bluuebunny/crossref_metadata_2025_split huggingface dataset:
S4-1: Overdiagnosis in Breast Cancer Screening: Methodological Considerations of Current Estimates.
Authors: Smith RA , Duffy SW 
Published: June 2012

Abstract
Background
A harm that has received considerable attention in breast cancer screening is overdiagnosis, i.e., the detection through screening of breast cancer that is non-progressive. Since there is no way to distinguish a truly non-progressive tumor from one that is progressive, overdiagnosis is a statistical phenomenon that is estimated as the difference between observed and expected incidence rates. However, there is no agreement on the true rate of overdiagnosis in breast cancer screening. Estimates vary widely, with the highest estimates reported in the scientific literature having received significant media attention under the premise that a signifiant fraction of newly diagnosed breast cancers are non-progressive and thus overtreated. We examined the range of overdiagnosis estimates in the context of factors that influence observed and expected breast cancer incidence rates over time.
Methods
Only studies that compared incidence rates of invasive breast cancer, or invasive breast cancer and ductal carcinoma in situ (DCIS), in a group invited or exposed to mammography compared with a group not invited or not exposed to mammography were included in our analysis. Studies were evaluated based on whether or not they adjusted for contemporaneous trends in the underlying incidence of disease, which may differ in different age groups, and age-specific effect on incidence rates due to lead time.
Results
We identified 17 studies (Table 1) that attempted to estimate overdiagnosis of breast cancer resulting from mammography screening. The main determinant of high estimated rates of overdiagnosis was a failure to adjust for lead time. The highest rate of overdiagnosis (33%) occurred in the one study that did not correct for either lead time or confounders. Studies that only partially corrected for lead time and confounding also had high estimates of overdiagnosis (mean = 30%), whereas studies that corrected for both lead time and confounders had the lowest estimate of overdiagnosis (mean =5%).
Conclusion
The possibility that some breast cancers detected by mammography are indolent and not life threatening within the patient's natural life is real. However, it is clear from our analysis that the wide range of estimates of overdiagnosis are due to whether or not studies have adjusted for factors in and outside of screening programs known to influence incidence rates over time. Our findings suggest that the true rate of overdiagnosis associated with breast cancer screening, to the extent that it exits at all, is small.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-1.
SR2-3: Integrative Genomic Analyses of Breast Cancer from The Cancer Genome Atlas (TCGA).
Authors: Creighton C 
Published: June 2012

Abstract
Cancer is a disease characterized by genetic aberrations, which lead to widespread deregulation of cell signaling and gene transcription. Over ten years ago, gene transcription profiling of human cancers was found to distinguish distinct intrinsic molecular subtypes of the disease (luminal A/B, HER2, basal, normal-like). TCGA is a large-scale collaborative effort which seeks to comprehensively catalogue the molecular aberrations in various cancers, including breast cancer, at levels of somatic mutation, copy alteration, DNA promoter methylation, protein signaling, and gene and miRNA transcription. Having all of these molecular data on the same set of ∼500 human breast tumors, allows us to construct a more complete molecular portrait of the intrinsic subtypes, along with their candidate molecular drivers. Among other things, integrative analysis of the p53 and PI3K pathways in breast cancer reveal differences in pathway alteration and pathway activity among the subtypes.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr SR2-3.
Abstract A78: Cancer in Hinkley: What was the real problem?
Authors: Morgan John W. , Reeves Mark E. 
Published: June 2012

