bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2744: Loss of VAV3 expression as a novel biomarker and indicator of chemosensitivity in basal-like breast cancer
Authors: Getz Julie E. , Anderson Eric M. , Black Michael A. , Hedenfalk Ingrid A. , Balagurunathan Yoganand , Willis Amanda L. , Mancini Catherine M. , Ramos Pilar , Cunliffe Heather E.
Published: February 2011

Microarray-based technologies have revealed at least five molecularly distinct subtypes of breast cancer that share similarities in their underlying disease biology and have more predictable responses to therapy: Luminal A, Luminal B, Basal-like, ERBB2 positive, and Normal Breast-like. The ability to objectively subclassify breast tumors adds significant prognostic information that is independent of standard clinical parameters and provides insight for clinical decision-making. Basal-like breast (BLB) cancer, accounts for approximately 16% of breast tumors diagnosed. The majority of BLB tumors do not express estrogen and progesterone receptors (ER/PR) and HER2/neu, and they commonly have mutations in the TP53 or BRCA1 genes. Patients diagnosed with BLB tumors have a relatively poor prognosis, and the molecular basis for disease progression in this subtype remains unclear.

Due to proposed differences in etiology and mesenchymal characteristics of BLB tumors, we hypothesized that regulators of cell morphology, contractility and motility may be distinctly deregulated in this subtype and may provide insight into molecular pathology operating in BLB tumors. We therefore investigated genes associated with the Rho/Rac/Cdc42 superfamily, a key regulator of cell morphology. Using unsupervised hierarchical clustering, we confirmed diverse regulation of this gene superfamily in publicly available breast tumor gene expression microarray datasets. Very low expression of VAV3 was observed in BLB tumors compared to all other intrinsic subtypes across six breast cancer cohorts.

Analysis of VAV3 transcript and protein expression in cell lines and tumor samples indicated low VAV3 expression correlates with BLB subtypes. We have confirmed that loss of VAV3 expression in BLB cell lines is not due to gene copy number loss by Fluorescence In Situ Hybridization and array Comparative Genomic Hybridization (aCGH). Kaplan Meyer analysis from publicly available breast tumor data suggested that elevated VAV3 expression in BLB tumors is predictive of response to chemotherapy. We are currently investigating whether exogenous VAV3 overexpression in BLB cancer cell lines increases their chemosensitivity. In conclusion, our findings support a hypothesis that VAV3 is a potential biomarker of BLB cancer, and VAV3 expression in BLB tumors may be a predictor of response to chemotherapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2744.
Abstract 2762: An open-label phase 1 study to evaluate the pharmacokinetics of axitinib (AG-013736) in healthy Chinese volunteers
Authors: Chen Ying , Jiang Ji , Zhang Jianyan , Tortorici Michael , Pithavala Yazdi K. , Lu Lei , Ni Grace , Hu Pei
Published: February 2011

Introduction: Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is mainly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP1A2, CYP2C19, and uridine glucuronyltransferase (UGT1A1). Axitinib currently is in Phase 3 development for renal cell carcinoma. As part of the global clinical development program for axitinib, studies are ongoing in cancer patients in China. A clinical assessment of axitinib pharmacokinetics in healthy Chinese subjects, including dose-proportionality, was conducted to support the regulatory submission in China.

Methods: This was an open-label, fixed-sequence study conducted in mainland China in 14 healthy volunteers. All subjects received a single axitinib dose of 5 mg, 7 mg, and 10 mg under fed conditions in study periods 1, 2, and 3, respectively, followed by safety and pharmacokinetic monitoring. Each study period was separated by a washout period of at least 7 days between successive axitinib doses. Serial blood sampling for axitinib pharmacokinetics was performed up to 32 hours postdose in each period. Plasma concentrations of axitinib were measured using a validated LC/MS/MS (liquid chromatography coupled with mass spectrometry) method. Axitinib plasma pharmacokinetic parameters were estimated using standard noncompartmental methods.

Results: Axitinib AUC0-∞ (area under the curve from time zero to infinity) and Cmax (maximal plasma concentration) estimates in healthy Chinese volunteers in this study are reported here. The geometric mean estimate of AUC0-∞ was 150, 251, and 321 ng[[Unable to Display Character: ∙]]h/mL for doses of 5 mg, 7 mg, and 10 mg, respectively. This represented AUC0-∞ increments of 1:1.7:2.1 for dose increments of 1:1.4:2, respectively (ie, a proportional increase in AUC0-∞ per dose increment). Similarly, the geometric mean estimate of Cmax was 33.5, 51.1, and 69.4 ng/mL for 5 mg, 7 mg, and 10 mg, respectively, representing Cmax increments of 1:1.5:2.1 for dose increments of 1:1.4:2, respectively (a proportional increase in Cmax per dose increment). Axitinib was well tolerated with no serious adverse events (AEs) or discontinuations; the only observed AE was mild abdominal distension in 1 subject.

