, and H in HER2-positive MBC after a median follow-up of 44 months. Methods: Main eligibility criteria included: HER2-positive disease, measurable metastatic disease previously untreated by CT, Karnofsky PS ≥70. Study treatment (until progression): NVBo was given as a 80 mg/m2 dose (following a first cycle at 60 mg/m2) D1 and D8 every 3 weeks, X at 1000 (750 if ≥65 y) mg/m2/bid D1-D14 every 3 weeks, H at 4 mg/kg on D1 (loading dose) then 2 mg/kg i.v. weekly starting on D8. Results: Main patient (pt) characteristics in the full population (n=50): median age: 53.5 years (18% ≥65); prior (neo)adjuvant CT 54%; visceral involvement 82%; >2 metastatic sites 34%; median number of cycles: 10 (range:1-81); 72% of pts received more than 6 cycles, 58% more than 8 cycles, and 32% more than 16 cycles; median number of NVBo administrations: 20 (range:1-161); median number of trastuzumab administrations: 30 (range:1-251); median relative dose intensity: NVBo 76%, X 78%, H 96%; G3/4 adverse events per pt: neutropenia 71%, hand-foot syndrome 20%, diarrhea 16%, vomiting 12%, asthenia 8%, febrile neutropenia 8% (0.5% of cycles), infection 6%, LVEF decline 4%, alopecia (grade 2) 14%. Efficacy (n=44 evaluable pts): objective response rate (RECIST) 77% (95% CI [62-89]), CR 21%, PR 57%, SD 18%, PD 5%, disease control (CR+PR+ SD ≥6 months) 93% (95% CI [81-99]); median duration of response was 13.3 months (95% CI [9.8-15.7]) and median progression-free survival was 12.8 months (95% CI [10.8-16.9]). Overall survival results are not mature yet. 26 pts are alive and 4 pts are still receiving full study treatment. Conclusions: The oral regimen of NVBo and X is active when combined with H for HER2-positive MBC. Treatment can be maintained until progression without intolerable toxicities in the majority of pts which allows ongoing synergism of the agents to continue. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pierre Fabre Medicament
Primary Parotid MALT Lymphoma: Clinical Characteristics and Treatment – a Single Institution Experience
Authors: Jason M. Jones, Thomas M. Habermann, Kay M. Ristow, Paul Kurtin, Ellen McPhail, Carrie A. Thompson, Joseph P. Colgan, Luis F. Porrata, Svetomir N. Markovic, Thomas E. Witzig, James A. Martenson, Grzegorz S. Nowakowski
Journal: Blood (2011)
Postoperative complications of radical nephrectomy with atrial thrombectomy: A contemporary population-based analysis.
Authors: Tudor Borza, Benjamin I. Chung, Steven L. Chang
Journal: Journal of Clinical Oncology (2014)

423 Background: The mainstay treatment for patients with stage T3c renal cell carcinoma is radical nephrectomy with atrial thrombectomy (RN−AT). Although this procedure is widely recognized to have substantial morbidity and mortality, little data exist on the actual rates of postoperative complications. Using a contemporary population−based cohort, we sought to determine the postoperative complication rates among patients undergoing RN−AT. Methods: We queried the Premier Perspective Database (Premier, Inc, Charlotte, NC) to identify patients that underwent nephrectomy (ICD9 55.51) between January 1, 2003 and December 31, 2010. We limited our analysis to patients who concurrently underwent cardiopulmonary bypass, determined through billing codes, as these patients were assumed to have undergone RN−AT. We captured patient and hospital data as well as determined 90−day postoperative complications defined by the Clavien System through review of ICD9 codes and disposition data. Results: Our study cohort included a weighted sample size of 1417 patients; the majority were men (63.7%) and Caucasian (61.9%) with a mean age of 58 years. One−third of patients had metastatic disease while one−quarter had significant comorbidities (i.e., Charlson Comorbidity Score (CCS) ≥2). Ninety−day major complication (Clavien grade 3−5) was present in 38% of patients with half (19%) suffering mortality (Clavien grade 5). The predictors of a major complication included age &lt;50 years (vs &gt;70 years, Odds Ratio [OR] 3.1, p=0.01), CCS ≥3 (vs CCS 0, OR 5.7, p&lt;0.0001), and surgery in an urban hospital (vs rural, OR 8.5, p=0.047). Increased complication rate was not associated with gender, race, metastatic disease, teaching institution, or hospital size. Conclusions: We confirm that RN−AT is associated with significant morbidity and mortality. The mortality rate for this procedure exceeds those reported for other complex surgeries. The higher complication rate seen in younger patients is likely secondary to selection bias. This information is important for preoperative counseling for patients considering RN−AT. Future studies are needed to compare the outcomes of RN−AT versus systemic therapy.
Pathways clinical decision support for appropriate use of key biomarker.
Authors: Peter G. Ellis, Kathleen Lokay
Journal: Journal of Clinical Oncology (2014)

172 Background: UPMC CancerCenter (UPMC) has utilized clinical pathways for almost ten years in an effort to ensure standardization to the evidence based care for its patients. UPMC oncologists participate in the various pathways disease committees that develop and maintain the pathways content and utilize the pathways through a web-based portal in their daily decision making and documentation. The pathways cover not only treatment recommendations but also guidance for work up such as recurrence risk tools (OncoType Dx) for node negative, HER2 negative, ER positive breast cancer who are candidates for chemotherapy. For patients with a low recurrence risk score, the pathways recommends hormonal therapy only, saving the patient both toxicities and costs of chemotherapy where appropriate. Methods: UPMC analyzed its use of chemotherapy in patients with a recurrence risk score of less than 19 through a retrospective review of physician-input data in its Via Pathways Portal for the twelve months ended May 31, 2014. During this time period, the Via Pathways recommended the recurrence risk test for node negative, HER2 negative, ER positive patients. For patients with a low risk score (less than 19), the Via Pathways recommended hormonal therapy only. For those low risk score patients receiving chemotherapy, the physician would document that an Off Pathway decision was being made, indicate the reason for going Off Pathway, and document the actual therapy delivered. Results: For the twelve months ended May 31, 2014, UPMC physicians documented 288 decisions for patient presentation of node negative, HER2 negative, ER positive patients with a recurrence risk score of less than 19. Of these decisions, 99% (n=284) were On Pathway for hormonal therapy. Of the remaining 1%, three (3) were for accrual to a clinical trial and one (1) was Off Pathway for chemotherapy. Conclusions: Pathways are a tool for promoting adherence to evidence based care by oncologists through the use of a point of care decision support system. Pathways have the potential to reduce costs and toxicities of treatment through the evidence based guidance developed by the pathways disease committees and the adherence to such guidance by oncologists utilizing the pathways decision support tool.