tbuckley/cabot-search huggingface dataset:
<i>ATM</i> gene promoter analysis in childhood lymphoid malignancies
Authors: F. Gumy-Pause, P. Wacker, P. Maillet, D. Betts, A.-P. Sappino
Journal: Journal of Clinical Oncology (2005)

8512 Background: Hereditary mutations of the ATM gene cause ataxia-telangiectasia, a recessive disorder associated with a high incidence of neoplasias. ATM gene alterations have been frequently identified in sporadic lymphoproliferative tumours, suggesting that the ATM gene contributes to lymphomagenesis. ATM promoter hypermethylation has been recently reported in adult carcinomas, but no information is available concerning the methylation status of ATM gene promoter in childhood lymphoid malignancies. Furthermore, there has been no reported involvement of ATM promoter mutations in cancer. In order to determine the methylation status and to assess the prevalence of the ATM promoter and exons 1a-1b mutations, 74 childhood lymphoid malignancies (25 B-precursor acute lymphoblastic leukemia (ALL), 24 T-ALL and 25 non-Hodgkin’s lymphoma (NHL)) were analysed. Methods: Following DNA extraction and bisulfite treatment, the methylation status of the ATM promoter was determined by methylation-specific PCR. The ATM promoter and exons 1a-1b mutations screening was performed by DHPLC after PCR amplification. Detected alterations were characterized by direct sequencing. Results: We found no evidence of ATM promoter hypermethylation in the 74 samples analysed. However, three different heterozygous sequences alterations were detected in 3 ALL samples (3/49 (6.0%); 1 B-precursor ALL and 2 T-ALL), but in none of the NHL samples screened. Two of these alterations were located in the promoter (10259C/T and 10329G/C) and one in the intron 1a (IVS1a+61A/G). These three substitutions were not observed in 74 healthy controls. Conclusions: Our observations indicate that epigenetic ATM silencing by methylation is uncommon in childhood lymphoid malignancies while ATM promoter alterations may occur in childhood ALL. Additional studies are required to confirm our results and to clarify the biological significance of these rare variants. No significant financial relationships to disclose.
Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.
Authors: K. Kalinsky, J. A. Sparano, M. Kim, K. D. Crew, M. A. Maurer, B. Taback, S. M. Feldman, H. Hibshoosh, L. Wiechmann, K. B. Adelson, D. L. Hershman
Journal: Journal of Clinical Oncology (2011)

TPS147 Background: To serve as a bridge between preclinical and early clinical testing, pre-surgical studies are being designed to expose patients to a limited duration of an anti-cancer agent before launching a lengthy clinical trial program. In this model, modulation of predictive tissue and serum biomarkers are assessed. At Columbia, we have completed 2 pre-surgical studies, with a third ongoing. The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). The first allosteric Akt inhibitor to enter clinical development, MK-2206 is well-tolerated and has demonstrated anti-cancer properties in preclinical and early phase clinical studies. The purpose of this study (NCI P8740) is to determine the effects of MK-2206 on women with newly diagnosed BC between breast biopsy and surgery. Methods: The main eligibility criteria for this open-label pre-surgical trial include operable, clinical stage I (at least T1c) to IIIC invasive BC. Patients not considered for neoadjuvant chemotherapy are eligible. Patients (n=30) will receive 2 doses of weekly MK-2206 (200 mg): first dose at day -9 and second at day -2 from surgery. This drug administration consistency will decrease the potential for noise in detecting true biomarker response. This time period was selected based upon the PK profile of weekly MK-2206. Our hypothesis is that MK-2206 will decrease phospho-AktSer473 in tumor tissue after 2 weekly doses. To maintain sample quality and ensure that phospho-Akt evaluated on FFPE tissue is comparable across samples (given the 20 minute half life of AKT), all samples will be processed rapidly by a standardized protocol. Secondary objectives include the following in FFPE tissue: modulation of downstream PI3K/Akt pathway signaling [IHC and reverse phase-protein microarray analysis (RPPA)]; change in tumor proliferation (Ki-67 staining); and exploration of whether PI3K/Akt signaling change depends upon tumor genetics (PIK3CA mutation or PTEN loss) or expression (HR/HER2 status). Pre- and post-MK-2206 blood will be collected for phospho-expression analysis in PBMCs (RPPA and western blotting). Patients will be enrolled and treated at affiliated institutions in the New York Cancer Consortium.
The impact of socioeconomic status on cancer care and survival.
Authors: S. L. Wong, N. Gu, M. Banerjee, J. D. Birkmeyer, N. J. Birkmeyer
Journal: Journal of Clinical Oncology (2011)