Abstract
Background: Hinkley, California, is a poor desert community known for a $333 million legal settlement and for the “Erin Brockovich” film that alleged a cancer excess from groundwater contaminated with chromium 6 [Cr(VI)] released by a public utility. The carcinogenic role for aqueous Cr(VI) in humans is disputed.
Methods: We assessed observed and expected counts of new cancers, including 19 cancer subtypes in the Hinkley tract for 1996–2008. Indirect standardization yielded expected counts adjusted for age, sex, race/ethnicity, population size, and change in population size. Observed numbers of cancers divided by adjusted expected counts defined standardized incidence ratios (SIR) with 95 percent confidence intervals (CI).
Results: After adjusting for demographic characteristics, the observed number of cervix cancers was significantly above the expected count (SIR; 95% CI=2.83; 1.82, 5.86). Findings for all cancers combined (SIR; 95% CI=0.91; 0.78, 1.04) and each of 15 specific cancers did not differ significantly from expected counts. Observed counts for childhood, hematopoietic, and respiratory cancers were slightly above expected counts, while observed counts for digestive and breast cancers were below expected. No nasopharyngeal carcinoma or pancreatic cancers were identified, and the observed prostate cancer count (SIR; 95% CI=0.65; 0.40, 0.98) was significantly below the expected number. The observed count for colorectal cancer was below the expected number, although a markedly larger fraction of Hinkley cases were diagnosed at advanced stage compared to the county, region and state.
Conclusions: These findings do not support claims of a generalized cancer excess in Hinkley, although the cervix, prostate, and colorectal cancer findings reveal underutilization of cancer screening in the Hinkley tract. These findings are consistent with previous assessments that did not identify a cancer excess in the Hinkley tract.
Funding: The California Department of Public Health, National Cancer Institute (Grant N01-PC-35136 and N01-PC-35139), and Centers for Disease Control and Prevention (Grant N02-PC-54404) funded cancer surveillance necessary for this study.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A78.
Abstract A148: Palomid 529, a dual mTor1/2 inhibitor, efficiently penetrates the blood-brain barrier and may be an attractive agent for treatment of glioblastoma
Authors: Fan Lin , Buil Levi , Beijnen Jos H. , Sherris David , van Tellingen Olaf 
Published: June 2012

Abstract
High-grade gliomas (WHO grade III anaplastic astrocytoma and grade IV glioblastoma multiforme) are the most common primary tumors in the central nervous system in adults and uniformly lethal. The current standard treatment (radiotherapy and temozolomide chemotherapy) has only a modest efficacy and better treatments are urgently needed. Activation of the EGFR/PI3K/Akt/mTor signaling cascade is a common event, especially in de novo glioblastoma (GBM) and, therefore, an attractive target for intervention by inhibitors. However, the blood-brain barrier (BBB) is an impediment for the delivery of many agents into the brain. Although GBM has the capacity to disrupt the blood-brain barrier, it is also a very invasive tumor with many tumor cells residing within areas of the brain where the BBB is still intact. Consequently it is important to consider the BBB penetration of novel candidate drugs for treatment of gliomas.
We here present a pre-clinical pharmacokinetic study of Palomid 529, which is a novel small molecule inhibitor of mTor. This agent is attractive because it inhibits both the Torc1 and Torc2 complexes, thereby preventing upstream Akt activation through feedback loops. We have used in vitro transwell assays and found that Palomid 529 has negligible affinities for P-glycoprotein (Pgp) and Bcrp1, the two most dominant drug transporters that are expressed at the BBB. Subsequent studies in transporter knockout mouse models receiving i.v. P529 as a micronized drug formulation at a high dose (54 mg/kg) or low dose (5.4 mg/kg) confirmed these results and demonstrated that Palomid 529 penetrates the BBB efficiently with brain-to-plasma ratios exceeding 1. Only at the lowest dose level a minor effect of Pgp and Bcrp1 was observed. Based on these results we are now executing pre-clinical testing of Palomid 529 against orthotopic brain tumor models.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A148.
Abstract B192: Preclinical characterization of BMS-833923 (XL139), a hedgehog (HH) pathway inhibitor in early clinical development
Authors: Gendreau Steven B. , Hawkins Don , Ho Ching-Ping , Lewin Anne , Lin Tara , Merchant Akil , Rowley R. Bruce , Wang Qiuju , Matsui William , Fargnoli Joseph 
Published: June 2012

