tbuckley/cabot-search huggingface dataset:
Targeted next-generation sequencing (NGS) of circulating tumor cells (CTCs) in hormone-sensitive prostate cancer (HSPC).
Authors: Stephen V. Liu, Paul W. Dempsey, William Strauss, Yucheng Xu, Tong Xu, Jacek K. Pinski, Tanya B. Dorff, David I. Quinn, Timothy J. Triche, Jessamine Winer-Jones, Andre De Fusco, Janine McMurdie, Amir Goldkorn
Journal: Journal of Clinical Oncology (2013)

11040 Background: Recently a succession of new hormonal therapies has emerged, highlighting the need for biomarkers to guide the management of HSPC. Biomarker development in HSPC has been hampered by the absence of primary tumor tissue in men who undergo radiation or present with metastatic disease. CTCs can address this challenge by providing real-time cancer tissue for biomarker analysis in HSPC. To test this approach we conducted a pilot of CTC capture and targeted NGS in HSPC. Methods: Under IRB approval, blood samples from patients with HSPC were labeled with EpCAM ferrofluid and placed into the LiquidBiopsy platform (Cynvenio Biosystems, Inc.), an immunoaffinity-based microfluidic device tailored to query genomic events. CTCs were identified by CK, CD45 and DAPI expression. A matched WBC pellet served as a control representing germline sequence. Amplicon libraries were generated using Life Technologies AmpliSeq 2.0 and sequenced on an Ion Torrent platform. Somatic single nucleotide variants (SNV) present in CTCs but not in WBC were identified. Results: CTCs were detected in all 8 patients with HSPC (CTC median 64.5, range 17-217). Germline variants were consistently detected in matched CTC and WBC samples. Significant SNVs (occurring in &gt; 1% of DNA in a sample) were found in 4 of 8 CTC samples (range 1-5 SNVs/sample, frequency 1.2%-11.9% with 620X-14,422X coverage). Notably, 3 patients had biochemical recurrence only (no clinical metastases) yet still yielded CTCs associated with SNVs in KIT, APC, RET, SMAD4 and PTEN. One patient who had untreated metastatic disease had the highest number of CTCs which harbored 4 SNVs. Conclusions: This pilot demonstrates the feasibility of using CTCs as real-time disease relevant substrate for NGS to identify personalized genomic targets in HSPC. A high number of CTCs were detectable in all patients and CTC germline variants correlated with matched WBC controls. Encouragingly, even with a relatively narrow, primary tumor-derived AmpliSeq platform, cancer relevant SNVs were detected in half of the patients including those with only biochemical recurrence, making targeted NGS of CTCs a promising approach for biomarker discovery and validation in HSPC.
Greatest percent involved core length and the risk of death from prostate cancer in men with highest Gleason score 7 or higher.
Authors: Matthew David Cheney, Ming-Hui Chen, Danjie Zhang, John Gary Phillips, Marian J. Loffredo, Anthony Victor D'Amico
Journal: Journal of Clinical Oncology (2014)

164 Background: Men with highest Gleason Score (GS) ≥ 7 and a lower GS (Combo GS) have a decreased risk of prostate cancer (PC) specific mortality (PCSM) following radiation therapy (RT) or RT and androgen deprivation therapy (ADT). Whether this risk is modulated based on the greatest percent involved core length (GPC) is unknown and investigated in the current study. Methods: The study cohort consisted of 333 men with GS ≥ 7 PC consecutively treated between 12/1989 and 7/2000 using RT (n = 268; 80%) or RT and 6 months of ADT (n = 65; 20%). Biopsy core and tumor lengths were used to calculate the GPC. Competing risks regression assessed whether increasing GPC was associated with an increased risk of PCSM in men with or without ComboGS adjusting for prognostic factors, age, and treatment. Results: After a median follow-up of 5.36 years (IQR: 3.22-7.61 years) 92 (28%) men died, 28 (30%) from PC. Increasing GPC was significantly associated with an increased risk of PCSM (AHR: 1.02; 95%CI: 1.00, 1.03; p=0.02) (Table). Men with GPC ≥ 50% vs. &lt; 50% had significantly higher estimates of PCSM when ComboGS was present (p&lt; 0.001) vs. absent (p=0.55). Of the 127 men with ComboGS and GPC &lt; 50%, 83% were treated with RT alone and 2 PC deaths were observed; none in men with GS 7 and favorable intermediate-risk PC. Conclusions: Men treated with RT for ComboGS, GPC &lt; 50%, GS 7 and favorable intermediate-risk PC may not require ADT to reduce the risk of PCSM. [Table: see text]
Imaging with [<sup>18</sup>f]-fluorodeoxyglucose positron emission tomography (FDG-PET) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as markers of drug effect in a phase I dose-escalation study of combined RAD 001 and cetuximab.
Authors: C. A. Martin, R. F. Perini, A. N. Avadhani, M. Redlinger, K. Harlacker, K. T. Flaherty, M. A. Rosen, C. R. Divgi, P. J. O'Dwyer
Journal: Journal of Clinical Oncology (2011)