6004 Background: Primary cancers of the lung, esophagus, and pancreas account for over 35% of all cancer deaths in the US and a sizable share of cancer costs. Despite little improvement in survival rates over time, how aggressively patients with poor prognosis cancers are treated has increased dramatically. In this study, we examine the aggressiveness of treatment and cancer outcomes by socioeconomic status (SES). Methods: Using SEER-Medicare data (incident cases from 1992-2002, follow-up to 2005), we examined lung (n=68167), esophagus (n=4350), and pancreas (n=12779) cancers. We constructed a summary measure of SES based on US ZIP code data from the 2000 Census data linked to the patient's ZIP code of residence. We assessed the effects of SES on treatment and 2-year survival rates. Results: Across SES groups, patients were similar with regard to cancer stage, though patients in the lowest SES group were much more likely to be black. The lowest SES patients were more likely to require urgent or emergent admissions and to be treated at very low volume hospitals and non-teaching hospitals. For all three cancer types, low SES patients were more likely to receive no cancer-directed treatment (e.g., 60% of the lowest SES patients received no treatment for pancreas cancer). Receipt of cancer-directed surgery, chemotherapy, and/or radiation therapy was consistently higher for the highest SES patients, with most patients receiving at one type of treatment and many receiving a combination of treatments. Crude hazard ratios (HR) for mortality suggested a slight survival benefit in the highest SES patients (compared to the lowest SES patients), but HR for esophagus and pancreas cancers were not significantly different once patient characteristics and cancer treatments were taken into account (HR 1.02; 95%CI 0.89-1.16 and HR 1.02; 95%CI 0.96-1.10, respectively). For lung cancer, results were marginally significant (HR 1.11; 95%CI 1.08-1.15). Conclusions: There is pronounced variation in types of cancer treatment received by different SES groups. Despite receiving more aggressive treatments, higher SES patients do not have improved survival rates. Reducing variation in treatment strategies may improve healthcare efficiency without changing patient outcomes.
Detection of alpha-methylacyl-CoA racemase (AMACR), a biomarker of prostate cancer, in patient blood samples using a nanoparticle electrochemical biosensor.
Authors: Matthew M. Cooney, Cheryl L. Thompson, Po-Yuan Lin, Kai-Lun Cheng, James D. McGuffin-Cawley, Fuh-Sheng Shieu, Anna C. Samia, Sanjay Gupta, Chung-Chiun Liu
Journal: Journal of Clinical Oncology (2012)

41 Background: A promising prostate cancer biomarker, alpha-methylacyl-CoA racemase (AMACR), has demonstrated the ability to distinguish cancer from healthy and benign cells with high sensitivity and specificity. However the lack of a good clinical assay has limited its translation into the clinic. Here we report on the development of a single use disposable biosensor for AMACR detection. Methods: This is a very inexpensive, small, single-use disposable sensor that requires only a drop of plasma and connects to a portable device. The biosensor utilizes the reaction of pristanic acid with a substrate that includes AMACR to produce Trans-2,3-dehydropritanayl-CoA plus H 2 O 2 . The biosensor utilizes iridium oxide nanoparticle catalyst to oxidize the H 2 O 2 produced in the above metabolic pathway. Thus the oxidation of H 2 O 2 yields a measurable current to quantify AMACR in the sample. This is the first in vitro assay method for AMACR based on this reaction mechanism. Results: In our study including plasma from 9 healthy males, 10 patients with high grade prostatic intraepithelial neoplasia and 5 prostate cancer patients we show 100% accuracy in separating prostate cancer patients from controls as well as those with benign prostate conditions. Conclusions: Our data provides strong evidence for the ability of this biosensor to perform as a reliable assay for prostate cancer detection and diagnosis.
Activity of bortezomib, a proteasome inhibitor, in breast cancer cells: Association with negative estrogen receptor and IKK/NF-κB expression
Authors: M. Tapia, J. Codony-Servat, J. Domingo-Domenech, B. Ferrer, P. L. Fernandez, J. S. Ross, M. Rolfe, P. Gascon, A. Rovira, J. Albanell
Journal: Journal of Clinical Oncology (2005)