Conclusions:. Dose-proportional linear pharmacokinetics for axitinib were observed for the 5 mg to 10 mg dose range in this study.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2762.
Abstract 2763: Utility of clinical biomarkers for detecting protein kinase CK2 inhibition: A report from the phase I trial of CX-4945
Authors: Lim John K.C. , Padgett Claire S. , Marschke Robert F. , Northfelt Donald W. , Andreopoulou Eleni , Von Hoff Daniel D. , Anderes Kenna , Chen Ta Kung , O'Brien Sean E.
Published: February 2011

Introduction: CX-4945 is a first-in-class, orally administered small molecule that potently and selectively inhibits protein kinase CK2, a previously unexploited molecular target with well documented roles in many cancers. In vitro, CX-4945 selectively kills cancer cells by modulating key survival pathways, resulting in cell cycle arrest, inhibition of cell proliferation, and promotion of apoptosis. CK2 hyperactivation of the PI3K/Akt pathway promotes the phosphorylation of several proteins which we have exploited as biomarkers for CX-4945 activity. A validated laser scanning cytometry method has been developed to quantify the phosphorylation of p21 and Akt in cells, and this has been employed to characterize these substrates in circulating blood cells collected from patients in the phase I clinical trial of CX-4945.

Procedures: Eligible patients with advanced solid tumors with progressive disease, or for whom there are no available standard therapies, were administered CX-4945 in successive dose cohorts using a standard 3×3 design at: 90, 160, 300, 460, and 700 mg per dose. Oral doses were administered twice daily for twenty-one consecutive days of a four week cycle. Serial plasma samples were collected for pharmacokinetic analysis on the first and final dosing days of Cycle 1 (i.e., Day 1 and Day 21). In addition, whole blood samples were collected at pre-treatment, 4 hours and 8 hours following the first dose of CX-4945 on Day 1 and Day 21, and peripheral blood mononuclear cells (PBMCs) were isolated for pharmacodynamic biomarker evaluations (specifically, total and phosphorylated forms of p21 and Akt). Plasma samples were also collected at these time points for quantification of plasma IL-6.

Results: Seventeen patients with advanced solid tumors from five separate dose cohorts have received oral doses of CX-4945 to date, and all patients in the study participated in the collection of PBMCs. Biomarkers from patients in Cohorts 3 and 4 demonstrated changes in their profile consistent with the inhibition of CK2. CX-4945 displays general linearity in PK parameters between the dose cohorts, with a terminal half life of approximately 25 hours at steady state.

Conclusions: To date, no DLTs have yet been observed, and the MTD remains to be defined in this Phase I study. Early signals suggest a modulation of the biomarker profile consistent with CK2 inhibition. Patient enrollment will continue, to further characterize CX-4945's safety, tolerance, pharmacokinetics and pharmacodynamic effects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2763.
Abstract 2764: Genome-wide examination of genetic variants associated with response to platinum-based chemotherapy in patients with small-cell lung cancer
Authors: Wu Chen , Xu Binghe , Yuan Peng , Ott Jurg , Guan Yin , Liu Yu , Shen Yuanyuan , Liu Zhe , Yu Dianke , Lin Dongxin
Published: February 2011

Backgrounds: Small-cell lung cancer (SCLC) accounts for about 20% of total lung cancer and systemic chemotherapy is the major therapy for this cancer. Although most SCLC patients are characterized by initial chemosensitivity to the standard first-line platinum-based regimens, a significant fraction of patients are intrinsic nonresponders. Currently, no reliable biomarkers can be used to predict which patients will respond to platinum-based therapy, and this has inadvertently led to less than optimal treatment of a significant proportion of patients.

Methods: We conducted a genome-wide scan of 440,093 single nucleotide polymorphisms (SNPs) using blood DNAs from 245 SCLC patients treated with the same carboplatin or cisplatin plus etoposide chemotherapy to discover variants associated with response. The results of genome-wide scan were validated in another independent set of 183 SCLC patients.

Results: By Set Association analysis, 20 SNPs were identified associated with treatment response, with odds ratios (OR) ranging from 2.36 (95% confidence interval [CI]=1.56 to 3.57) to 4.38 (95% CI=2.12 to 9.29) and these results were confirmed in the replication phase. Most of these SNPs (14/20) were clustered on chromosomes 22p11.23, 6q24.3, and 20p12.2 where the BTBD3, STXBP5 and BCR genes were located. For example, 85.4% of nonresponders carried the rs41383844 (located downstream of BTBD3) AA genotype whereas 56.4% of responder carried this genotype (OR=5.24, 95% CI=2.47 to 11.13; P=1.63×10−5).

Conclusion: These results suggested that germline genetic variations significantly influence the effectiveness of platinum-based chemotherapy in SCLC patients. Further studies arewarranted to test the value of these findings for personalized chemotherapy.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2764.
Abstract 2767: Effect of obesity on glutamine levels after L-asparaginase
Authors: Mittelman Steven D. , Hart Nancy , Tom Lana , Nuno Diandra , Butturini Anna
Published: February 2011

L-asparaginase is used as a first-line agent in the treatment of acute lymphoblastic leukemia (ALL). It is believed to act primarily via depletion of the non-essential amino acid asparagine (ASN), since ALL cells are unable to synthesize sufficient ASN to meet their high metabolic demands. However, there is evidence that the depletion of glutamine (GLN) by L-asparaginase might also be important in its anti-leukemia activity.