3048 Background: Preclinical studies suggest that mTOR inhibitors may have both metabolic and anti-angiogenic effects. We employed FDG-PET as a pharmacodynamic marker of mTOR inhibition, and DCE-MRI as an indicator of changes in tumor blood flow in a phase 1 combination study of RAD001 and cetuximab. Methods: 29 patients with EGFR-expressing solid tumors were randomized to a 3-week run-in of single agent RAD001 (30-70 mg PO) or cetuximab (400 mg/m2 IV loading, 250 mg/m2 IV maintenance) weekly, followed by the combination weekly. The primary endpoints were phase II dose finding and toxicity characterization. FDG-PET and DCE-MRI were performed at three time points (baseline, run-in, and combination), to assess for changes in tumor metabolic activity and perfusion, and for subsequent correlation to treatment response (CT or MRI after every two cycles of combination therapy). Results: RAD 001 was tolerated at the highest dose level. Grade 3 or worse toxicity included thrombocytopenia, hypokalemia, elevation in AST and alkaline phosphatase, and skin toxicity. 10 patients were evaluable for response. 5 patients had stable disease lasting 4-19 months (colon, parotid, anal and 2 ovarian). Mean % change in SUVmax from baseline for those treated with RAD001 during run-in (n=12) was -23.4 (range +1.4 to -52.9%), and a dose relationship was evident. The SUV change in pts treated first with cetuximab (n=13) was -9.6% (-53 to +35%). In 10 pts in whom RAD001 was added after cetuximab, there was an additional 11% decrease in SUV, while in patients treated first with RAD001, the SUV change was +12.4%, suggesting that an initial inhibitory effect was being circumvented by the tumor. Mean % change in SUVmax from baseline for the group with SD was lower than in the group with PD. The Ktrans measured by DCE-MRI did not change (-0.9%, n=7), irrespective of run-in drug. Conclusions: Metabolic responses by FDG-PET compared to DCE-MRI changes reveal that the metabolic effects of RAD001 alone and in combination with cetuximab predominate, while antiangiogenic effects appear to be minimal in this patient population.
Endothelial Notch1 Activity Facilitates Metastasis
Authors: Elfriede Wieland, Juan Rodriguez-Vita, Sven S. Liebler, Carolin Mogler, Iris Moll, Stefanie E. Herberich, Elisa Espinet, Esther Herpel, Amitai Menuchin, Jenny Chang-Claude, Michael Hoffmeister, Christoffer Gebhardt, Hermann Brenner, Andreas Trumpp, Christian W. Siebel, Markus Hecker, Jochen Utikal, David Sprinzak, Andreas Fischer
Journal: Cancer Cell (2017)
Outcome of patients with advanced non-small-cell lung cancer and ECOG performance status 2: A retrospective analysis of the GOIM trials
Authors: V. Gebbia, D. Galetta, V. Lorusso, G. Colucci, M. Caruso
Journal: Journal of Clinical Oncology (2005)

