Proffered Papers: Oral Presentation Abstracts
Prostate Cancer Prevention Ovarian Cancer Risk Reduction
PR-1 A randomized factorial trial of vitamins E and C in the PR-2 Investigation of mismatch repair deficiency in ovarian
prevention of cancer in men: The Physicians’ Health Study II. Julie E. cancers. Tuya Pal,1 Domenico Coppola,1 Santo Nicosia,2 Shiyu Zhang,3 Ji-
Buring, Howard D. Sesso, J. Michael Gaziano, for the Physicians’ Health Hyun Lee,1 Jenny Wey,1 Rebecca Sutphen,1 Joellen Schildkraut,4 Steven
Study Research Group. Brigham and Women’s Hospital, Boston, MA. Narod,3 Thomas Sellers1. 1H. Lee Moffitt Cancer Center and Research
Background: Basic science and observational studies support a Institute, Tampa, FL; 2University of South Florida, Tampa, FL; 3Women’s
potential role of antioxidants, including vitamins E and C, in the prevention College Hospital, Toronto, ON, Canada; 4Duke University Medical Center,
of cancer. Previous trials have suggested a possible benefit of vitamin E, in Durham, NC.
particular on prostate cancer. Few long-term trials have evaluated vitamin Background: Defects in the mismatch repair (MMR) pathway are
C alone in the prevention of cancer. Despite uncertainty regarding long- believed to be etiologically important in a reasonable proportion of
term effects, use of vitamin supplementation remains highly prevalent in epithelial ovarian cancers. Various laboratory methods can be used to
the US. identify MMR-deficient ovarian cancers, including microsatellite instability
Methods: The Physicians’ Health Study II (PHS II) evaluated the roles of (MSI) analysis and immunohistochemistry (IHC). Specifically, in colorectal
supplementation with vitamin E (400 IU every other day) and vitamin C cancers (CRC), tumor characteristics previously shown to be useful in
(500 mg daily) on risk of cancer in a randomized, double-blind, placebo- identifying MMR-deficient tumors include MSI-high (MSI-H) phenotype and
controlled trial of 14,641 U.S. male physicians initially aged ≥50 years. The loss of MMR protein expression on IHC analyses. Similar findings have
trial included 1,274 (8.7%) men with prevalent cancer at randomization. been demonstrated in ovarian cancer, however the sample sizes of those
The randomized vitamin E and C trial components terminated as scheduled studies have been limited.
on August 31, 2007, and identification of cancer endpoints that occurred Objectives/Methods: We sought to investigate tumor characteristics
prior to that date will continue through September 30, 2008. The primary including: (1) MSI-high status, (2) Expression of 3 MMR proteins (MLH1,
endpoint of the vitamin E component was prostate cancer, with total MSH2, and MSH6) through IHC studies, and (3) The concordance between
cancer (defined as excluding non-melanoma skin cancer) as a secondary MSI and IHC results. The tumors analyzed came from women between the
endpoint. For vitamin C, the primary endpoint was total cancer. All ages of 18 and 80 years with newly-diagnosed epithelial ovarian cancer
endpoints were reviewed and confirmed by an Endpoints Committee of ascertained between December 13, 2000 and September 30, 2003in a
physicians blinded to randomized treatment assignment. High rates of population-based study covering a 2-county region of west central Florida.
morbidity and mortality follow-up have been maintained in the PHS II. MSI-H was defined by instability in 2 or more of the 5 NCI-standardized
Results: During a median (interquartile range) follow-up of 7.6 (7.1 to microsatellite markers (ie: BAT25, BAT26, D2S123, D17D250, D5S346).
9.6) years among men with a mean baseline age of 64.3 years, there have Tissue microarrays were created to evaluate the loss of MMR protein
been 1,929 cases of cancer, including 1,013 cases of prostate cancer. Based expression on IHC based on a scoring system of 0-9 to evaluate both stain
upon preliminary results, those randomized to vitamin E had a relative risk and intensity, and take the product of these 2 numbers; loss of expression
of prostate cancer of 0.95 (490 events in the active group vs. 523 in the of protein expression was defined as <3). These interim results are part of
placebo group; 95% CI, 0.84-1.07; p=0.39), and a relative risk of total a larger multicenter study, currently underway, to investigate the clinical
cancer of 1.04 (978 vs 951; 95% confidence interval, 0.95-1.14; p=0.38). relevance of the MMR pathway in a population-based sample of ovarian
For those randomized to vitamin C, the relative risk of total cancer was cancers, including MSI analysis, IHC studies, MLH1 promoter
1.00 (964 events in the active group, 965 in placebo; 95% CI, 0.92-1.10; hypermethylation, and germline mutation analysis of the MMR genes.