3169 Background: We reported that bortezomib (Velcade), a proteasome inhibitor, suppressed cell growth and induced apoptosis to varying extents (IC50 range, 4nM to 1000 nM) in a panel of breast cancer cells (Codony et al, Proc AACR 2004). Notably, bortezomib effects were unrelated to EGFR/HER2 expression. Here we addressed whether estrogen receptor (ER) and IκB kinase (IKK)/nuclear factor (NF)-κB expression were related to bortezomib effects and also studied the relation between these two systems in breast cancer. Methods: Proteasome activity was measured by fluorogenic proteasome assay. Expression of ER, IKKs (α, β and NEMO), NF-κB (p65, p50, p52, RelB and c-Rel) and IκB (α, β and ε) subunits were assayed by WB. Ductal breast carcinoma in situ (DCIS) and infiltrating carcinoma specimens were assayed by IHC for ER and p65 expression. p65NF-κB nuclear staining was interpreted as an activated form of NF-κB. Results: ER-positive cell lines were relatively bortezomib resistant (MCF7, IC50 100 nM; BT474, IC50 1000 nM) while ER-negative cells were generally more sensitive (SKBR3, IC50 4 nM; MDA-MB-468, IC50 4 nM; MDA-MB-231, IC50 6 nM; MDA-MB-453, IC50 100 nM). ER-positive cell lines expressed all the assayed proteins of the IKK/NF-κB system while ER-negative cell lines lacked one or more elements of IKK/NF-κB. ER-negative SK-BR-3 cells were 200-fold more sensitive than ER-positive BT-474 cells; however bortezomib inhibited proteasome activity similarly in both cells. SKBR3 cells overexpressed c-Rel and RelB while had low levels of IKK-α, IκB-α and IκB-β. In clinical specimens, normal breast showed mainly weak p65NF-κB cytoplasmic staining and occasional faint nuclear staining. DCIS had strong and diffuse cytoplasmic p65NF-κB staining. Twelve out of 14 (86%) ER-negative infiltrating breast cancers exhibited p65NF-κB activation (i.e. nuclear staining), whereas only 2 out of 6 (33%) ER-positive specimens had p65NF-κB activation (p=0.037). Conclusions: An ER-negative status, coupled with a dysregulated IKK/NF-κB system, were linked to a greater antitumor effect of bortezomib. In vivo data further establishs that ER-negative breast cancers have commonly activated NF-κB. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Millennium Millennium
Blood-based screening for methylation changes in colorectal cancer patients using novel nanotechnologies.
Authors: Nita Ahuja, Ruby Kwak, Brian Keeley, Alejandro Stark, Angela Anna Guzzetta, Christopher Lee Wolfgang, James Gordon Herman, Christine A Iacobuzio-Donahue, Tza Huei Wang
Journal: Journal of Clinical Oncology (2013)

384 Background: Identification of blood-based biomarkers for cancer screening is essential in order to develop novel and minimally invasive methods for colorectal cancer screening. Our lab has successfully applied a novel nanotechnology that allows us to detect and amplify a single tumor DNA fragment in a plasma sample. This DNA is tested for methylation of several genes including TFPI2 which has shown to be highly sensitive and specific for the detection colorectal cancer in stool. Methods: Whole blood was obtained from 18 colorectal cancer patients and plasma was isolated. Plasma was processed using Methylation On Beads nanotechnology (MOB) and bisulfate treated. Methylation status was determined via quantitative PCR method. Results: Two genes, TFPI2 and IGFBP3, were detected with a high sensitivity. TFPI2, demonstrated a methylation frequency of 94.4%, which is concordant with the TFPI2 methylation frequency of 99% in primary colorectal cancer tissues. IGFBP3 showed the methylation frequency of 61.1%, which corresponds with the methylation frequency of 52% in retrospective colorectal cancer tissues in previous studies. Quantification using standard curves indicated a single copy level of DNA found in plasma. Conclusions: Blood-based screening is challenging due to extremely low quantities of circulating DNA in blood. Utilizing a novel nanotechnology that detects DNA at a single copy level, the methylation changes in colorectal cancer were successfully detected in plasmas at similar frequencies as in tissue samples. This study has demonstrated the feasablility and applicability to blood-based screening. Future studies will focus on improving the sensitivity and determining the specificity of this method.
First one thousand families: Our multidisciplinary experience in the heredo-familial cancer unit from a Spanish University Hospital.
Authors: Ivan Marquez Rodas, Soledad Luque Molina, Mercedes Sanz, Maria Isabel Peligros, Carmen Flores Sanchez, Cristina Mata, Maria Die Trill, Santiago Lizarraga, Patricia Rincon, Oscar Bueno, Sara Lopez-Tarruella, Yolanda Jerez Gilarranz, Andres Jesus Muñoz Martin, Aitana Calvo, Cristina Lopez, Pedro Menchen, Jose Antonio Pajares, Cecilia Gonzalez Asanza, Jesus Solera, Miguel Martin
Journal: Journal of Clinical Oncology (2015)