Abstract
Background: Aberrant HH pathway signaling has been implicated in human malignancies ranging from semi-malignant tumors of the skin to highly aggressive cancers of the brain, lung, pancreas, breast, prostate, and lymphohematopoietic lineages. Dysregulation of this pathway contributes to uncontrolled proliferation, invasion, metastasis, evasion of apoptosis, and resistance to chemotherapy.
Results: BMS-833923 is a potent inhibitor of SMO, a GPCR-like 7-transmembrane receptor that is a critical regulator of the HH pathway. In vitro, BMS-833923 inhibits the expression of downstream effectors in the HH pathway (GLI1 and PTCH1) in cell lines that express wild-type SMO and those which express activated mutant forms of SMO (IC50 values of 6–35 nM). In FACS-based binding assays, BMS-833923 inhibits BODIPY cyclopamine binding to SMO in a dose-dependent manner with an IC50 of 21 nM. Prior work has demonstrated that HH pathway blockade inhibits the in vitro clonal expansion of multiple myeloma (MM) precursor cells in both established cell lines and in clinical samples from patients with MM (Peacock et al 2007, PNAS 104:4048). Consistent with these observations, BMS-833923 inhibited the in vitro growth of MM clones and proportion of ALDH+ cancer stem cells derived from bone marrow samples from subjects with MM. Furthermore, BMS-833923 inhibited the clonogenic growth of multiple tumor cell lines derived from patients with hematological malignancies including CML, ALL and AML, suggesting that targeting the HH pathway may have broad therapeutic utility for patients with hematologic malignancies. In vivo pharmacodynamic studies show that BMS-833923 robustly inhibits HH pathway activity with a long duration of action after a single oral dose in medulloblastoma and pancreatic carcinoma xenograft models. The pharmacodynamic effects of BMS-833923 observed in these models translate into tumor growth inhibition at well-tolerated doses. These results are consistent with pharmacokinetic parameters demonstrated in nonclinical studies.
Conclusions: BMS-833923 is an orally bioavailable, potent and selective inhibitor of the HH pathway as measured by in vitro cell-based assays and in vivo pharmacodynamic and efficacy models, supporting the clinical development of BMS-833923 in both hematological and non-hematological malignancies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B192.
Abstract B197: Phase II, single-arm study of tasisulam-sodium (LY573636-sodium) as 2nd–4th line therapy for platinum resistant ovarian cancer
Authors: Gordon Michael , McMeekin D. Scott , Temkin Sarah , Tew William , Yapp Stephanie , Scambia Giovanni , Streltsova Olga , Kaiser Christopher , Ilaria Robert , Look Katherine 
Published: June 2012

Abstract
Background: Tasisulam-sodium (tasisulam) is a novel anti-cancer agent that induces mitochondrial mediated apoptosis and anti-angiogenesis. The mechanism of action is being further evaluated. Phase I trials defined the dose and schedule for this agent and suggested activity in chemotherapy-resistant ovarian cancer (OvCa).
Methods: Patients (Pts) with no more than 2 prior systemic regimens for platinum-resistant OvCa received tasisulam by 2-hour intravenous infusion every 21 days, targeting a maximum concentration (Cmax) of 420 µg/mL. The primary endpoint was objective response rate (ORR). Secondary endpoints were clinical benefit rate [(CBR = complete response (CR) + partial response (PR) + stable disease (SD)], progression-free survival (PFS), overall survival (OS) and safety.
Results: From February 2007– May 2008, 55 pts were enrolled [median age of 55 years (range: 27–78); ECOG PS of 0–2]. Fifty pts had measurable disease by RECIST. A median of 3 cycles (range: 1–18) was administered. Hematologic adverse events (AEs) were the most common grade (G) 3/4 AEs, regardless of causality. G 3/4 thrombocytopenia or neutropenia occurred in 7.3%/20.0% and 12.7%/14.5% of pts, respectively. Febrile neutropenia occurred in 3.6% of pts, and G 3/4 anemia in 12.7%/1.8%. Other G 3/4 non-hematologic AEs in ≥ 2% of pts included infections (12.7%), pain (10.9%), metabolic abnormalities (14.5%), vomiting (7.3%), GI obstruction (5.6%) and dehydration and renal failure (3.6% each). Five deaths occurred on study (or within 30 days of discontinuation), 3 of which were confounded by complications of the underlying disease. A total of 8 investigator-assessed (RECIST) responses were reported in the 50 patients with measurable disease, and 6 were confirmed, for a response rate of 12.0% (90% CI: 4.4–19.6). Another 17 pts (34.0%) had SD for a CBR of 46% (90% CI: 34.4–57.6%). Median PFS was 1.9 months (90% CI: 1.5–3.0; 16.4% censored) and median OS was 12.9 months (90% CI: 8.6–17.7; 47.3% censored) in the 55 enrolled pts. Study is on-going with 3 pts still on treatment.
Conclusion: Tasisulam has encouraging activity in platinum-resistant OvCa. An alternative treatment schedule is currently being explored in this patient population to minimize the risk of serious myelosuppression while preserving efficacy.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B197.
Abstract B27: Correlation between TNFα and LCL161 anti-tumor activity in patient derived xenograft models of human cancer
Authors: Firestone Brant , Conway Colleen , Yang Guizhi , Gao Hui , Porter Dale , Slisz Joanna , He Dan , Mosher Rebecca , Monahan John , Straub Christopher , Morrissey Michael , Yao Yung-mae , Zawel Leigh 
Published: June 2012