p=0.95). Results: Of the 232 who agreed to participation, tumor samples were
In addition to updating the results above, we will also present the collected on 219 (94%). The distribution of by race and ethnicity of study
results for other site-specific cancers, as well as analyses that consider the participants was similar to the distribution of cancer cases in the
effects of compliance, effect modification by baseline risk factors and catchment area, with ~90% of participants being non-Hispanic Whites. The
baseline cancer, and potential adverse effects. distribution of histologic subtypes, stage and median age at diagnosis was
Conclusion: These preliminary data from a large-scale prevention trial also similar to that seen in the general population. Of the 219 cases, all
of long duration indicate no beneficial effect of vitamin E supplementation had IHC analysis and 201 had MSI analysis. The frequency of MSI-H was
on either prostate or total cancer, nor a beneficial effect of vitamin C 29%. The frequency of loss of expression on IHC was 17%. The numbers of
supplementation on total cancer. These data will help inform clinical and tumors which were concordant for MSI and IHC results was 141 (including
public health recommendations regarding effects of vitamin E or vitamin C 16 cases with MSI-H and loss of MMR protein expression and 125 cases
supplementation on risks of total and site-specific cancers. with no MSI-H and presence of MMR protein expression). Conversely, there
were 60 discordant cases (including 42 cases which were MSI-H, but MMR
protein expression was present; and 18 cases which were not MSI-H, with
loss of MMR protein expression).
Conclusions: In contrast to previous studies of CRC, our results indicate
limited concordance between MSI-H status and loss of MMR protein
expression. Thus, MSI analysis and IHC studies for MMR protein expression
may be of limited utility in the identification of ovarian tumors with MMR
Frontiers in Cancer Prevention Research • November 16-19, 2008 • Washington, DC 63
Proffered Papers: Oral Presentation Abstracts
ER Stress, Autophagy, Protein Homeostasis, and Results: The effect of leisure-time PA since age 50 on ER+/PR+ differed
Protein Degradation significantly from the effects on ER+/PR- (Pdiff = 0.028), ER-/PR+ (Pdiff =
0.024), and ER-/PR- (Pdiff = 0.028), with more active women having
PR-3 A novel function of poly(ADP-ribose) polymerase-1 in reduced risk for ER+/PR+ carcinomas compared to less active women (OR
modulation of autophagy and necrosis under oxidative stress. Qing = 0.71, 95% CI = (0.60 - 0.85) for the highest vs. lowest quintile; linear
Huang, You-Tong Wu, Hui-Ling Tan, Choon-Nam Ong, Han-Ming Shen. trend P = 0.0001), but no effects for the other receptor-types. Effects of PA
National University of Singapore, Singapore. during age 30-49 years were similar but less pronounced.
Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is The association between leisure-time PA and ER+/PR+ carcinoma risk was
activated and contributes to necrotic cell death through ATP depletion. On significantly modified by breastfeeding (pinteraction = 0.045) with a
the other hand, oxidative stress is known to stimulate autophagy, and protective effect for women who ever breastfed (OR = 0.62 (0.50 - 0.77)
autophagy may act as either a cell death or cell survival mechanism. This highest vs. lowest PA 50+ quintile), while no risk reduction was observed
study aims to explore the regulatory role of PARP-1 in oxidative stress- for women who never breastfed, irrespectively whether they were parous
mediated autophagy and necrotic cell death. Here we first show that or nulli-parous (OR= 0.95 (0.72 - 1.25)). Effect modification was also
hydrogen peroxide (H2O2) induces necrotic cell death in Bax-/- Bak -/- observed for benign breast diseases, but statistically significant only for PA
mouse embryonic fibroblasts (MEFs) through a mechanism involving PARP- during 30-49 years (pinteraction = 0.023). For women who ever had a benign
1 activation and ATP depletion. Next, we provide evidence that autophagy breast disease a clear protective effect was observed (OR = 0.68 (0.52 -
is activated in cells exposed to H2O2. More importantly, we identify a 0.89) for PA 30-49; OR = 0.56 (0.42 - 0.74) for PA 50+), but there was no
novel autophagy signaling mechanism linking PARP-1 to the effect for women without benign breast diseases. No effect modification
serine/threonine protein kinase LKB1-AMP-activated protein kinase was found for family history of breast cancer, BMI, and parity.
(AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to Conclusions: These findings suggest that leisure-time PA may reduce
stimulation of autophagy. Finally, we demonstrate that autophagy plays a postmenopausal breast cancer risk at least in part via hormonal pathways.
cytoprotective role in H2O2-induced necrotic cell death as suppression of The protective effects of PA appear to be more pronounced for women
autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly who had ever breastfed or ever had a benign breast disease. However,
sensitizes H2O2-induced cell death. Taken together, these findings these observed effect modifications need further confirmation.
demonstrate a novel function of PARP-1: promotion of autophagy via the
LKB1-AMPK-mTOR pathway to enhance cell survival in cells under PR-5 A pooled analysis of 14 cohort studies of body mass index
oxidative stress. and pancreatic cancer risk. Jeanine M. Genkinger,1 Stephanie A. Smith-
Warner,2 for the Pooling Project of Prospective Studies of Diet and Cancer
Investigators2. 1Lombardi Comprehensive Cancer Center, Washington, DC;
2Harvard School of Public Health, Boston, MA.