We have previously shown that children who are obese at the time they are diagnosed with high-risk ALL have a 50% higher chance of relapse. Since adipose tissue is known to produce GLN, the present study was designed to test whether obese subjects diagnosed with high-risk ALL would have less suppression of GLN after an injection of PEG-Asparaginase than their lean counterparts.

Four lean (BMI 35 ± 19 %ile, 2 male/2 female) and 3 obese (BMI 98 ± 1 %ile, 2 male/1 female) adolescents with new diagnosis of high-risk ALL were studied so far. Amino acid levels were measured by HPLC in the CHLA clinical laboratory prior to and at weekly interval after injection of PEG-Asparaginase (2500 IU/m2). One lean subject received the drug intravenously, the remainder intra-muscularly. The other drugs used in induction were vincristine, daunomycin and prednisone, per CCG 1961 protocol, not on study. No dose adjustments were made based on obesity.

Prior to treatment, there were no differences in plasma ASN (44.3±17.2 vs. 42.5±17.3 μM obese vs. lean, p=0.90) or GLN (539±78 vs. 567±247 μM, obese vs. lean, p=0.85) levels between groups. Two weeks after treatment, ASN levels were suppressed to ≤2 μM in both groups. In contrast, GLN levels after PEG-Asparaginase were different in obese vs. lean patients: in the obese patients, GNL level significantly increased by the second week after treatment (709±111 μM, p=0.02 vs. week 0) while no significant changes were detected in lean subjects (509±141 μM, p=0.36 vs. week 0). The change in GLN level from week 0 to 2 was +170±43 and −58±107 μM in obese and lean subjects, respectively (p=0.02).

Thus, obesity appears to affect GLN levels after a single injection of PEG-Asparaginase. The differences in plasma GLN levels might reflect larger differences in GLN levels in the local leukemia microenvironment (e.g. bone marrow, adipose tissue). Although the clinical significance of this observation is limited by the small patient sample, these data highlight the need for further studies to investigate the role of obesity on the efficacies of chemotherapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2767.
Abstract 277: Downregulation of the receptor tyrosine kinase cMet is impaired in pancreatic adenocarcinoma cells
Authors: Hill Kristen S. , Lorinczi Marta , Elferink Lisa A.
Published: February 2011

Increased signaling from cMet, the receptor for Hepatocyte Growth Factor (HGF) has been implicated in the progression of many cancers, particularly pancreatic cancer, correlating with cellular transformation, tumor invasion and poor patient prognosis. In contrast to other cancers, receptor mutations that result in increased cMet signaling have yet to be detected in pancreatic cancers. This led us to hypothesize that post translational mechanisms such as impaired cMet down regulation, a process that normally functions to attenuate cMet signaling in vivo, could be a factor for increased cMet signaling in pancreatic tumors. To test this, we examined the lysosomal down regulation of cMet in a panel of pancreatic adenocarcinoma cell lines. Here we report that uncoupled cMet down regulation in pancreatic tumor cells correlates with increased cMet stability and signaling in response to HGF. In pancreatic Suit-2 cells, impaired binding of the E3 ubiquitin ligase Cbl to cMet, results in reduced receptor ubiquitination and increased cMet recycling to the cell surface. Conversely, transient HGF induced cMet ubiquitination in pancreatic BxPC-3 cells correlates with prolonged cMet stability and signaling, suggesting that the kinetics of cMet ubiquitination rather than receptor ubiquitination per se is critical for efficient cMet down regulation. These data mark the first evidence that disrupted cMet down regulation could be a contributing factor in the aggressiveness of certain pancreatic tumor cells and highlights the importance of the endocytic machinery as a novel therapeutic target.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 277.
Abstract 2778: Association between mammographic density and serum 25-hydroxyvitamin D levels
Authors: Crew Katherine D. , Flom Julie , Tehranifar Parisa , Terry Mary Beth
Published: February 2011

Background: Previous studies have demonstrated an inverse association between vitamin D and risk of breast cancer. In addition, dietary vitamin D intake has been associated with lower mammographic density (MD), a strong intermediate marker of breast cancer risk. We examined the relationship between MD and serum 25-hydroxyvitamin D [25(OH)D], an integrated measure of vitamin D status from food, supplements, and sun exposure, in a multi-ethnic cohort of women undergoing screening mammography.

Methods: Using a cross-sectional study design, 195 women without a history of breast cancer completed a routine screening mammogram, in-person interviews collecting data on demographics, lifestyle factors, and breast cancer risk factors, and donated a blood sample. We digitized mammograms and evaluated the proportion of dense area on cranial-caudal images using Cumulus software. Serum 25(OH)D was measured in batched, archived specimens by Diasorin radioimmunoassay. We used a multivariate linear regression model to investigate the association of percent density with serum 25(OH)D. We examined confounding by age, race/ethnicity, body mass index (BMI), season of blood draw, and breast cancer risk factors.

