tbuckley/cabot-search huggingface dataset:
A comparison of biologics in first-line advanced colorectal cancer: A Bayesian network meta-analysis of EGFR inhibitors and bevacizumab.
Authors: Alexander Kumachev, Marie Yan, Scott R. Berry, Yoo-Joung Ko, Maria Carmen Riesco Martinez, Keya Shah, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2014)

543 Background: Adding bevacizumab (B) or EGFR inhibitors (E) to chemotherapy have improved outcomes when compared to chemotherapy (chemo) alone in the first-line treatment of mCRC, however it is unclear which of these combinations is optimal. As the 2 RCTs presented to date were not powered to detect overall survival (OS) benefits and have shown conflicting OS results, a meta-analysis may be beneficial. Methods: We conducted a systematic review of RCTs comparing (1) E + chemo vs. B + chemo (2) E + chemo vs. chemo only, or (3) B + chemo vs. chemo only, using MEDLINE, Embase, Cochrane Central, and ASCO abstracts up to June 2013 with Cochrane methodology. Data on PFS and OS were extracted using the Parmar method. For RCTs involving E, only the K-ras WT data was included. The patient characteristics and outcomes of the reference arms of the RCTs were examined to assess for heterogeneity. Bayesian pairwise and network meta-analyses (NMA) were conducted to estimate the direct, indirect and combined PFS and OS hazard ratios comparing E to B using WinBUGs. Results: Seventeen RCTs (8,048 patients) were identified; 15 of them contained extractable data for quantitative analysis. Direct pairwise meta-analyses (2 RCTs) comparing E vs. B showed that PFS HR=1.00 (95% credible regions (CR): 0.86-1.17) and OS HR=0.76 (95% CR: 0.63-0.92) in favour of E. Indirect comparisons of E vs. B (through the intermediate of chemo only: 5 RCTs comparing E + chemo vs. chemo only, 8 RCTs comparing B + chemo vs. chemo only) showed that PFS HR=1.31 (95% CR: 0.98-1.85) and OS HR=1.06 (95% CR: 0.93-1.22). Combining direct and indirect comparisons with NMA (15 RCTs) showed that the PFS HR=1.10 (95% CR: 1.00-1.21) (trend in favour of B) and OS HR=0.95 (95% CR: 0.85-1.06). Conclusions: The results of direct pairwise meta-analysis, dominated mostly by FIRE-3, suggested E improves OS without PFS benefits when compared to B. However, the results from indirect or combined NMA synthesizing all relevant data from the existing literature did not confirm those findings. The findings of FIRE-3 may be due to chance or trial specific reasons. The results of the upcoming CALGB 80405 will provide further direct evidence to help refine these estimates.
Venous thromboembolic complications in patients with malignant glioma treated on a bevacizumab clinical trial.
Authors: A. L. Sumrall, D. A. Reardon, A. Desjardins, K. Peters, E. Lou, S. G. Turner, L. Bailey, H. S. Friedman, J. J. Vredenburgh
Journal: Journal of Clinical Oncology (2011)

9090 Background: Although the prognosis for malignant glioma remains poor, the introduction of bevacizumab has improved survival for patients with this devastating illness. Bevacizumab is a humanized monoclonal antibody to vascular endothelial growth factor (VEGF). Patients with malignant gliomas are felt to have an incidence of thromboembolism in 20-30%. As patients with malignant gliomas are at increased risk for venous thrombosis by nature of their diagnosis, one worries about potentially increasing this risk with the addition of bevacizumab. Previous reports have shown an incidence of approximately 25% of venous thromboembolic disease in cancer patients receiving concurrent chemotherapy and bevacizumab. Methods: We performed a retrospective analysis of all clinical trial participants receiving bevacizumab for malignant glioma from April 2005 to January 2011. 617 patients with malignant glioma were included: 529 with glioblastoma (GBM) and 88 with anaplastic glioma (AG). Of those, 204 patients were newly diagnosed. This group was treated with standard temozolomide and radiation, combined with bevacizumab and a topoisomerase I inhibitor. 413 patients with recurrent tumors were included. Their treatment regimens varied, but all had progressed on standard therapy. After being diagnosed with a venous thromboembolic complication, patients were started on anticoagulation with heparin, low molecular weight heparin, or warfarin. They were followed until death or progression of disease. Results: The incidence of venous thrombosis was 7% (n=43), and incidence of pulmonary embolism was 2.9% (n=18). Of those, 1.3% (n=8) were patients with anaplastic glioma. Newly diagnosed patients represented only 2.3% (n=14). Of those patients, 0.6% (n=4) had a history of previous venous thrombosis but were no longer on anticoagulation. The mean time on treatment prior to diagnosis of the venous thromboembolic complication was 105.8 days; and a median time of 87 days. Of the patients treated for thromboembolic disease, 0.5% (n=3) had intracranial hemorrhage. Conclusions: Use of bevacizumab does not increase the risk of venous thromboembolic complications in patients with malignant gliomas.
Can equitable care eliminate colon cancer disparities?
Authors: Manali I. Patel, Yifei Ma, Kim Felder Rhoads
Journal: Journal of Clinical Oncology (2012)