Energy Balance and Physical Activity
Background: Overweight and obesity have been hypothesized to
PR-4 Physical activity and postmenopausal breast cancer: Effect promote pancreatic carcinogenesis by increasing insulin and IGF-1 levels.
modifications by hormone receptor status and breast cancer risk These factors may stimulate cell division, promote tumor development and
factors. Karen Steindorf,1 Martina E. Schmidt,1 Tracy Slanger,1 Silke increase local blood flow. Studies have reported inconsistent results
Kropp,1 Nadia Obi,2 Dieter Flesch-Janys,2 Jenny Chang-Claude1. 1German between overweight and obesity and pancreatic cancer risk.
Cancer Research Center, Heidelberg, Germany; 2University Clinic Hamburg- Methods: A pooled analysis of the primary data from 14 prospective
Eppendorf, Hamburg, Germany. cohort studies was conducted. The study sample consisted of 786,042 men
Background: Physical activity (PA) has been inversely associated with and women among whom 2,135 pancreatic cases were identified. All
postmenopausal breast cancer risk. Most studies regarded breast cancer as studies measured height and weight at baseline; weight in early adulthood
a single disease, at best separated by menopausal status. Yet, breast was measured in 11 studies. Study-specific multivariate relative risks (MV
cancers are heterogeneous and likely to have different etiologies. RR) and 95% confidence intervals (CI) were calculated by Cox proportional
Furthermore, little is known about the biological mechanisms by which hazards models, and then pooled by a random effects model.
physical activity reduces breast cancer risk and about potential modifying Results: Compared to individuals with a BMI between 21-22.9 kg/m², a
effects of other risk factors. Information on the association of PA with 16% (95% CI: 1-34%) and 47% (95% CI: 23-75%) higher pancreatic
breast cancer according to hormone receptor and risk factor status may cancer risk was observed among overweight (BMI between 25-29.9 kg/m²)
provide insight into mechanisms of action. and obese (BMI≥30 kg/m²) individuals, respectively. Results were similar
Materials and Methods: We analyzed these associations in 3,414 for men and women. A positive association was observed for BMI in early
postmenopausal cases and 6,569 controls from a population-based case- adulthood (pooled MV RR = 1.29, 95% CI= 1.07-1.55) comparing BMI≥25
control study on breast cancer conducted 2002-2005 in two regions in kg/m² to a BMI between 21-22.9 kg/m². Pancreatic cancer risk was higher
Germany (MARIE study). Comprehensive data on risk factors were among individuals who were overweight in early adulthood (BMI≥25
collected. PA in the age periods 30-49 and 50+ years was assessed, kg/m²) and not obese at baseline (BMI<30 kg/m²) (pooled MV RR=1.30,
including leisure-time PA (sports, cycling, walking) and non-recreational PA 95% CI=1.08-1.57), among those who were not overweight in early
(occupational and household activities). Polytomous logistic regression was adulthood (BMI<25 kg/m²) and obese at baseline (BMI≥30 kg/m²) (pooled
used to model the association between the PA variables and breast cancer MV RR=1.38, 95% CI=1.13-1.67) and among those who were overweight
according to estrogen- and progesterone- receptor-status (ER/PR). Case- in early adulthood (BMI≥25 kg/m²) and obese at baseline (BMI≥30 kg/m²)
case comparisons were performed to evaluate heterogeneity between (pooled MV RR=1.55, 95% CI=1.24-1.95) compared to individuals with a
cancer subgroups (Pdiff). Effect modifications by other cancer risk factors BMI in early adulthood<25 kg/m² and BMI at baseline<30kg/m². Although
were evaluated by including an interaction term with leisure-time PA as the association with BMI at baseline and BMI in early adulthood and
continuous variable into unconditional logistic regression models, pancreatic cancer risk was not significantly modified by smoking status,
separately for each ER/PR type. statistically significant positive associations were observed in never and
past smokers, whereas a non-significant and weaker association was
observed in current smokers.
64 American Association for Cancer Research
Proffered Papers: Oral Presentation Abstracts
Discussion and Conclusions: Overall, positive associations were comprehensively evaluate genetic variation in VDR and other pathway
observed for overweight and obese individuals and pancreatic cancer risk. genes in relation to RCC risk. While replication and fine mapping studies
As pancreatic tumors are highly fatal, determining preventive factors offers will be required to confirm these findings, this study suggests that genes in
a feasible approach to reducing this disease’s morbidity and mortality. the vitamin D pathway may modify RCC risk.
These results are in line with The World Cancer Research Fund
recommendation to maintain body weight within the normal range, as
overweight and obesity are also linked to other cancers, diabetes and Epigenetics and Genome-Wide Screening
PR-7 A European genome-wide association study of urinary
bladder cancer. Lambertus A. Kiemeney,1 Steinunn Thorlacius,2 Patrick
Personalized Assessment on Cancer Risk Sulem,2 Frank Geller,2 Katja Aben,1 Anne Kiltie,3 Timothy Bishop,3 Giuseppe
Matullo,4 Paolo Vineis,4 Stefano Porru,5 Maurice Zeegers,6 Frank Buntinx,7
PR-6 Variation in VDR pathway genes and renal cancer risk. Sara Rajiv Kumar,8 Tony Fletcher,9 Kvetoslava Koppova,10 Peter Rudnai,11
Karami,1 Paul Brennan,2 Rosenberg Phillip,1 Rayjean Hung,2 Mark Purde,1 Eugene Gurzau,12 Gunnar Steineck,13 Jose I. Mayordomo,14 Jeffrey R.