Results: A total of 195 women enrolled, 116 donated a blood sample and were evaluable for analysis; median age: 49.9 years (range 40.0-60.9); white/African American/African Caribbean/Hispanic Caribbean: 26%/43%/19%/12%. The prevalence of vitamin D deficiency [25(OH)D <20 ng/ml] was 24% among whites, 52% in African Americans, 33% in African Caribbeans, and 43% in Hispanics (Chi-square p-value=.09). Age and BMI were inversely associated with MD (p<0.001). After adjusting for known confounders, we found no association between serum 25(OH)D and percent density.

Discussion: In contrast to some previous reports, vitamin D does not appear to be related to MD in this multiethnic cohort. Vitamin D status, a potentially modifiable risk factor, may have a protective effect against breast cancer development which is not mediated by changes in breast density.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2778.
Abstract 2789: C-reactive protein and risk of lung cancer
Authors: Chaturvedi Anil , Caporaso Neil , Katki Hormuzd , Wong Hui-Lee , Chatterjee Nilanjan , Pine Sharon , Chanock Stephen , Goedert James , Engels Eric
Published: February 2011

Background: Chronic inflammation could act as a co-factor to tobacco smoke in increasing lung cancer risk, underscoring the potential for both lung cancer prevention and screening. We investigated the association of circulating high-sensitivity C-reactive protein (CRP) and CRP single nucleotide polymorphisms (SNPs) with prospective risk of lung cancer.

Methods: We conducted a nested case-control study of 592 lung cancers and 670 controls with available pre-diagnostic serum and 378 cases and 447 controls with available DNA within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N=77,464). Controls were matched to cases on age, sex, entry year, follow-up time, and smoking status (cumulative amount and time since quitting). We measured CRP levels in baseline serum samples and genotyped 5 common CRP SNPs.

Results: Elevated CRP levels were associated with increased lung cancer risk (odds ratio [OR] for individuals in the fourth quartile (Q4, ≥5.6 mg/L) vs. those in Q1 (<1.0 mg/L)=1.98; 95% CI=1.35-2.89), with a trend for increasing risk across CRP quartiles (p-trend<0.001). This association was most apparent for squamous cell carcinomas (OR=2.92; 95% CI=1.30-6.54), in the 2-5 years before lung cancer diagnosis (OR=2.33; 95% CI=1.24-4.39), and among former (OR=2.48; 95% CI=1.53-4.03) and current smokers (OR=1.90; 95% CI=1.06-3.41). Although CRP SNPs and haplotypes were associated with significant differences in CRP levels, they were not associated with lung cancer risk. Ten-year standardized absolute risks of lung cancer were higher with elevated CRP levels, among both former (Q4=2.55% vs. Q1=1.39%) and current smokers (Q4=7.37% vs. Q1=4.03%).

Conclusions: Elevated CRP levels are associated with subsequently increased lung cancer risk, in support of an etiologic role for chronic pulmonary inflammation in lung carcinogenesis. The separation in lung cancer absolute risks across circulating CRP levels among former and current smokers provides preliminary evidence for the utility of CRP measurements in lung cancer risk stratification.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2789.
Abstract 2791: Blood C-reactive protein levels and colon cancer risk
Authors: Yang Gong , Chow Wong-Ho , Shu Xiao-Ou , Li Honglan , Xiang Yongbing , Wen Wanqing , Ji Butian , Rothman Nathaniel , Zhang Xianglan , Cai Qiuyin , Gao Yu-Tang , Zheng Wei
Published: February 2011

Background: Circulating C-reactive protein (CRP), a sensitive marker of low-grade systemic inflammation, has been associated with an increased risk of colon cancer in some but not all studies. Few studies have evaluated the association by the time interval between blood collection and cancer diagnosis.

Objective: To prospectively evaluate the association between blood CRP levels and colon cancer risk, as well as the potential effect of time window of CRP measures on the association.

Design: A nested case-control study of 209 cases of colon cancer and 279 controls identified from the Shanghai Women's Health Study with up to 10 years of follow-up. Conditional logistic regression was used to estimate odds ratios (OR) of developing colon cancer and their 95% confidence intervals (CI) associated with blood CRP levels.

Results: Blood CRP levels were positively associated with colon cancer risk (P trend = 0.003). Women in the highest quartile of CRP had an adjusted OR of 2.52 (95% CI: 1.36 − 4.70) compared with women in the lowest quartile. The risk was higher for women whose CRP was measured in blood collected ≤5 years prior to diagnosis (OR for the highest quartile of CRP = 3.67; 95% CI: 1.41 − 9.56; P for trend = 0.006), compared to women with samples collected >5 years before diagnosis (corresponding OR = 1.98; 95% CI: 0.83 − 4.74; P for trend = 0.15).