91 Background: Previous studies suggest lack of insurance and variations in quality of care may drive disparities in colon cancer (CC), but equitable care may close these gaps. To clarify the role of equitable care on racial disparities, we compared CC survival in one of California’s largest Health Maintenance Organization (HMO) to survival in all other hospitals across the state. We hypothesized that disparities would be less pronounced in the HMO. Methods: All CC cases treated from 1996-2006 were identified in the California Cancer Registry linked to hospital discharge abstracts from the Office of Statewide Health Planning and Development. Enrollees in the state’s largest HMO were identified as such. Five year mortality was compared between HMO enrollees and all other patients using Cox proportional hazard models. Results: 62,184 CC records were included. 25% were HMO enrollees. The HMO treated a higher percent of black patients (9.2% versus 5.5%) and fewer Medicaid patients (2.1% versus 4.5%). There was no disparity in the HMO setting blacks as compared with whites (HR 0.90 95% CI 0.79-1.02); but black patients fared worse in the non-HMO settings (HR 1.15 95% CI 1.07-1.23). Conclusions: CC disparities are differentially distributed across California hospitals systems. Since there were no disparities in California’s large HMO, where care is typically protocol-driven, our findings suggest delivery of equitable care may eliminate disparities. These findings are consistent with other studies in the literature. Future research should assess the effect of emerging Accountable Care Organizations on the elimination of racial disparities in other cancers and diseases.
Use of imaging for staging of early breast cancer in two integrated health care systems.
Authors: Erin Elizabeth Hahn, Tania Tang, Janet S. Lee, Corrine Munoz-Plaza, Joyce O Adesina, Ernest Shen, Braden D. Rowley, Jared L Maeda, David M Mosen, John C. Ruckdeschel, Michael K Gould
Journal: Journal of Clinical Oncology (2014)

184 Background: The initial ASCO “Top 5” list, created as part of the Choosing Wisely campaign, recommends against use of imaging for staging of early stage breast cancer in asymptomatic women at low risk for metastasis. The objective of this study was to measure and compare use of imaging for staging in two large integrated health care systems, Kaiser Permanente (KP) and Intermountain Healthcare (IH). We also sought to distinguish whether imaging was used for routine staging or for diagnostic purposes. Methods: We identified stage 0-IIB breast cancer patients diagnosed between January 1, 2010 and December 31, 2012 with first primary malignancy from tumor registries in three KP regions (Southern California, Northwest, and Mid-Atlantic) and IH. Using the KP and IH electronic health records, we identified use of imaging tests (PET, CT, bone scan) during the staging window (30 days prior to diagnosis up to initial surgery). We performed chart abstraction on a random sample of patients who received an imaging test to identify indication. Results: For the total sample of 10,014, mean age at diagnosis was 60 (range 22-99); with 21% stage 0, 47% stage I, 32% stage II. Overall, 8% of patients (792 patients) received at least one imaging test during the staging window, including 8% at KP and 6% at IH (p=0.0005). Chart abstraction (N=129) revealed that overall, almost half of all imaging tests (48%) were performed to evaluate a symptom, sign or prior imaging finding, including 55% at KP and 32% at IH. Conclusions: Use of imaging for staging of low-risk breast cancer was very low in both health care systems, with clinically trivial differences between them. Approximately half of imaging services were in response to a sign or symptom. Strategies to reduce use of imaging at staging for early stage breast cancer patients within these health care systems are unlikely to yield meaningful improvement. [Table: see text]
Moving next-generation sequencing into the clinical realm: Detection of somatic mutations in cancer by targeted amplicon sequencing.
Authors: Chih-Jian Lih, Thomas Forbes, Michele Mehaffey, Eric Sause, David Sims, Paul McGregor, Barbara A. Conley, Shivaani Kummar, Paul M. Williams
Journal: Journal of Clinical Oncology (2012)