Marie Navratilova,3 Dana Mates,4 David Zaridze,5 Menashe Idan,1 Vladimir Gulcher,2 Unnur Thorsteinsdottir,2 Augustine Kong,2 Thorunn Rafnar,2 Kari
Janout,6 Helena Kollarova,6 Vladimir Bencko,7 Vitaliy Matveev,5 Neonila Stefansson2. 1Radboud University Nijmegen Medical Centre, Nijmegen,
Szesznia-Dabrowska,8 Ivana Holcatova,7 Marideth Yeager,9 Steven Netherlands; 2deCODE Genetics, Reykjavik, Iceland; 3St. James’s University
Chanock,9 Nat Rothman,1 Wong-Ho Chow,1 Paolo Boffetta,2 Lee E. Moore1. Hospital, Leeds, United Kingdom; 4University of Torino, Turin, Italy;
1NCI, Rockville, MD; 2IARC, Lyon, France; 3Masaryk Memorial Cancer 5University of Brescia, Brescia, Italy; 6University of Birmingham,
Institute, Brno, Czech Republic; 4Occupational Health Department, Institute Birmingham, United Kingdom; 7Catholic University of Leuven, Leuven,
of Public Health, Bucharest, Romania; 5Institute of Carcinogenesis, Belgium; 8German Cancer Research Center, Heidelberg, Germany; 9London
Moscow, Russian Federation; 6Department of Preventive Medicine, Palacky, School of Hygiene and Tropical Medicine, London, United Kingdom; 10State
Olomouc, Czech Republic; 7Institute of Hygiene and Epidemiology, Prague, Health Institute, Banska Bystrica, Slovakia; 11National Institute of
Czech Republic; 8The Nofer Institute of Occupational Medicine, Lodz, Environmental Health, Budapest, Hungary; 12Environmental Health Center,
Poland; 9CGF, Rockville, MD. Cluj-Napoca, Romania; 13Karolinska Hospital, Stockholm, Sweden;
The conversion of vitamin D to its main biologically active form, 1,25- 14University Hospital, Zaragoza, Spain.
dihydroxy vitamin D, occurs in the kidney. Since the most biologically active We conducted a genome-wide SNP association study on 1,803 urinary
form of vitamin D exerts its activity through binding to the intracellular bladder cancer (UBC) cases and 34,336 controls from Iceland and the
vitamin D receptor (VDR), most studies of genetic susceptibility have Netherlands using Illumina HumanHap300 and HumanCNV370-duo
primarily focused on variation within the VDR gene. But, the concert of Beadchips. The 10 most significant SNPs were genotyped using Centaurus
genes that interact with VDR are vast; therefore, an analysis of genetic single track assays in 7 follow up case-control groups (2,165 cases and
variation in VDR and other genes in its pathway may provide insight into 3,800 controls) from Italy (Torino and Brescia), the UK, Belgium, Eastern
the role of vitamin D in renal cell carcinoma (RCC) etiology. In this case- Europe (Hungary, Romania and Slovakia), Sweden and Spain.
control study, we investigated the relationship between RCC risk and 139 The strongest association was observed with allele T of rs9642880 on
single nucleotide polymorphisms (SNPs) in 8 target genes (VDR, RXRA, chromosome 8q24, 30 kb upstream of MYC (allele-specific odds ratio (OR)
RXRB, CYP24A1, GC, STAT1, THRAP4 and TRAP5) of the expanded vitamin = 1.22; P = 9.34 x 10-12). Approximately 20% of individuals of European
D pathway from subjects residing in Central and Eastern Europe. 1,097 ancestry are homozygous for rs9642880[T], and their estimated risk of
RCC cases and 1,476 controls were recruited for this study where genomic developing UBC is 1.49 times that of noncarriers. A weaker signal, but
DNA was analyzed using an Illumina Oligo Pool-All (OPA) assay. First, the nonetheless of genome-wide significance, was captured by rs710521[A]
minimum-p-value permutation (Min-P) test was used to identify genes that located near TP63 on 3q28 (allele-specific OR = 1.19; P = 1.15 x 10-7).
were associated with RCC risk and that remained significant at a cut off No association was observed between UBC and the four 8q24 variants
level of 10%. Next, a haplotype-based sliding window analysis of three previously associated with prostate, colorectal and breast cancers, nor did
consecutive SNPs was used to identify chromosome regions of interest that rs9642880 associate with any of these three cancers. Individuals with low
remained significant at a False Discovery Rate (FDR) of 10%. For these risk tumors (i.e. confined to the bladder mucosa and not poorly
regions, haplotype relative risks were computed using the HaploStats differentiated) had a higher frequency of rs9642880[T] than individuals
package in R. Significant Min-P values were observed for two genes, which with high risk tumors (OR = 1.15, P = 0.011). No difference was found in
were selected for in-depth analysis: VDR (P-value: 0.024) and RXRA (P- the frequencies of rs9642880[T] between ever-smoking and never-smoking
value: 0.100). Two chromosomal regions of interest within the VDR gene cases.