1556 Background: Patients with hereditary cancer syndromes (HCS) need a multidisciplinary approach: Different organs and systems may be involved and different risk reducing strategies (medical and surgical) should be provided. In 2010 we implemented a multidisciplinary heredo-familial cancer unit (HFCU) in Hospital General Universitario Gregorio Marañón (Madrid, Spain). Methods: A retrospective analysis of the first 1000 families attended in our HFCU (2010-2014). Results: 1167 patients, from 1000 different families were attended. 929 patients (79.6%) fulfilled international criteria for HCS; 84 are pending of gathering more information. Genetic test results were available for 426 patients, with 136 cases bearing pathological mutations. New mutation detection rate (first time diagnosis in a family) was 44/235 (18.7%). Two patients with no HCS criteria were diagnosed with BRCA1 and MSH2 mutations respectively. For the 136 patients with a pathological mutation, prophylactic surgery and /or follow up were offered according to international recommendations and patient's preferences (Table). In two BRCA1 mutation carriers, an early ovarian cancer was detected in prophylactic surgery. Conclusions: The first one thousand families attended in our HFCU demonstrate that a multidisciplinary assistance is the core of this clinical activity. The intervention resulted in risk reduction surgery in 31% of cases and intensive surveillance in all cases. A longer follow up is warranted in order to evaluate the long-term impact of these interventions and for improving the different steps of the cancer genetic counseling process. MUTATION CARRIERS (%) Prophylactic surgery (%) Only follow-up (%) BRCA1/2: 96 (70.6) 36 (38) 60 (62) MLH1/MSH2/MSH6: 18 (13.2) 0 18 (100) APC/MYH: 6 (4.4) 2 (33.3) 4 (66.7) p53: 2 (1.5) 0 2 (100) CDKN2A: 2 (1.5) 0 2 (100) PTEN: 1 (0.8) 1 (100) 0 MEN1: 2 (1.5) 0 2 (100) RET : 3 (2.2) 2 (66.7) 1 (33.3) VHL : 1 (0.8) 0 1 (100) CDH1 : 1 (0.8) 1 (100) 0 NF1: 1 (0.8) 0 1 (100) PTCH: 1 (0.8) 0 1 (100) FH: 1 (0.8) 0 1 (100) Rb: 1 (0.8) 0 1 (100) TOTAL: 136 (100) 42 (30.9) 94 (69.1)
HBV screening before adjuvant chemotherapy in patients with early breast cancer: A cost-effectiveness analysis.
Authors: William W. L. Wong, Lisa K. Hicks, Hong-Anh Tu, Murray Krahn, Kathleen I. Pritchard, Jordan J. Feld, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2014)

11 Background: The seroprevalence of hepatitis B virus (HBV) infection among Canadian was 0.4%, and 1.6% among immigrants. Most infected individuals have clinically silent disease. Cytotoxic chemotherapy causes reactivation in 30% of the HBV infected patients. This can be severe and fatal, may also lead to interruption of chemotherapy. HBV screening before adjuvant chemotherapy (ADJ) for breast cancer (BC) seems to be a plausible strategy. Our objective is to estimate the health and economic effects of HBV screening strategies. Methods: We developed a state transition microsimulation model to examine the cost effectiveness of 3 strategies for 55 year old BC patients undergoing ADJ: (1) No screen; (2) Screen Imm: Screen immigrant only and treat; (3) Screen all: Screen all and treat; with antiviral therapies. In the model, health states were constructed to reflect the natural history of BC and HBV. Model data were obtained from published literature. We used a payer perspective, a lifetime time horizon, and used a 5% discount rate. Results: Screen all would prevent 43 severe reactivations (SR), 9 deaths from reactivation (DR), 22 chemotherapy interruptions (CI), 36 decompensated cirrhosis (DC), 48 HCCs, and 67 HBV deaths per 100,000 persons screened over the lifetime of the cohort. Screen Imm would prevent 34 SR, 4 DR, 20 CI, 30 DC, 41 HCCs, and 52 HBV deaths. Screen all was associated with an increase of at least 0.00368 quality adjusted life years (QALY) and cost C$116 more per person, translating to an incremental cost effectiveness ratio (ICER) of C$31,518-51,276/QALY gained compared with No screen, depends on different antiviral therapies. Screen all was the most cost effective, while Screen Imm was ruled out due to extended dominance (ED) by No Screen and Screen all. Conclusions: HBV screening before ADJ for BC patients would prevent a significant number of reactivations, and is likely be cost effective. [Table: see text]
Use of KRAS mutation status to predict clinical outcomes in patients with metastatic colorectal cancer (mCRC) treated with the VEGF signaling inhibitor cediranib.
Authors: J. M. Jürgensmeier, P. M. Hoff, L. Pike, J. D. Robertson, S. Morgan, G. McWalter, D. Wilson, J. C. Smith
Journal: Journal of Clinical Oncology (2011)