60 Background: Molecular targeted therapies are increasingly important in treating cancer patients; robust analytically validated clinical assays are required for patient selection in early-stage clinical trials. The goal of Molecular Characterization Laboratory (MoCha) is to develop clinical diagnostic assays using next generation sequencing methods to support clinical studies in DCTD (CTEP). Methods: We developed a custom assay for somatic mutation detection using Fluidigm access array technology for amplicon generation followed by sequencing with the Illumina Miseq. A panel of 62 amplicons covering 6 Kb genomic regions was designed to detect 92 DNA loci, including common therapeutically actionable targets, in 37 genes. Analytical studies were performed using genomic DNA samples from fresh or formalin fixed cancer cell-lines and a normal hapmap individual (CEPH). We subsequently applied this assay to characterize DNA samples from both tumor tissues and blood specimens from ovarian cancer patients. Results: The assay detected known variants in both frozen and fixed DNA samples reproducibly with high sensitivity and specificity (&lt;2%). Using a series of positive control plasmid spikes mixed into a normal reference CEPH DNA at pre-defined copy number ratios, we verified the assay is sensitive to detect variants at 5% allelic frequency with a minimum 400 X coverage. We identified somatic mutations in TP53 and PIK3CA in a few patients, and a germ-line variant D1583N in ATM genes occurring in one-third of tested patients. Conclusions: We developed and validated a next generation sequencing assay suitable for patient selection for clinical trials. Plans are to correlate sequencing and clinical results when clinical data are available.
Active immunization toward the MAGE-A3 antigen in patients with metastatic melanoma: Four-year follow-up results from a randomized phase II study (EORTC16032-18031).
Authors: W. Kruit, S. Suciu, B. Dreno, V. Chiarion-Sileni, L. Mortier, C. Robert, M. Maio, F. Lehmann, V. G. Brichard, A. Spatz, A. M. Eggermont, U. Keilholz
Journal: Journal of Clinical Oncology (2011)

8535 Background: Active immunization towards MAGE-A3 tumor antigen is a potential new approach to treat cancer. Current data from pilot studies have shown that a strong and persistent immune response is obtained when an immunostimulant is added to recombinant MAGE-A3 protein. This open labeled, randomized Phase II trial (NCT00086866) has been designed to evaluate the safety and the clinical activity observed with two different ASCI formulations (Primary endpoints: rate of grade 3/4 adverse events [AEs] + rate of objective clinical response [OCR]). Methods: 72 Patients (Pts) with MAGE-A3 positive unresectable stage III- IV M1a cutaneous melanoma were randomly assigned to both MAGE-A3 ASCI formulations: i.e. recMAGE-A3 combined with AS02B or AS15 immunostimulants. A maximum of 24 immunizations were administered over 4 years. Results: Out of the 165 screened pts, 97 had a MAGE-A3 positive tumor and 36 eligible pts were randomized in each arm. After a median follow-up of 48-months, 5 pts have demonstrated an OCR; 3 CR (11, 28+ and 55+ months) and 1 PR (6 months) in the AS15 arm and 1 PR (7 months) in the AS02B arm. SD (between 3 and 36 months) was seen in 5 pts in each arm. The number of pts who completed the 1-year immunization period (>16 doses) was 8 (AS15 arm) vs. 5 (AS02B). The median overall survival was 33.0 (AS15) vs 19.9 months (AS02B). Both treatments were well tolerated, with most AEs being of grade 1 or 2. Considering highest grades during study period, the frequency of grade 3 AE possibly related to treatment was very low: 5.6% (AS15) vs 2.8% (AS02B). No related grade 4 was reported. All patients developed a humoral immune response and a specific CD4+ T-cells response more frequent and of higher amplitude in the AS15 arm than in the AS02B arm (69% vs 21% respectively). Conclusions: Immunization with both MAGE-A3 ASCI formulations has been well tolerated. In the AS15 arm, the rate of OCR was promising, as was the duration of response, time to progression (up to 4 years), and the overall survival as well (median = 33 months). In addition, in this arm, cellular and humoral immune responses were observed in more than 2/3rd of pts. The AS15 formulation deserves further evaluation.
Biomarker analyses from a phase l study of pertuzumab combined with erlotinib in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: E. Felip, M. Ranson, S. Cedres, M. Brewster, V. Mcnally, M. Venturi, A. Passioukov, G. Ross, D. Galdermans
Journal: Journal of Clinical Oncology (2010)