Abstract
LCL161, a small molecule antagonist of inhibitor of apoptosis proteins (IAPs), induces TNF -mediated apoptosis in a subset of tumor cell lines including the MDA-MB-231 breast cancer line. To investigate the in vivo activity of LCL161, MDA-MB-231 tumor bearing mice were treated with a once weekly oral dose. We observed anti-tumor activity that was associated with pharmacodynamic responses including degradation of CIAP1 and induction of cleaved caspase 3. The loss of CIAP1, specifically the E3 ligase activity of this protein, has been shown to directly impact the stability of a number of client proteins including NIK (NF-κB inducing kinase), Mad1 (MAX-binding protein), and others. Gene expression analysis on LCL161 treated MDA-MB-231 tumors revealed a striking upregulation of NF-κB regulated target genes. These data were further supported by the observation that TNFα, a direct target of NF-κB, was induced in LCL161 treated MDAMB-231 tumor lysates. To explore whether TNFα expression levels could be used to predict single agent efficacy in a more clinically relevant context, a series of human primary tumor xenografts were profiled for baseline TNFα mRNA levels and evaluated for response to LCL161 in vivo. We observed that tumors with the highest TNFα expression levels showed the greatest sensitivity to LCL161. These studies demonstrate an essential role of the NF-κB pathway in IAP antagonist anti-tumor activity. Ongoing efforts focus on delineating the contribution of the canonical and non-canonical NF-κB pathways to efficacy and on leveraging this mechanism for LCL161 patient selection.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B27.
Abstract B270: Profiling the biochemical and cellular activities of TAK-901, a potent multi-targeted Aurora-B kinase inhibitor
Authors: Farrell Pamela , Shi Lihong , Matuszkiewicz Jennifer , Balakrishna Deepika , Elliott Sarah , Halkowycz Petro , Feher Victoria , Paraselli Bheema , Grimshaw Charles , Sang BiChing , de Jong Ron 
Published: June 2012