3613^ Background: The value of KRAS mutations as predictive markers of clinical benefit of anti-EGFR antibody therapy in patients with mCRC has been shown in randomized trials. Less is known of the influence of KRASmutations in patients with mCRC treated with VEGF signaling inhibitors and literature on the prognostic value of KRAS mutations in this setting is inconsistent. The Phase III HORIZON II (HZII) study evaluated the efficacy of cediranib 20 mg + FOLFOX (FF) or XELOX (X) vs placebo + FF or X in patients with mCRC; cediranib 20 mg met the co-primary endpoint of progression-free survival (PFS; HR=0.84) but not overall survival (OS; HR=0.94). A retrospective analysis of KRAS mutation status and correlation with PFS and OS in patients was performed to evaluate its prognostic and predictive value. Methods: Analysis of KRAS codon 12 and 13 mutations was performed at a central laboratory using a commercially available, allele-specific, ARMS-based polymerase chain reaction assay. Results: KRAS mutation status was determined in 489/860 patients (cediranib 20 mg arm, n=285/502; placebo arm, n=204/358); of these 489 patients, 42.3% had mutant KRAS and 57.7% were wild-type. Baseline characteristics were similar in the KRAS mutant, KRAS wild-type and KRAS status unknown groups. There was a trend towards improved PFS and OS in the KRAS wild-type subgroup compared with the KRAS mutant subgroup, which was independent of treatment arm (PFS: HR=0.85, 95% CI: 0.70,1.03, median 8.5 vs 8.3 months; OS: HR=0.71, 95% CI: 0.57,0.88, median 20.9 vs 16.9 months). There were no statistically significant differences in treatment effect between KRAS subgroups for the cediranib vs placebo arm (PFS: wild-type HR=0.78, mutant HR=0.82; OS: wild-type HR=0.92; mutant HR=1.01). Conclusions: This is the first reported analysis of KRAS mutation status in a randomized Phase III clinical study with a VEGFR-TKI. KRAS mutation status did not influence the PFS or OS treatment effect and therefore cannot be used as a predictive marker for outcome. These data show that KRAS codon 12 or 13 mutations have prognostic value in mCRC independent of treatment.
NPC-1C: A novel, therapeutic antibody to treat pancreas and colorectal cancers.
Authors: L. A. Diaz, N. S. Azad, D. Laheru, D. T. Le, C. E. Devoe, D. Cosgrove, L. Zheng, P. M. Arlen, J. A. Bristol
Journal: Journal of Clinical Oncology (2011)

235 Background: NPC-1C (ensituximab) is a chimeric monoclonal antibody being developed as a novel biologic treatment for pancreatic and colorectal cancers. This antibody was selected from a panel of hybridomas generated from mice immunized with semi-purified membrane-associated proteins derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C epitope appears to be expressed specifically by human colon and pancreatic tumor tissues and cell lines. Methods: Antitumor activity was established in vitro by measuring ADCC with a standard 4-hour 111-Indium release assay on pancreatic and colorectal cancer cell lines. In vivo antitumor efficacy of NPC-1C was tested using pre-established subcutaneous human pancreatic tumor xenograft models. Results: In vitro, the NPC-1C antibody exhibits ADCC activity specifically against human colon and pancreatic tumor cells, but not against control tumor cell lines. The in vivo data showed significant, and reproducible, antitumor action, including some complete tumor regressions. The clinical application for this antibody was bolstered by several examples of human tumor tissues stained with biotin-conjugated NPC-1C that showed a strong correlation of NPC-1C staining against pancreatic and colon tumors. Approximately 45% of tumors stained strongly positive. The staining pattern was typical of elaborated mucin expression, but also showed cytoplasmic and cell membrane staining. Conclusions: A phase I open label, multicenter dose escalation clinical trial with NPC-1C is currently accruing patients with advanced pancreatic and colorectal cancer who are refractory to standard therapy. The primary objectives of the phase I clinical trial are to determine the safety and tolerability of escalating doses of NPC-1C monoclonal antibody therapy and to assess pharmacokinetics and select immune responses to the antibody at each dose level. Secondary objectives are to evaluate evidence of clinical benefit and to explore the immunologic correlates associated with administration of NPC-1C. Results from this trial will determine the minimum standard dosage levels to be used in further trials. [Table: see text]