7540 Background: Pertuzumab (P) is a fully humanised, murine monoclonal antibody that targets the dimerisation epitope of human epidermal growth factor receptor (HER) 2, preventing dimerisation between HER2 and other HER receptors and inducing antibody-dependent cell-mediated cytotoxicity. P as a single agent is not associated with meaningful activity against NSCLC, though stable disease (SD) has been observed in a phase II study (Herbst et al. Clin Cancer Res 2007;13:6175). Erlotinib (E) inhibits HER1 tyrosine kinase signalling and is widely registered for treatment of relapsed NSCLC. By inhibiting extracellular receptor dimerisation, as well as internal signal transduction through HER1, the combination of E and P would be expected to result in extensive blockade of HER signalling. Preclinical and initial response data seem to confirm this (Felip et al. ESMO 2008, abs 269P). Methods: 15 pts in 2 cohorts were treated in this Phase I, dose-escalating study. There was no evidence of pharmacokinetic interaction and the majority of treatment-related adverse events were CTC grade 1 or 2; full doses of each drug were recommended for further phase II evaluation. Potential biomarkers possibly associated with antitumour activity of P and E were measured in tumour tissue and evaluated against clinical disease status. Proteins of potential significance were measured by immunohistochemistry (IHC) and mRNA by reverse transcriptase real-time quantitative polymerase chain reaction (RT qPCR). The panel of biomarkers measured included HER1 (epidermal growth factor receptor [EGFR]), HER2 and HER3. Results: Progression-free survival and tumour response were evaluated in all 15 pts. There were 3 partial responses (20%), with 1 further pt experiencing SD of ≥ 6 months. 13 pts had tumour samples that were suitable for full quantification of EGFR, HER2 and HER3 by RT qPCR as well as other markers by IHC. Interestingly, higher levels of mRNA for some HER receptors, as well as IHC markers, may correlate with treatment response. Conclusions: The biomarker analyses may provide some initial insight into markers of efficacy, although the data are limited by small numbers. Full data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche, Roche Diagnostics GmbH Roche Roche
Postoperative radiotherapy treatment evolution in prostate cancer patients: A trend moving away from guidelines?
Authors: Elisabeth E. Arrojo, Alvaro Martinez, Michael Ghilezan, Jeffrey D. Forman, Eduardo Fernandez
Journal: Journal of Clinical Oncology (2016)

111 Background: Randomized prospective clinical trials have demonstrated the benefit of adding postoperative radiotherapy (P-RT) for patients with prostate cancer with adverse pathological factors who underwent radical prostatectomy. Based on scientific evidence, the American Urological Association and American Society of Therapeutic Radiologists and Oncology, recommend offering P-RT to this type of patients. Methods: Retrospective analysis of 156,795 patients with prostate cancer diagnosed between 2004 and 2012, who underwent radical prostatectomy. The clinic-pathological information has been extracted from the database "Surveillance Epidemiology and End Results Program". Stage IV patients, and those with "Unknown" information on the type of surgery, radiotherapy, stage or grade, were excluded. Results: Stage II was the most common (81.9%), followed by stage III (18% of the patients). A 60% of the patients had Gleason &gt; / = 8. Only 11.7% of the patients were &gt; / = 70 years old. Treatment with P-RT decreased significantly between 2004 and 2012 (-0.44%; p = 0.0003). Analyzed by subgroups, P-RT decreased significantly in stage II (-0.72%; p &lt; 0.0001) and III (-2.69%; p = 0.005), in patients with Gleason 6-7 (-1.05%; p = 0.0002) and &gt; / = 8 (-1.79%; p = 0.0001) and &lt; 70 years (-0.37%; p = 0.0001), whereas in &gt; / = 70 years decreased but not significantly (-0.53%; p = 0.13). Conclusions: The use of P-RT in patients with prostate cancer who underwent radical prostatectomy is declining. What is most striking, is that the magnitude of this decline, is greatest in patients with higher risk factors, as the percentage of patients with Gleason score &gt; / = 8 and/or Stage III (extracapsular invasion and/or involvement of seminal vesicles) receiving P-RT, declined more than the decline in the percentage of patients with Gleason 6-7 and/or stage II receiving P-RT, which clearly departs from the recommendations contained in the main treatment guidelines.
AR DNA binding domain inhibitors to treat AR splice variant-driven prostate cancer.
Authors: Jeremy Jones, Maya otto-Duessel, Ye Zhou, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2016)