were identified using the haplotype-based sliding window technique. The
first region identified two haplotypes within intron 2, centered around
rs4760648, that significantly increased RCC risk (haplotype 1: OR= 1.25;
95% CI= 1.04-1.50 and hapotype 2: OR= 1.26; 95% CI= 1.02-1.54) when
compared to patients with the most common referent haplotype. The
second signal identified a haplotype (rs886441 and rs12717991) located
within intron 4 of the VDR gene that was associated with increased risk
among participants with the TG (OR= 1.29; 95%CI= 1.08-1.54) haplotype
compared to participants with most common referent haplotype, CA. The
global p-values in R for these haplotypes were 0.025 and 0.028,
respectively. Across the RXRA gene, a single haplotype located
downstream, 3’ of the coding sequence, centered around rs3118523 was
shown to increase RCC risk (OR= 1.41; 95% CI= 1.10-1.82) among
individuals with the variant haplotype compared to those with the most
common haplotype. This is the first study to our knowledge to
Frontiers in Cancer Prevention Research • November 16-19, 2008 • Washington, DC 65
Proffered Papers: Oral Presentation Abstracts
Infection and Cancer: Methods: Since 2000, high risk individuals were offered annual
Burden, Discovery, and Controversy surveillance by magnetic resonance imaging (MRI(CP)). In case of
suspected lesions, surgery or additional follow up (FU) was provided. In
PR-8 Trichomonas vaginalis infection and prostate cancer case of doubt, the examination was repeated within 2-4 months.
incidence and mortality: A prospective study in the Physicians’ Results: A total of 66 (28 M) individuals with an average age of 56 yrs
Health Study. Jennifer R. Stark,1 Gregory Judson,1 John F. Alderete,2 (range: 40-72) were studied (60 from p16, six from FPC families). The
Siobhan Sutcliffe,3 Vasanthakrishna Mundodi,2 Ashwini S. Kucknoor,2 median FU was 3.4 yrs (range: 0-7). In 20% of the patients, a
Edward L. Giovannucci,1 Elizabeth A. Platz,4 Katja Fall,5 Tobias Kurth,1 Jing (pre)malignant lesion was detected. Ductectasias or IPMN (intraductal
Ma,6 Meir J. Stampfer,1 Lorelei A. Mucci1. 1Harvard School of Public Health, papillary mucinous neoplasm) were identified in eight patients (12%). Three
Boston, MA; 2Washington State University, Pullman, WA; 3Washington patients underwent a prophylactic partial resection of the pancreas;
University, St. Louis, MO; 4Johns Hopkins University, Baltimore, MD; histology showed IPMN in one and PanIn-II lesions in two patients. Five
5Karolinska Institutet, Stockholm, Sweden; 6Brigham and Women’s patients (8%) were diagnosed with PC. Three asymptomatic patients
Hospital, Boston, MA. underwent partial pancreatectomy. One patient had no evidence for
Background: Several inflammation-related factors have been residual disease after surgery. The second patient had positive resection
implicated in prostate cancer risk and progression, but the origin of margins and nodes but survived 21 months. The third patient had
inflammation is unclear. Infections are one possible source, but studies of metastatic carcinoid at surgery (in addition to pancreatic cancer). The
specific infections have been largely inconclusive. A recent prospective remaining two patients did not undergo surgery because of metastatic
study found that antibody seropositivity against Trichomonas vaginalis was disease (pulmonary metastases of melanoma, metastatic pancreatic cancer).
positively associated with subsequent incidence of prostate cancer. This Conclusion: (Pre)malignant lesions were identified in a high proportion
parasitic protozoan has received relatively little attention despite being the of patients. Small lesions of a few mm can be detected by MRI(CP). In view
most common non-viral sexually transmitted infection. We sought to of the substantial morbidity of pancreatic surgery, a major challenge is to
further explore and extend this hypothesis in an independent population, decide at what stage and to what extent prophylactic surgery should be
both for prostate cancer incidence as well as progression. performed. Close observation of high risk groups provides valuable
Methods: We conducted a prospective case-control study nested within information on the natural history of neoplastic lesions in the pancreas.
the Physicians’ Health Study that included 673 prostate cancer cases and
673 individually matched controls. T. vaginalis antibody serostatus was
assessed by an ELISA that detects IgG antibodies against purified, Mechanisms of Cancer Health Disparities
recombinant T. vaginalis -actinin protein. We used conditional logistic
regression for analyses of total prostate cancer incidence and Cox PR-10 Poverty, insurance status, and colorectal cancer in Colorado:
proportional hazards models to estimate hazard ratios for lethal prostate 1995-2006. Alma M. Palisoc,1 Tim E. Byers,2 Sara E. Miller,3 Jack L. Finch4.
1Preventive Medicine Residency Program, Colorado School of Public
cancer (prostate cancer-specific death or development of bony metastases).