Abstract
Aurora A, B, and C comprise a family of serine-threonine protein kinases that are key cell cycle regulators ensuring an orderly and accurate execution of mitosis and cell division. Aurora A localizes to centrosomes and spindle poles and is required for mitotic spindle assembly and centrosome maturation, whereas Aurora B is a chromosome passenger protein essential for phosphorylation of histone H3, chromosome segregation, and cytokinesis. Aurora A and B are overexpressed in many malignancies, making them attractive therapeutic targets. Derived from the azacarboline scaffold representing a unique kinase hinge-binder chemotype, TAK-901 is a novel inhibitor of Aurora A, B, and C kinases with IC50 values in the low nanomolar range. It potently inhibits Aurora A-TPX2 and Aurora B-INCENP (IC50 = 21 and 15 nM, respectively) and is a time-dependent, tight binding inhibitor of Aurora B-INCENP. Dissociation of TAK-901 from Aurora B-INCENP was slow with a t1/2 of 920 minutes, and the affinity constant for TAK-901 binding to Aurora B-INCENP was determined to be 0.02 nM. TAK-901 induced inhibition of cell proliferation in cultured human cancer cell lines from different tissues with IC50s ranging from 40 to 500 nM. Consistent with Aurora B inhibition, TAK-901 treatment produced polyploidy in human PC3 prostate cancer and HL60 acute myeloid leukemia cells as measured by immunofluorescence and flow cytometry. Examination of a broad panel of kinases revealed that multiple kinases, including FLT3, FGFR and the Src family kinases, were inhibited by TAK-901 with IC50 values similar to those for Aurora A and B. In cells, TAK-901 suppressed the Flt3 and FGFR2 autophosphorylation with IC50 values close to that of Aurora B as measured by cellular histone H3 phosphorylation, whereas the IC50s for inhibition of cellular Src and BcrAbl were 20-fold weaker. In a panel of pathway specific reporter-based cell models, TAK-901 inhibited the NFkB and JAK/STAT pathways with submicromolar potency. However, phosphorylation or subcellular localization of the signaling mediators NFkB and STAT5 were unaffected by TAK-901 treatment. The expression of a subset of NFkB-regulated genes was altered by TAK-901. Furthermore, TAK-901 treated human PBMCs exhibited multiple differentially expressed genes, as identified using gene expression profiling by microarray analysis, which were subsequently confirmed by quantitative RT-PCR. The mechanism by which TAK-901 alters expression of these genes remains unknown and is under investigation. Altogether, these findings have led to increased understanding of the biological activities of TAK-901 and identification of potential novel biomarkers for clinical use. TAK-901 is currently in Phase I clinical trials.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B270.
Abstract B4: Regorafenib: a new oral multikinase inhibitor of angiogenic, stromal and oncogenic (receptor tyrosine) kinases with potent preclinical antitumor activity
Authors: Wilhelm Scott , Adnane Jalila , Lynch Mark , Hornberg Jorrit , Schütz Gunnar , Thierauch Karl-Heinz , Zopf Dieter 
Published: June 2012

Abstract
Angiogenesis is a critical driver of tumor growth and progression, and is controlled by a number of interconnected signaling pathways. In these pathways, the two tyrosine kinase receptors, vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and EGF homology domain 2 (TIE2) play crucial roles in the neovascularization, stabilization, and maintenance of normal and tumor vasculature. Regorafenib, a novel oral multikinase inhibitor, potently inhibits both VEGFR2 and TIE2 in biochemical and cellular kinase phosphorylation assays. It inhibits additional angiogenic kinases ie VEGFR1, VEGFR3, platelet-derived growth factor receptor- , and fibroblast growth factor receptor-1 and the mutant oncogenic kinases KIT and RET, which play a role in human gastrointestinal stromal and thyroid cancers, respectively, and B-RAF. The mechanism of action of regorafenib on the tumor vasculature was demonstrated in vivo by dynamic contrast-enhanced magnetic resonance imaging using Gadomer as contrast agent. Regorafenib significantly decreased tumor perfusion and extravasation of the contrast agent in a rat GS9L glioblastoma tumor xenograft model grown i.m. in the rat leg compared to rat muscle tissue after a single oral administration of 10 mg/kg. The pharmacodynamic effects persisted for 48 hours after the last drug administration and correlated with the tumor growth inhibition in a QDx4 once daily oral dosing study. A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after QDx5 daily oral dosing at 10 and 30 mg/kg of regorafenib in tumor-bearing mice. Regorafenib exhibited potent dose-dependent tumor growth inhibition in various preclinical murine xenograft models including breast (MDA-MB-231), NSCLC (NCI-H460), renal (786-O), and several colorectal (Colo-205, HCT-15, HT-29) carcinoma, some of which carry mutant K-RAS and/or B-RAF. Tumor shrinkage was observed in the breast MDA-MB-231 and the renal 786-O carcinoma models. The compound was well tolerated and no significant weight loss or lethality was observed. Immunohistochemical analyses of the breast xenograft tumor revealed a strong reduction in staining of the proliferation marker Ki-67 and of the phosphorylated extracellular regulated kinases 1 and 2. Non-clinical metabolism studies have detected two pharmacokinetically stable regorafenib metabolites, with similar but distinct kinase profiles. These data demonstrate that regorafenib is a well-tolerated, orally active multikinase inhibitor with a unique target profile that may have therapeutic benefit in human malignancies.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B4.