Conclusion: Our findings support the hypothesis that low-grade systemic inflammation is associated with an increased risk of colon cancer. Cancer-induced inflammation may partly explain the observed association.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2791.
Abstract 2792: Serum vitamin D and colorectal cancer risk in a large male cohort
Authors: Weinstein Stephanie J. , Yu Kai , Horst Ronald , Virtamo Jarmo , Albanes Demetrius
Published: February 2011

Only a few studies have prospectively evaluated biologic measures of vitamin D in relation to colorectal cancer risk, with some suggesting an inverse association, although inconsistencies remain. The accepted biomarker of vitamin D status, 25-hydroxyvitamin D [25(OH)D], integrates total vitamin D intake and vitamin D synthesized as a result of UVB exposure from sunlight. We conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men based on 239 colon and 192 rectal cancer cases, along with an equal number of controls matched on age (+/- 1 year) and date of blood draw (+/-30 days). Baseline serum samples were assayed for 25(OH)D using the DiaSorin LIAISON 25(OH)D TOTAL assay, with interbatch and intrabatch CVs of 12.3% and 10.5%, respectively. Conditional logistic regression models provided odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D and colon and rectal cancers separately, adjusted for years of smoking and serum α-tocopherol, β-carotene, and retinol (and conditioned on the matching factors). 25(OH)D concentrations were categorized using clinically defined cutpoints of <25, 25 to <37.5, 37.5 to <50, 50 to <75 (referent), and > 75 nmol/L. Both colon and rectal cancer cases had non-significantly higher 25(OH)D concentrations compared with controls (p=0.14 and 0.63, respectively). We observed no inverse association between 25(OH)D and colon or rectal cancer (Table). Patterns in risk did not differ by season of blood draw or time from blood draw to diagnosis. Additional analyses with 25(OH)D residually-adjusted for season and with season-specific cutpoints were similarly null. In our study, few subjects had high (> 75 nmol/L) 25(OH)D, which may account for our finding no evidence of serum 25(OH)D being prospectively associated with colon or rectal cancer risk.ORs and 95% CIs for the association between serum 25(OH)D and risk of colon and rectal cancersSerum 25(OH)D (nmol/L)ColonRectum Cases/ControlsOR (95% CI)Cases/ControlsOR (05% CI)<25.077/870.63 (0.36-1.12)68/700.62 (0.33-1.18)25.0 - <37.563/600.91 (0.52-1.59)42/460.56 (0.27-1.13)37.5 - <50.040/440.73 (0.39-1.36)33/330.82 (0.39-1.71)50.0 - <75.047/401.00 (reference)39/321.00 (reference)≥75.012/81.44 (0.49-4.26)10/110.62 (0.22-1.76)P trend 0.11 0.23

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2792.
Abstract 2799: Serum vitamin D and risk of bladder cancer in the ATBC Study
Authors: Mondul Alison M. , Weinstein Stephanie J. , Mannisto Satu , Virtamo Jarmo , Albanes Demetrius
Published: February 2011

Background: Urinary bladder cancer is an important health concern in developed countries, particularly for men, among whom incidence is 3-5 times greater than in women. Vitamin D is thought to protect against cancer at many sites. However, to our knowledge, no studies have examined the association between serum vitamin D and bladder cancer.

Methods: Within the ATBC Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and β-carotene supplements on cancer incidence, 250 bladder cancer cases were randomly sampled by month of blood collection such that there were 25 cases included from each month with 25 cases total from June - August because fewer blood collections were conducted during the summer months. Controls were sampled from ATBC study participants who were alive and cancer free at the time the case was diagnosed and were matched 1:1 with cases on age at randomization (± 1 year) and date of blood collection (± 30 days). Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals of bladder cancer by a priori categories of baseline serum 25-hydroxy vitamin D (<25, 25 - <37.5, 37.5 - <50, ≥ 50 nmol/L).

Results: After multivariable adjustment, lower serum vitamin D was associated with a statistically significantly increased risk of bladder cancer (OR, 95% CI vs. ≥ 50 nmol/L; 37.5 - <50 nmol/L: 2.04, 1.13 − 3.70; 25 - <37.5 nmol/L: 1.90, 1.07 − 3.35; <25 nmol/L: 1.83, 1.06 − 3.14; p-trend = 0.03), although the risk did not appear to increase with progressively lower vitamin D levels. Rather, men in any category of serum vitamin D below 50 nmol/L were at approximately two-fold risk compared to men with serum vitamin D ≥50 nmol/L (OR, 95% CI: 1.91, 1.20 − 3.04; p value = 0.006). Although the results were not statistically significant, there was a suggestion that the vitamin D - bladder cancer association was stronger among men who smoked less, were not assigned to the α-tocopherol intervention arm, or whose blood samples were obtained during the sunnier months.

Conclusion: In this population of male smokers, lower vitamin D was associated with an increased risk of bladder cancer. Future studies should examine this association in other populations, especially women and non-smokers. Replication in a larger sample may clarify possible subtle effect modification by smoking, season, and intake of other nutrients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2799.
Abstract 2802: Altered expression and the missense polymorphism of the human base excision repair gene NTH1 in gastric cancer
Authors: Goto Masanori , Shinmura Kazuya , Konno Hiroyuki , Sugimura Haruhiko
Published: February 2011