7152 Background: The better tolerability of new doublets due to progress in supportive care, anti-emetic prophylaxis, and better toxicity profile of newer cytotoxic drugs allowed investigators of the GOIM to include pts with PS 2 and low co-morbidity rate in prospective clinical trials. Methods: In this paper we report a retrospective analysis of the clinical outcome and prognostic variables of pts with advanced NSCLC and PS 2 enrolled in clinical trials ran by the GOIM until 2003. A total of 1,108 pts were enrolled from 1993 until 2003 in three phase II and four phase III controlled clinical trials comprising a total of 203 pts with PS 2 (18.3% of the whole population). Pts were treated with CDDP 80–100mg/m2 plus VNR 25–30 mg/m2 d1+8, or GEM 1 gr/m2 d 1+8, the MVP or the IFO/VNR regimens. Results: ORR rate according to the WHO criteria was lower in the PS pts than in PS 0–1. Preliminary evaluation showed clinical improvement in cancer-related symptoms in 31% of pts. Median TTP of PS2 pts was 2.9 months (1–8 mos) with a 6-month progression-free probability rate of 16%. On the other hand, median TTP of patients with PS 0–1 was 5.7 mos (1–13.5 mos) with a 6-month progression-free probability rate of 43%. This difference in median TTP was highly significant (p = 0.008; HR 1.96). Median OS of pts with PS 2 was 5.5 mos with a 1-year survival rate of 13%, while that of pts with PS 0–1 was 9 mos with a 1-year survival rate of 30%. The difference in median survival was highly significant (p = 0.001; HR = 1.95). Analysis of prognostic factors showed no correlation between age and survival (r2 = 0.01; p = 0.08), and a statistically weak correlation between number of co-morbidities and survival (r2 =0.02; p = 0.044) in PS2 pts. Conclusions: These data confirm the prognostic role of PS in pts with advanced NSCLC and support the urgent need of further trials to better define the role and type of treatment to give to NSCLC pts with PS2. No significant financial relationships to disclose.
A comparative study of pediatric CNS tumor activity as assessed by [18F]-FDG PET imaging and proton magnetic resonance spectroscopic imaging.
Authors: S. J. Hipp, E. A. Steffen-Smith, P. Herscovitch, N. J. Patronas, J. M. Solomon, R. Bent, S. M. Steinberg, K. E. Warren
Journal: Journal of Clinical Oncology (2011)

2101 Background: Magnetic resonance spectroscopic imaging (MRSI) allows in vivo analysis of tumor metabolism in discrete areas of the tumor. Changes in the ratio of two metabolites, choline and N-acetyl aspartate, (Cho:NAA) have been associated with tumor grade, treatment response and outcome. Fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is the current standard of care to assess tumor metabolism, and FDG uptake has correlated with tumor grade and proliferative status. The relationship between tumor metabolic activity on MRSI and FDG-PET is unclear. The objective of this study was to compare the determination of metabolically active tissue between MRSI and FDG-PET in pediatric brain tumors. Methods: Children with a brain tumor or residual lesion after therapy underwent FDG-PET and a standard MRI with MRSI within a two-week period. FDG uptake and maximum Cho:NAA were each used to classify tumors as inactive, active, and highly active. The agreement between the two measures was determined using the percent agreement and the kappa statistic (K). Results: FDG-PET and MRSI were acquired in 37 patients (15M/22F) with a median age of 12.3 years. Tumor diagnoses included 20 brainstem gliomas, 8 high-grade, 8 low-grade gliomas and 1 patient with Lhermitte-Duclos disease. Four studies were excluded. Increased metabolic activity was identified in the majority of both PET and MRSI studies (Table), but overall agreement between MRSI and PET was weak (K=0.16), with only 14 of 33 studies yielding the same classification. The percent agreement between PET and MRSI was 42% (95% CI = 25 – 61%, p = 0.49). Patients continue to accrue to see if the results are applicable in a larger population. Conclusions: Pediatric brain tumors have a heterogeneous metabolic expression pattern on MRSI and FDG-PET. There was little agreement between maximum Cho:NAA values and maximum FDG-PET activity. MRSI classification PET classification Inactive (n=14) Active (n=9) Highly active (n=10) Inactive (n=8) 6 2 0 Active (n=23) 7 7 9 Highly active (n=2) 1 0 1
SRC-3 Ubiquination, Mediated By Cullin3, Potentiates Gambogic Acid-Induced Apoptosis in Non-Hodgkin's Lymphoma
Authors: Zichu Zhao, Lu Wen, Sha Yi, Xia Zhang, Jingyu Hu, Jun Ruan, Fei Zhao, Guohui Cui, Jun Fang, Yan Chen
Journal: Blood (2015)
Increased EGFR gene copy number detected by fish is associated with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma (BAC) (S0126)
Authors: F. R. Hirsch, D. R. Gandara, J. McCoy, J. Crowley, H. J. West, P. H. Gummerlock, P. A. Bunn, W. A. Franklin, M. Varella-Garcia
Journal: Journal of Clinical Oncology (2005)