293 Background: Nearly all prostate cancer (PC) cells depend on androgen receptor (AR) signaling for growth. Resistance to novel PC drugs like abiraterone and enzalutamide appears to occur through ligand-independent AR signaling, often by expression of AR splice variants (ARv’s) that lack the ligand binding domain (LBD). Thus, drugs that inhibit AR activity via domains other than the LBD may provide a way to inhibit the growth of drug-resistant PC. We discovered the first non-competitive, ligand-independent AR inhibitor, pyrvinium pamoate (PP), which functions by interacting with the DNA-binding domain (DBD) and preventing the recruitment of RNA polymerase II to transcription start sites. PP inhibits AR activity with low nanomolar potency and functions synergistically with competitive antagonists. Here, we undertook experiments to learn more about PP’s mechanism of action and developed an orally available derivative for translation to human studies. Methods: AR immunoprecipitation (IP) followed by mass spec sequencing was used to identify proteins that differentially bind to AR in the presence of PP. Additionally, RNA-seq was used to identify pathways affected by PP treatment. Functional studies of hits were conducted using over-expression and knock down in relevant PC cell lines. PP derivatives were developed through a medicinal chemistry approach. Lead compounds were tested in a battery of assays to determine potency in cultured cells and in vivo, as well as their solubility and pharmicokinetics. Results: RNA-seq results suggest that AR and hormone pathways are the primary target of PP in PC cells but that the splicing machinery is also be affected. Mass spec results also demonstrate that PP affects the interaction between AR and splicing machinery, as well as many transcription and translation-related proteins. Medicinal chemistry efforts led to a molecule with superior aqueous solubility, oral availability, and a half-life &gt; 6hrs. This compound inhibited the activity of AR and ARv’s in cultured cells and in xenograft models. Conclusions: PP was the first identified AR DBD inhibitor and the development of an orally available derivative holds great promise for the treatment of ARv-driven PCs.
New development in CAR-T cell therapy
Authors: Zhenguang Wang, Zhiqiang Wu, Yang Liu, Weidong Han
Journal: Journal of Hematology & Oncology (2017)

Chimeric antigen receptor (CAR)-engineered T cells (CAR-T cells) have yielded unprecedented efficacy in B cell malignancies, most remarkably in anti-CD19 CAR-T cells for B cell acute lymphoblastic leukemia (B-ALL) with up to a 90% complete remission rate. However, tumor antigen escape has emerged as a main challenge for the long-term disease control of this promising immunotherapy in B cell malignancies. In addition, this success has encountered significant hurdles in translation to solid tumors, and the safety of the on-target/off-tumor recognition of normal tissues is one of the main reasons. In this mini-review, we characterize some of the mechanisms for antigen loss relapse and new strategies to address this issue. In addition, we discuss some novel CAR designs that are being considered to enhance the safety of CAR-T cell therapy in solid tumors.
Treatment trends for stage III non-small cell lung cancer for noninsured patients compared with other types of insurances: A National Cancer Database analysis.
Authors: Khaled Abou El Ezz, David Charles Olson, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2012)

262 Background: This study investigated trends in management of stage III NSCLC in patients with no insurance versus other insurance types using the National Cancer Database (NCDB). Methods: 281,277 patients with Stage III NSCLC were identified from 2000 to 2009 using the NCDB. Reported use of surgery, radiation, chemotherapy, or no treatment were analyzed by insurance status. Results: Radiation/chemotherapy was most often used to treat stage III NSCLC among non-insured (41.7%), Medicare (31.3%), Medicaid (42.3%), and private insured patients (43.9%). Non-insured were just as likely to receive radiation/chemotherapy as Medicaid (41.7% vs. 42.3%, p=0.36) but less likely than privately insured (41.7% vs. 43.9%, p&lt;0.001). Non-insured were more likely to receive no treatment than privately insured (20.8% vs. 11.7%, p&lt;0.001) and Medicaid (20.8% vs. 16.8%, p &lt;0.001) but less likely than Medicare (20. 8% vs. 24.6%, p&lt;0.001). Tri-modality treatment was given less often to non-insured patients than privately insured (4.6% vs. 10.2%, p&lt;0.001) and Medicaid (4.6% vs. 6.2%, p&lt;0.001) but more often than Medicare patients (4.6% vs. 3.7%, p&lt;0.001). Conclusions: Stage III NSCLC was most often given chemotherapy/radiation regardless of insurance status. Non-insured patients received this treatment as often as Medicaid but less often than privately insured. Non-insured patients also received no treatment more often than Medicaid and privately insured and less often than Medicare. Future studies could examine if average age among the populations impacted these findings. [Table: see text]