Reactive oxygen species generated in living cells during normal cellular metabolism and in response to exogenous inducers cause the formation of oxidatively damaged bases in DNA. These oxidized base lesions are primarily removed by the base excision repair (BER) pathway. A BER enzyme, NTH1, has activity that is capable of removing oxidized pyrimidines, such as thymine glycol, from DNA. To clarify whether the NTH1 gene is involved in gastric carcinogenesis, we first examined the NTH1 expression level in eight gastric cancer cell lines, and the results showed that NTH1 expression was downregulated in all of them, including cell line AGS. Next, a comparison of excisional repair activity against thymine glycol by empty-vector-transfected AGS clones and FLAG-NTH1-expressing AGS clones showed that a low NTH1 expression level led to low capacity to repair the damaged base in the gastric epithelial cells. Reduced mRNA expression of NTH1 was also detected in 36% (18/50) of primary gastric cancers. Moreover, immunohistochemical analysis revealed that NTH1 was predominantly localized in the cytoplasm in 24% (12/50) of the primary gastric cancers in contrast to the nuclear localization in non-cancerous tissue, suggesting impaired excisional repair ability for nuclear DNA. Next, we found two novel genetic polymorphisms, i.e., c. −163C>G and c. −241_-221del, in the NTH1 promoter region, and a luciferase assay showed that both were associated with reduced promoter activity. However, there were no associations between the polymorphisms and risk of gastric cancer in a gastric cancer case-control study. Next, all the coding exons of the NTH1 gene and their boundary regions in DNAs of 23 Japanese patients with gastric cancer was searched for genetic polymorphisms by direct sequencing. A novel variant, c. −31A>G, and a single nucleotide polymorphism, c.98G>A (Arg33Lys, rs2302172) were detected at an allele frequency of 2.2%, and 4.3%, respectively. However, the c. −31A>G polymorphism did not affect reduction of promoter activity. We are going to reveal functional characterization of c.98G>A and to examine excisional repair activity against new substrates, such as oligonucleotide containing etheno adducts. Our data suggested that downregulation of NTH1 expression, abnormal localization of NTH1 and the missense polymorphism may be involved in the pathogenesis of a subset of gastric cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2802.
Abstract 2803: A pooled analysis of circulating 25(OH)D and upper gastrointestinal cancer risk in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Authors: Abnet Christian C. , Chen Yu , Chow Wong-Ho , Gao Yu-Tang , Helzlsouer Kathy J. , Marchand Loic Le , McCullough Marjorie L. , Shikany James M. , Shu Xiao-Ou ,   for the Vitamin D Pooling Project Investigators.
Published: February 2011

Upper gastrointestinal (UGI) cancers of the stomach and esophagus have high incidence and mortality worldwide, but are uncommon in Western countries. While it is clear that vitamin D plays important roles in human health, only one prospective study has examined the association between circulating 25-hydroxyvitamin D (25(OH)D) concentrations and risk of UGI cancers. This study examines the association in eight prospective cohort studies from China, Finland, and the USA that are part of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. 25(OH)D concentrations in serum or plasma were measured from 1065 UGI cancer cases and 1066 age-, sex-, race-, and season of blood draw-matched controls. In controls, the median (interquartile range) of circulating 25(OH)D was 39.1 (25.8-56.7) nmol/L, while in cases it was 39.4 (26.3-56.1). 25(OH)D exposure was categorized as six clinically defined categories. A meta-analytic approach showed no significant heterogeneity of effect among the included studies. In multivariate-adjusted models, circulating 25(OH)D concentration was not significantly associated with UGI cancer risk. Compared to the referent group, 50 to <75 nmol/l, those in the lowest (<25 nmol/L) or highest (>=100 nmol/L) categories had odds ratios (95% confidence intervals (CI)) of 0.90 (0.65-1.24) and 0.81 (0.39-1.69), respectively. Subgroup analysis by race showed that among Asians, being in the lowest category was associated with a statistically significant decreased risk of UGI cancer with odds ratio (95% CI) = 0.53 (0.31-0.91) compared to the referent group, but no association in Caucasians, odds ratio (95% CI) = 0.98 (0.67-1.44). Never smokers with concentrations <25 nmol/L were also at lower risk of UGI cancers with odds ratio (95% CI) = 0.55 (0.31-0.96). These results do not support the hypothesis that interventions aimed at increasing vitamin D status would lead to lower risk of these highly fatal cancers.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2803.
Abstract 281: Insulin-like growth factor II differential activation of the IGF-1 and insulin receptors in African-American and Caucasian breast cancer tissues
Authors: Singh Sharda Kalla , Tan Qianwei , Leon Marino De , Leon Daisy De
Published: February 2011

African-American (AA) women with breast cancer are more likely to have advanced disease at diagnosis, higher risk of recurrence and poorer prognosis than Caucasian (CA) females.

Insulin-like growth factor- II (IGF-II) is a potent mitogen that induces cell proliferation and survival signals through activation of the IGF-I (IGF-IR), insulin (INSR) and hybrid receptors. We hypothesize that differential expression of the IGF1R and INSR isoforms (IR-A, IR-B) between AA and CA women potentiates IGF-II mitogenic effects, thus contributing to the health disparity observed between these ethnic groups. We examined IGF-II, IGF1R and INSR isoforms protein expression and phosphorylation in paired breast tissue samples from AA and CA women by western blot analysis, immunohistochemistry and ELISA techniques. IGF-II expression was significantly higher in AA cell lines and tissue samples when compared to Caucasians. Furthermore, significantly increased expression of IGF1R was observed in AA normal tissues as compared to CA normal tissues, while IGF1R expression was similar between AA normal and malignant tissues. Moreover, AA tumor samples expressed significantly lower levels of IR-B protein than CA tumor samples. IGF1R, INSR, IRS-1 and Shc phosphorylation were significantly higher in AA tumor samples. We conclude that the differential expression and phosphorylation of IGF-II, IGF1R and INSR between AA and CA females coupled with differential activation of downstream signaling pathways may contribute to the increased risk of malignant transformation seen in young AA females, and the more aggressive breast cancer phenotype observed among AA breast cancer patients and represent, along with IGF-II, potential therapeutic targets against health disparities in breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 281.
Abstract 2810: Physical activity and colorectal adenomatous polyps: The Minnesota cancer prevention research unit case-control study
Authors: Tu Huakang , Bostick Roberd M.
Published: February 2011