7030 Background: BAC subtypes are increasing in incidence, particularly in younger, never-smoking women. Studies with EGFR inhibitors have demonstrated response rates of 20–30% in patients (pts) with advanced BAC. However, no methods have been established to select pts for such treatments. Methods: In this study EGFR copy number by fluorescence in situ hybridization (FISH) was assessed and correlated to treatment response and survival. Tumor tissue from 81 pts with advanced stage BAC treated with gefitinib 500mg/day in the SWOG protocol S0126 were analyzed by FISH and classified in two main categories: FISH positive (high polysomy/gene amplification) and FISH negative (disomy, trisomy and low polysomy). Results: Fifty-five pts with measurable disease were evaluated for response using the RECIST criteria. Among 19 FISH positive pts, 12 (63%) had disease control (response or stable disease) versus 14/36 pts (39%) in the FISH negative group (exact p-value=0.099). Eighty-one pts were evaluable for survival, and the median survival time for the FISH negative pts was 8 (95%CI 6–15) months. While the median survival for the FISH positive pts has not yet been reached, it is approaching 18 months, with a hazard ratio of 2.02 (95%CI 1.03- 3.99; p=0.042). The median progression-free survival time for FISH negative pts was 4 ((95%CI 2- 5) months versus 9 (3- 20) months for FISH positive pts with a hazard ratio of 1.67 (95%CI 0.96- 2.91; p=0.072). EGFR copy number by FISH remained a significant predictive factor after accounting for smoking status, sex, histology and performance status. Conclusions: This study demonstrated a strong association between increased EGFR gene copy number detected by FISH and sensitivity for gefitinib treatment in pts with advanced stage BAC. The results suggest that FISH methodology can be used to select pts with BAC for treatment with EGFR tyrosine kinase inhibitors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Bristol-Myers Squibb, Genentech, ImClone, OSI, Roche Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Genentech, GlaxoSmithKline Beecham, ImClone, Millenium, OSI, Roche AstraZeneca, Lilly Oncology
Treatment patterns in patients with HER2-positive early-stage breast cancer (ESBC) receiving adjuvant treatment with a trastuzumab-containing regimen.
Authors: K. Sail, D. Lalla, M. Brammer, M. Halm, D. A. Patt
Journal: Journal of Clinical Oncology (2011)

624 Background: Patients with HER2-positive (HER2+) ESBC generally receive trastuzumab (H) containing chemotherapy adjuvant regimens, either anthracycline (A) containing (AC-TH or similar) or non-anthracycline containing (TCH or similar). This study evaluated patient characteristics and treatment patterns of patients with HER2 + ESBC who receive a H-containing regimen in a community setting. Methods: We conducted a retrospective study utilizing US Oncology’s iKnowMed EMR system. Female patients with HER2+ ESBC initiating adjuvant ACTH, TCH, ACTH-like or TCH-like regimens from 1-1-2006 to 6-30-2009 were identified. Patients in clinical trials or receiving concurrent treatment for other primary cancers were excluded. Patients were followed through 9-30-2010 to observe the duration of adjuvant treatment and reason for regimen discontinuation. Pearson chi square test for frequencies and logistic regression analyses were used for between group comparisons and to determine variables that predicted receipt of anthracycline based regimens. Results: We identified 1,029 patients with HER2+ ESBC who initiated an adjuvant regimen containing H between 1-1-2006 to 6-30-2009. Of these, 225 patients initiated ACTH, 158 patients initiated an ACTH-like regimen, 470 initiated TCH and 176 patients initiated a TCH-like regimen. Younger patients (OR: 2.33) and patients with higher stage at diagnosis (OR: 2.37) are significantly more likely (p<0.001) to receive an A based regimen. The treatment duration in the H product label is 448 days for ACTH and 365 days for TCH. The median (mean) treatment duration observed in this study was 392 (371) days for ACTH, 364 (305.1) days for ACTH like, 364 (299) days for TCH and 371 (329.7) for TCH like patients. The major reason for discontinuation was completion of treatment; toxicity was reported as a reason for discontinuation in 7.2% for ACTH and 1% for TCH. Conclusions: Younger patients with more aggressive disease were more likely to receive ACTH or ACTH like regimens of chemotherapy. The median duration of treatment was closer to the duration in product label for the TCH group versus ACTH with more patients on ACTH stopping treatment due to toxicity.
PTEN expression in archival tumor samples in patients (pts) with advanced malignancies in two phase I studies of AP23573 (AP), an mTOR inhibitor
Authors: L. A. Janisch, A. A. Desai, M. Mita, R. Parsons, M. Goldston, H. L. Knowles, C. L. Bedrosian, E. K. Rowinsky, A. W. Tolcher, M. J. Ratain
Journal: Journal of Clinical Oncology (2005)