Results: The seroprevalence of T. vaginalis infection was 21% in Health, University of Colorado Denver, Denver, CO; 2University of Colorado
controls and 25% in cases. Among cases, the average time between blood Cancer Center; Colorado School of Public Health, University of Colorado
draw and prostate cancer diagnosis was 9.3 years (range 0.3 years - 17.9 Denver, Denver, CO; 3Comprehensive Cancer Program, Colorado
years). Though not statistically significant, the magnitude of the Department of Public Health and Environment, Denver, CO; 4Colorado
association between T. vaginalis seropositivity and overall prostate cancer Central Cancer Registry, Colorado Department of Public Health and
risk (OR: 1.23; 95% CI: 0.94, 1.61) was similar to the original study, which Environment, Denver, CO.
observed a 43% increased risk. Further, seropositive men had a 2.2-fold Background: Poverty in Colorado is an important factor that lowers the
increase in risk of extraprostatic disease (95% CI: 1.08, 4.37) and a 2.7- advantages of being diagnosed with colorectal cancer (CRC) at the earlier
fold greater risk of lethal prostate cancer (95% CI: 1.37, 5.28; 39 cases stage of disease and decreases survival due to CRC. Health insurance
developed bony metastases or died of prostate cancer). Time-to event status can also lead to disparities in early detection of CRC.
analyses included 7,776 person-years of follow-up and showed that, Methods: Data from the Colorado Central Cancer Registry in the
compared to seronegative cases, cases with serologic evidence of infection Colorado Department of Public Health and Environment and information
prior to cancer diagnosis had a 50% greater rate of progression to lethal from the 2000 U.S. census were used to determine the proportions of
prostate cancer (95% CI: 1.01, 2.16). Colorado residents with CRC residing in areas designated as “less than
Conclusions: In this large prospective study, we observed a modest 10% poverty” or wealthier areas, “10-19% poverty” or middle poverty
association between anti-T. vaginalis antibodies and overall prostate areas, and “20+% poverty” or poorest areas. Since income was not
cancer risk and found that T. vaginalis infection was principally associated reported to the cancer registry, the poverty level of the census block group
with clinically relevant, potentially lethal disease. If our findings are area, obtained through the 2000 U.S. Census, where each cancer case
confirmed, T. vaginalis infection may represent a common risk factor for resided was used to assign the poverty level for that case. The analyses
which chemoprevention could reduce burden of aggressive prostate cancer. presented included CRC cases over a 12-year period, from 1995-2006, in
order to compare early stage diagnosis by area poverty level and age (less
than 65 vs. 65 and older). Early stage at CRC diagnosis and insurance
Pancreas status by area poverty level for 1998-2006 and five-year cause-specific
survival among Colorado CRC cases from 1999-2002 were also analyzed.
PR-9 Results of surveillance for hereditary pancreatic cancer using Results: Among the 21,212 colorectal cancer cases reported to the
MRI(CP). Hans F.A Vasen, Martin N. Wasser, Bert A. Bonsing, Anneke M. cancer registry from 1995-2006, 64.5% resided in wealthier areas, 24.8%
van Mil, Daniel W. Hommes, Hans Morreau, Wouter H. de Vos. Leiden were from middle poverty areas, and 10.7 % were from the poorest areas
University Medical Centre, Leiden, Netherlands. of the state. The proportion of early stage diagnosis was lower among the
Introduction: Surveillance for pancreatic cancer (PC) in high risk CRC cases from the poorest areas (42.0%) compared to those from the
groups may lead to early detection and may improve overall survival. We wealthier areas (44.2%). Among those less than aged 65, there was a
screened for early pancreatic neoplasia in individuals with a p16- germline substantial decrease in early stage at CRC diagnosis as poverty level
mutation or with a strong family history of PC (FPC). increased (42.0% from wealthier areas vs. 37% from poorest areas). This is
66 American Association for Cancer Research
Proffered Papers: Oral Presentation Abstracts
in contrast to those aged 65 and older (45.5% from wealthier areas vs. regardless of the location of the cells within the epithelium and underlying
44.4% from the poorest areas). In addition, of those younger than age 65 mucosa, suggesting loss of polarity and expansion of the progenitor cell
whose insurance status was available from the cancer registry for 1998- population. Cells positive for CD44, a marker associated with both invasion
2006 (n=5,288), having no insurance or only Medicaid coverage was a and stem cells, are also more numerous in HBEC-S cultures compared to
disadvantage for early stage diagnosis compared to those with private HBEC-V cultures. In situ, precursor lesions of human squamous cell
insurance in all three poverty groups. More importantly, five-year cause- carcinoma and adenocarcinoma overexpress Snail compared to normal
specific survival decreased as poverty level increased (64.1% from lung tissues, indicating that Snail is up-regulated during early lung cancer
wealthier areas, 58.1% from middle poverty areas, 50.8% from the poorest development. Together, these findings indicate that the role of Snail in
areas of the state). This association between survival differences and early lung cancer development includes induction of EMT, promotion of
socioeconomic status was apparent in those younger than 65 (67.8%, invasion, and expansion of resident pulmonary stem cell populations.
66.9%, 48.7%) and in those 65 and older (61.5%, 53.9%, 51.9%).
Conclusions: Poverty and lack of health insurance are disadvantages
that lead to disparities in early detection of and survival from colorectal Breast Cancer
PR-12 Is the screening-related increase of breast cancer mainly
caused by lesions that would undergo spontaneous regression if
Evolution in Cancer Prevention, EMT, Carcinogenesis left untreated? Per-Henrik Zahl,1 Jan Mæhlen2. 1Norwegian Institute of
Public Health, Oslo, Norway; 2Ulleval University Hospital, Oslo, Norway.