Background: Although it is well established that greater physical activity is associated with lower risk of colorectal cancer, there have been few studies of its association with adenomatous polyps, precursors of colorectal cancer.

Methods: The 1991-1994 Minnesota Cancer Prevention Research Unit case-control study of 566 colonoscopy-positive adenomatous polyp cases, 687 colonoscopy-negative controls, and 535 community controls investigated the association of physical activity with risk of incident, sporadic colorectal adenomatous polyps. Daily hours of moderate and vigorous physical activity were elicited by a standardized questionnaire and metabolic equivalent (MET) hours were calculated.

Results: The age- and sex-adjusted odds ratios (ORs) for adenomas comparing the highest to the lowest quartile of MET hours were 1.02 (95% confidence interval [CI]: 0.73, 1.44) using colonoscopy-negative controls, and 0.96 (95% CI: 0.69, 1.34) using community controls; after multivariate-adjustment the corresponding ORs were 1.11 (95% CI: 0.77, 1.60) and 1.00 (95% CI: 0.70, 1.43). Analyses stratified by nonsteroidal anti-inflammatory drug (NSAID) use excluding aspirin, adenoma size, and adenoma location did not any yield statistically significant results.

Conclusions: Taken together with the strong, consistent inverse associations of physical activity with colorectal cancer, our null results suggest the possibility that physical activity may be more related to risk for transitioning from colorectal adenoma to carcinoma than to adenoma genesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2810.
Abstract 2815: Soy increases risk of rectal cancer among Singapore Chinese women
Authors: Butler Lesley M. , Koh Woon-Puay , Wang Renwei , Yuan Jian-Min , Yu Mimi C.
Published: February 2011

Background. Estrogens are thought to play a protective role in colorectal carcinogenesis, however, recent findings for positive associations with circulating estrogens and colorectal cancer risk among postmenopausal women suggest otherwise. Soy isoflavones are phytoestrogens that can display either estrogenic or antiestrogenic properties depending on estrogen receptor signaling, as well as the estrogen milieu. Inconsistent findings for soy and colorectal cancer risk from observational studies may be due to the relatively low and mainly adulthood intake, as well as differences in the estrogen milieu levels in the most studied populations.

Methods. We examined the relationship between soy isoflavone intake and colorectal cancer in a population-based cohort of 61,314 Singapore Chinese men and women that was established between 1993 and 1998. As of December 31, 2007, 1,167 (640 male and 527 female) incident colorectal cancer cases had been diagnosed. Diet was assessed at baseline with a validated 165-item quantitative food frequency questionnaire. We used Cox regression methods to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for age at baseline, interview year, dialect group, education level, smoking, alcohol use, body mass index (BMI), physical activity, family history of colorectal cancer and total energy intake.

Results. No association was observed between total soy isoflavone intake and risk of colorectal, colon or rectal cancer, overall or among men. Among women, we observed a 43% increase in rectal cancer risk (HR=1.43; 95% CI: 0.92, 2.21; P for trend = 0.11), comparing 4th to 1st quartile of intake (P for interaction by sex=0.04). The association with soy isoflavones was stronger among women who were postmenopausal at baseline (HR=1.64; 95% CI: 1.03, 2.60; P for trend = 0.01). The associations for rectal cancer among postmenopausal women were similar with individual soy isoflavones, soyfoods and soy protein intake. The estrogen milieu was low among postmenopausal women in our cohort. For example, only 6% reported ever use of exogenous hormones and the median BMI was 23.2 kg/m2.

Conclusion. We report a detrimental effect for dietary soy isoflavones on rectal cancer risk among postmenopausal women. Our finding suggests that in a low estrogen milieu phytoestrogens have procarcinogenic effects in the rectum that require lifelong exposure to relatively high levels of intake.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2815.
Abstract 2816: Low-carbohydrate diets and prostate cancer growth: How low is “low enough”
Authors: Masko Elizabeth M. , Thomas Jean A. , Antonelli Jodi A. , Lloyd Jessica C. , Phillips Tameika E. , Poulton Susan H. , Pizzo Salvatore V. , Freedland Stephen J.
Published: February 2011

Introduction: Previous dietary studies indicate carbohydrate intake may influence prostate cancer biology, as LAPC-4 and LNCaP xenograft mice fed a no-carbohydrate ketogenic diet (NCKD; 84% fat-0% carbohydrate-16% protein kcal) had significantly smaller tumors and longer survival times compared to mice fed a Western diet (40% fat-44% carbohydrate-16% protein kcal). The NCKD mice were also found to have higher levels of circulating IGFBP-3 and the lowest levels of insulin, IGF-1, and IGF-1:IGFBP-3 ratio despite consuming more calories than the Western group. As it is nearly impossible for a human to consume and maintain a no-carbohydrate diet similar to that in the previous xenograft studies, we sought to determine whether diets containing 10% or 20% kcal from carbohydrates could slow tumor growth in a similar manner to the NCKD in a xenograft model.