9661 Background: AP, a novel non-prodrug analog of rapamycin, inhibits mTOR signaling in tumors, leading to cell cycle arrest, tumor cell shrinkage and inhibition of angiogenesis. Mutations that affect tumor suppressor genes, such as PTEN, are proposed to enhance sensitivity to mTOR inhibition. PTEN regulates cell growth by inhibition of the PI3K pathway, which promotes protein translation and cell cycle progression. Methods: Archival tumor specimens were obtained from at least 54 pts in 2 phase I trials evaluating the MTD of AP as a 30-min. IV infusion daily x 5 days every 2 weeks or once weekly. PTEN expression was characterized by immunohistochemical staining where cytoplasmic PTEN expression levels were evaluated using an intensity score of 0–3. In-situ tumor component was identified and a PTEN expression level score of 0–3 was noted where a loss of PTEN is defined as a change in intensity ≥ to 1 unit relative to that of normal epithelium. Results: 24 pt samples have been evaluated to date. 20/22 (91%) of pt tumors expressed near-normal levels of PTEN. Of 22 pts, 2 pts (9%) had a PR, 6 pts (27%) had a MR, 5 pts (23%) had SD, 7 pts (32%) had PD, and 2 pts were not evaluable. 2/24 samples could not be evaluated. One pt with mixed mullerian uterine sarcoma treated on the daily x 5 schedule at 3 mg (the lowest dose) and who continues on trial after 20+ months with a PR had tumor with absent PTEN expression. Another pt treated on the daily x 5 schedule at 18.75 mg (the MTD) with clear-cell renal cell carcinoma and who continued on trial for 10 months with SD had a modest reduction in PTEN levels. Analyses of additional specimens are ongoing. Conclusions: These data suggest that PTEN levels alone in archival tumor specimens in a heterogeneous population with advanced malignancies did not appear to correlate with response. At the same time, in the 2 pts where PTEN levels were absent or reduced both had a sustained response, which included a PR at the lowest dose. Analyses were performed on archival tumors and not on existing tumors where the implications of reduced PTEN expression may be more meaningful. In addition, these results highlight the importance of a panel of biomarkers reflecting mTOR activity, rather than PTEN alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ariad Ariad Ariad Ariad Ariad
Effect of gemcitabine on specific antitumor responses of modified vaccinia Ankara (MVA) expressing survivin in a murine pancreatic carcinoma model.
Authors: H. Ishizaki, K. Chijiiwa, E. Manuel, T. Srivastava, G. Song, D. J. Diamond, J. D. Ellenhorn
Journal: Journal of Clinical Oncology (2011)

256 Background: Survivin is overexpressed by 70% to 80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b + /Gr- 1 + myeloid derived suppressor cells (MDSCs). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine. Methods: In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study. Results: Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with decreased CD11b + /Gr-1 + MDSCs. To analyze thesurvivin specific immune response to MVA-survivin immunization, we utilizeda peptide library of 15mers with 11 residues overlapping fromfull-length murine survivin. Splencytes from miceimmunized with MVA-survivin produced intracellular γ-interferon inresponse to in vitro stimulation with the overlapping peptidelibrary. Increased survivin-specific CD8 + T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine. Conclusions: Thesedata suggestthat vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcometumor-induced peripheral immune tolerance, and this effect has potential for clinical benefit in pancreatic cancer. No significant financial relationships to disclose.