PR-11 Snail-induced and EMT-mediated early lung cancer Objective: In Norway mammography screening is associated with a
development: Promotion of invasion and expansion of stem cell 50% long-term increase of the incidence of invasive breast cancer. Based
populations. Tonya C. Walser,1 Jane Yanagawa,1 Jie Luo,1 Ming Liu,1 Lee on an analysis of incidence data from the Norwegian screening program,
Goodglick,1 Long-Sheng Hong,1 Michael C. Fishbein,1 Jerry W. Shay,2 John we have recently argued that the majority of these extra cancers would
D. Minna,2 Steven M. Dubinett1. 1David Geffen School of Medicine at have undergone spontaneous regression in the absence of screening (Zahl
UCLA, Los Angeles, CA; 2University of Texas Southwestern Medical Center, PH, Mæhlen J, Welch HG. The natural history of breast cancer detected by
Dallas, TX. screening mammography. Archives of Internal Medicine 2008; Nov 24th).
The pulmonary environment at risk for carcinogenesis contains At mammography a large number of ductal carcinoma in-situ (DCIS) are
inflammatory mediators capable of potently promoting epithelial- detected and treated as low grade cancer. The objective of the present
mesenchymal transition (EMT) through the induction of E-Cadherin study is to repeat this analysis on a data set containing both invasive
transcriptional repressors, including Snail. EMT is often activated during cancer and DCIS.
cancer invasion and metastasis, but the role of Snail-mediated EMT during Materials and Methods: The data from the Norwegian Cancer
early lung cancer development has not been defined. Here, we report that Registry include invasive cancer and DCIS from the last 16 years for
Snail-mediated induction of EMT in immortalized human bronchial women of four counties in which the age group 50-69 years (n =166 000)
epithelial cells (HBECs) results in increased invasion and expansion of was been invited to biennial mammography screening from 1996. We
resident pulmonary stem cell populations. By western analysis, HBECs compared the 6-year cumulative incidence in two age matched and partly
stably transduced to express Snail (HBEC-S) have up-regulated Snail and overlapping cohorts. The first cohort (the test group) included women born
concomitantly down-regulated E-Cadherin compared to HBEC vector 1932-46 invited biennially during the 6-year observation period 1996-
control cells (HBEC-V). Snail expression by HBECs results in EMT, as 2001. The second cohort (the control group) included women born 1928-42
numerous lung epithelial markers - Occludin, Mucin 1, Mucin 5AC, and invited once at the end of the 6-year observation period 1992-97.
Cytokeratin (Ck) 18, β-Catenin, and γ-Catenin - are down-regulated in Note that for both cohorts the age span was 50-64 years at the start of the
HBEC-S compared to HBEC-V, while several mesenchymal markers - respective observation periods.
Vimentin, p63, and CD44 - are up-regulated. Microarray gene expression Results: The 6-year cumulative incidence of invasive cancer and DCIS
analysis suggests that Snail initiates a program of invasion and stem cell combined was 28 % higher in the first cohort than in the second cohort.
population expansion. Specifically, TIMPs are down-regulated, while MMPs (2206 vs. 1739 per 100 000; RR = 1.27 (95% CI: 1.20 - 1.34). A sensitivity
and numerous stem cell markers are up-regulated in HBEC-S compared to analysis of the potential effect of HRT showed that at most 2% of the 27%
HBEC-V. Confirming the gene array data, MMP-3, MMP-9, and MMP-13 difference could be explained by differences in the HRT use. We also tested
are up-regulated by up to 3.5-fold in supernatants from HBEC-S compared if low sensitivity could explain the difference - it could not explain the
to HBEC-V, as measured in a Luminex-based multiplex assay. HBECs are difference (P<0.001).
characterized as multipotential pulmonary epithelial progenitor cells, Conclusion: We have shown that the screening related incidence
because they are largely Hoechst-, CD44+, CD24-, Ck14+, Ck5+, and ALDH+ increase in the first four years of the 6-year observation period in the first
by flow cytometry analysis. Importantly, the ALDH+ stem cell population is cohort is not compensated for by a corresponding incidence increase when
expanded by approximately 30% in HBEC-S compared to HBEC-V. A role the previously un-screened women in the second cohort were invited in
for Snail in EMT, invasion, and stem cell population expansion was year 5-6. Increasing use of HRT and low sensitivity in the screening did not
confirmed by studies conducted in three-dimensional (3D) cell culture explain the difference. We propose that most of the screening-related
models. In a 3D spheroid culture model, HBEC-V forms compact spheroidal incidence increase of invasive cancers and DCIS is due to tumors that in
colonies, whereas HBEC-S forms stellate cell aggregates with invasive the absence of screening would have undergone spontaneous regression.
processes. In a 3D organotypic model of squamous metaplasia, HBEC-V
forms well-organized and differentiated epithelial cell layers atop a
modified basement membrane. In contrast, HBEC-S epithelial cell layers are
disorganized, discohesive, and exhibit invasive behavior. E-Cadherin
staining is intense in HBEC-V but nearly absent in HBEC-S. Staining with
markers for basal cells of the lung epithelium, Ck14 and p63, is
appropriately restricted to the basal epithelial cell layer in HBEC-V cultures.