METHODS: A total of 150 male SCID mice were injected with LAPC-4 cells and placed on a Western diet (35% fat-49% carbohydrate-16% protein kcal) ad libitum. Two weeks post-injection, all mice were randomized to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate. Ten mice not injected with tumor were fed an ad libitum low-fat diet (12% fat-72% carbohydrate-16% protein kcal) and served as the reference group in a modified-paired feeding protocol for the other three groups. Calorie intake and body weights were measured thrice weekly and tumor volumes twice per week. Mice were sacrificed when tumors reached 1,000mm3.

RESULTS: Despite consuming 5-10% extra calories on average, all mice receiving low-carbohydrate diets were significantly lighter than the mice consuming the low-fat diet (p<0.04). Overall, the mice fed a NCKD were significantly lighter than the other two arms at multiple time points (p<0.05). There were no significant differences in tumor volumes among groups at any time except at Day 52 and 59, where 10% carbohydrate mice had larger tumors (p<0.05). However, after adjusting for the fact that tumor volumes were compared at multiple time points (i.e. multiple comparisons), these were no longer significant. Dietary treatment did not impact overall survival (p=0.34). NCKD mice had significantly higher glucose levels at sacrifice compared to the mice fed 10% and 20% carbohydrates (p=0.001), but similar levels of urinary ketones (p=0.37).

CONCLUSIONS: LAPC-4 xenograft mice fed a low-carbohydrate diet (10-20% carbohydrate kcal) had similar survival to mice consuming a NCKD (0% carbohydrate kcal). Thus, the survival benefit of a NCKD may be achievable with less restrictive low-carbohydrate diets.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2816.
Abstract 2819: Serum parietal cell antibodies, gastrin G17 concentration and risk of gastric cancer: A 15 year prospective assessment
Authors: Roth Mark , Qiao You-Lin , Kamangar Farin , Fan Jin-Hu , Diaw Lena , Ren Jian-Song , Taylor Philip R. , Giffen Carol A. , Dawsey Sanford M. , Abnet Christian C.
Published: February 2011

Background: We conducted a prospective nested case-cohort analysis within a high-risk Chinese population to determine if baseline serum PCAs or gastrin was associated with an increased risk of gastric or esophageal cancer during 15 years of follow-up.

Methods: The study included 200 cases of gastric cardia adenocarcinoma (GCA), 200 gastric non-cardia adenocarcinomas (GNCA), 100 esophageal squamous cell carcinomas (ESCC), and a 400 person subcohort of the Linxian General Population Nutritional Intervention Trial cohort. Serum PCA and gastrin G17 concentrations were measured using enzyme-linked immunosorbent assays. Mean sample concentrations were calculated by averaging duplicate optical density measures. Cox proportional hazards models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs), using case-cohort models. Models assessed high PCA (Q4 vs Q1) or low gastrin G17 (Q1 vs Q4) and cancer risk. H. pylori status and pepsinogen serology were previously determined (Kamangar et al. Br J. Ca 2007, Ren et al. Gut 2009).

Results: The average time from baseline to cancer diagnosis was 8.1 years. Serum PCA concentrations were non-significantly lower in those who developed GCA than in the subcohort, and were inversely associated with GCA risk. Serum gastrin G17 concentrations were significantly lower in those who developed GNCA than in the subcohort, and were inversely associated with GNCA risk. Neither serum PCA nor gastrin G17 concentration was associated with ESCC risk. These associations were independent of gender, age, smoking, serum pepsinogen I and II concentrations, and H. pylori status. PCA concentration, median (IQR)PwilcoxonPCA Q4 vs Q1PtrendSubcohort (N= 424)0.84 (0.26-5.8)---ESCC (N=95)1.02 (0.32-6.3)0.231.28 (0.65-2.53)>0.5Cardia (N=193)0.59 (0.23-3.2)0.0700.53 (0.30-0.93)0.013Noncardia (N=193)0.85 (0.27-5.4)0.830.76 (0.42-1.35)>0.5      G17 concentration median (IQR)PwilcoxonG17 Q1 vs Q4PtrendSubcohort (N= 424)3.16 (0.78-8.33)-- ESCC (N=95)3.23 (0.57-10.39)0.731.06 (0.55-2.03)0.91Cardia (N=193)3.23 (0.87-6.89)0.681.54 (0.83-2.87)0.30Noncardia (N=193)2.20 (0.30-5.70)0.00203.72 (1.83-7.57)0.00020

Conclusion: High serum parietal cell antibodies were associated with a decreased risk of GCA, and low serum gastrin G17 levels were associated with an increased risk of GNCA in this high-risk population.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2819.