In contrast, HBEC-S cultures are uniformly positive for the markers
Frontiers in Cancer Prevention Research • November 16-19, 2008 • Washington, DC 67
Proffered Papers: Oral Presentation Abstracts
Colorectal Cancer Prevention: Inflammation, Infection, PR-14 Regression of rectal polyps in familial adenomatous
and Immunity polyposis patients with freeze-dried black raspberries. Gary D.
Stoner,1 Henrietta Hasson,2 Christine L. Sardo,1 Li-Shu Wang,1 Dennis K.
PR-13 Inhibition of chronic colitis-induced carcinogenesis in IL-10 Pearl,1 Anthony J. Buchta,3 Carol A. Burke2. 1The Ohio State University,
knockout mice by dietary supplementation of black raspberries. Jie Columbus, OH; 2The Cleveland Clinic Foundation, Cleveland, OH; 3Central
Liao,1 Yeon Tae Chung,1 Li-Shu Wang,2 Allison Yang,1 Gary Stoner,2 Guang- Ohio Compounding Pharmacy, Columbus, OH.
Yu Yang1. 1Northwestern University, Chicago, IL; 2The Ohio State University Familial adenomatous polyposis (FAP) is a dominantly inherited disease
College of Medicine, Columbus, OH. characterized by the early onset of colonic polyposis and a risk of colon
Epidemiological and experimental studies indicate that inflammation is cancer of nearly 100% by the age of 40. The traditional management of
associated with the development of colon cancer. For example, it is known FAP is colectomy followed by lifelong endoscopic surveillance of the
that patients with ulcerative colitis have an increased incidence of colon rectum and removal of rectal polyps. Our laboratory has reported on the
cancer, and anti-inflammatory drugs and bioactive food components that ability of freeze-dried black raspberry (BRB) powder to prevent chemically-
suppress colonic inflammation reduce the risk of colon cancer. IL-10 is an induced cancer in the rodent colon. Administration of BRB powder at 2.5, 5
important regulatory anti-inflammatory cytokine associated with the and 10% in a synthetic diet to rats treated with the carcinogen,
development of colonic colitis. 100% of IL-10 knockout (KO) mice develop azoxymethane, reduced the development of colonic adenocarcinomas by
colitis after 3 months of age; histopathology reveals transmural 50 - 80%. BRBs prevent cancer in rodents by reducing cell proliferation,
inflammation, predominantly in the cecum. We have shown that the inflammation and angiogenesis, and by stimulating apoptosis and
administration of a diet containing twice the recommended amount of iron differentiation. We also showed in a Phase I clinical trial that BRB powder
leads to the development of colonic adenocarcinoma in more than 80% of is well tolerated by humans when administered in a slurry of water at
IL-10 KO mice within 5 months. In the present study, we evaluated the 45g/day for 7 days. Based upon these results, we undertook the present
effects of a dietary supplementation of black raspberries on spontaneous study to determine if BRB might regress rectal polyps in FAP patients.
colitis-induced carcinogenesis in IL-10 KO mice. Beginning at 4 weeks of Fourteen FAP patients who had undergone a colectomy were treated with
age, mice were administered black raspberry powder in AIN-93G diet at BRB daily for a period of nine months. Seven patients received BRB powder
concentrations of 5% and 10% until termination of the experiment at 23 (20g/3x/day) orally in a slurry of water plus two suppositories (each
weeks. The colorectal tumor incidence in IL-10 KO mice fed control AIN- composed of 700 mg BRB) that patients inserted into the rectum one hour
93G diet was 71.4% (10/14 mice with tumors). Significant reductions in before bedtime. The other seven patients were randomized to receive an
colonic tumor incidence [38% (5/13 mice) and 30.8% (4/13 mice)] were oral placebo plus the two rectal suppositories. Rectal polyp counts were
observed in mice receiving 5% and 10% black raspberry diets, respectively. taken at time zero and after nine months of BRB treatment. The number of
Histopathologic analysis of chronic inflammatory activity in the colon rectal polyps was reduced by a median of 43% at nine months overall
showed that the berries significantly inhibited the overall inflammatory including a median reduction of 59% in patients treated by both routes
index, including the extent of inflammation, ulcer formation and epithelial and 36% in patients treated with the suppositories only. Polyps and
hyperplasia. Mechanistic studies suggest that inhibition of colitis- aberrant crypt foci were collected both before and after berry treatment,
associated carcinogenesis by dietary berries might relate to their effects on and molecular studies are underway to determine the mechanism(s) for
modulation of myeloperoxidase-labeled inflammatory cells, nitro-oxidative BRB-induced rectal polyp regression in FAP patients.
stress, and cell proliferation. We conclude that black raspberries, as a food- (Supported by NCI grant CA103180 and USDA grant 38903-03560).
based prevention agent, have potential for the prevention of inflammation-
related carcinogenesis in the colon.
(Supported by NIH grants R01-CA104741 and -CA103180).
68 American Association for Cancer Research