Cancer Prevention Research Research Articles

A Retrospective: On Clinical Studies with 5-Fluorouracil.

See related article by Curreri et al., [Cancer Res 1958:18:478–484][1] . Visit the Cancer Research 75th Anniversary [timeline][2]. The 1950s saw the rise of rational drug design to target DNA synthesis in cancer cells. The concept was simple; cancer was replicating uncontrolled compared with

The latent class twin method.

The twin method refers to the use of data from same-sex identical and fraternal twins to estimate the genetic and environmental contributions to a trait or outcome. The standard twin method is the variance component twin method that estimates heritability, the fraction of variance attributed to additive genetic inheritance. The latent class twin method estimates two quantities that are easier to interpret than heritability: the genetic prevalence, which is the fraction of persons in the genetic susceptibility latent class, and the heritability fraction, which is the fraction of persons in the genetic susceptibility latent class with the trait or outcome. We extend the latent class twin method in three important ways. First, we incorporate an additive genetic model to broaden the sensitivity analysis beyond the original autosomal dominant and recessive genetic models. Second, we specify a separate survival model to simplify computations and improve convergence. Third, we show how to easily adjust for covariates by extending the method of propensity scores from a treatment difference to zygosity. Applying the latent class twin method to data on breast cancer among Nordic twins, we estimated a genetic prevalence of 1%, a result with important implications for breast cancer prevention research.

Job Talks and Interviews: How to Stand Out and Fit In: A Report from the American Society of Preventive Oncology Junior Members Interest Group.

The mission of the American Society of Preventive Oncology (ASPO) includes fostering the continuing professional development of its members. One major activity of ASPO is to prepare the next generation of cancer prevention and control researchers for successful careers. The process of applying for

Transforming Cancer Prevention through Precision Medicine and Immune-oncology.

We have entered a transformative period in cancer prevention (including early detection). Remarkable progress in precision medicine and immune-oncology, driven by extraordinary recent advances in genome-wide sequencing, big-data analytics, blood-based technologies, and deep understanding of the tumor immune microenvironment (TME), has provided unprecedented possibilities to study the biology of premalignancy. The pace of research and discovery in precision medicine and immunoprevention has been astonishing and includes the following clinical firsts reported in 2015: driver mutations detected in circulating cell-free DNA in patients with premalignant lesions (lung); clonal hematopoiesis shown to be a premalignant state; molecular selection in chemoprevention randomized controlled trial (RCT; oral); striking efficacy in RCT of combination chemoprevention targeting signaling pathway alterations mechanistically linked to germline mutation (duodenum); molecular markers for early detection validated for lung cancer and showing promise for pancreatic, liver, and ovarian cancer. Identification of HPV as the essential cause of a major global cancer burden, including HPV16 as the single driver of an epidemic of oropharyngeal cancer in men, provides unique opportunities for the dissemination and implementation of public health interventions. Important to immunoprevention beyond viral vaccines, genetic drivers of premalignant progression were associated with increasing immunosuppressive TME; and Kras vaccine efficacy in pancreas genetically engineered mouse (GEM) model required an inhibitory adjuvant (Treg depletion). In addition to developing new (e.g., epigenetic) TME regulators, recent mechanistic studies of repurposed drugs (aspirin, metformin, and tamoxifen) have identified potent immune activity. Just as precision medicine and immune-oncology are revolutionizing cancer therapy, these approaches are transforming cancer prevention. Here, we set out a brief agenda for the immediate future of cancer prevention research (including a "Pre-Cancer Genome Atlas" or "PCGA"), which will involve the inter-related fields of precision medicine and immunoprevention - pivotal elements of a broader domain of personalized public health.

The systematic design and biophysical evaluation of cationic sulfonamide aminolipids for siRNA delivery

Event Abstract Back to Event The systematic design and biophysical evaluation of cationic sulfonamide aminolipids for siRNA delivery Jason B. Miller1, 2*, Victor Tieu3* and Daniel J. Siegwart1, 2* 1 UT Southwestern Medical Center, Department of Biochemistry, United States 2 UT Southwestern Medical Center, Simmons Comprehensive Cancer Center, United States 3 University of California, Berkeley, Department of Bioengineering, United States Introduction: The use of RNA interference (RNAi) as a therapeutic is an exciting and rapidly developing field that offers a promising alternative to small molecule drugs for the treatment of dysregulatory diseases, including cancer [1],[2]. Small interfering RNA (siRNA) can be designed against any mRNA target, and upon loading into the RNA-induced silencing complex (RISC) can enable the sequence-specific recognition and degradation of the target oncogene. Because siRNA has a high molecular weight (~13 kDa) and is highly hydrophilic and anionic, it is unable to passively diffuse across cell membranes and into the cell [3]. To date, many successful carriers have been designed using amphiphilic lipid-like compounds containing amine-rich cores [4][5], but the challenge of efficient endosomal release remains a major bottleneck in the field of RNAi therapeutics. Cationic sulfonamide amino lipids (CSALs) are a novel class of modular synthetic lipids that possess chemical and structural properties that make them promising candidates for RNAi-based anticancer therapies. Sulfonamide functionalities, though prevalent in many pharmaceutical drugs, have not been explored in lipid carriers for siRNA delivery. Due to a positively-charged quaternary ammonium, CSALs are excellent candidates for enhanced siRNA binding and endosomal membrane interaction and disruption upon cell uptake, which can enable siRNA release. Materials and Methods: CSALs were readily chemically synthesized from commercially available reagents via a zwitterionic aminolipid intermediate bearing a sulfobetaine headgroup. The sidearm functionality was introduced by reaction at the alcohol positions, while the characteristic sulfonamide was introduced by further sequential reaction with thionyl chloride and a primary amine bearing the amino headgroup. A systematic, modular design enabled the evaluation of the effect of structural modifications on the biophysical properties of CSAL nanoparticles in terms of size, surface charge, siRNA encapsulation, and in vitro siRNA delivery efficacy to human cervical cancer cells. Results and Discussion: Systematic SAR of CSALs was established by modifying the linker length between the sulfonamide and the amine headgroup, sterics at tertiary amine headgroup and quaternary ammonium, the number of hydrophobic tails, and a sidearm alcohol functionality on the periphery of the amine core in terms of both sterics and electronics (Figure 1). CSALs showed the ability to form stable nanoparticles (Dh ~100 nm) in the presence of helper lipids DSPC, cholesterol, and PEG-lipid. Lead materials, showed excellent uptake into cells as evaluated by confocal microscopy, efficient siRNA encapsulation (97%) and in vitro target gene silencing in human cervical cancer cells with up to 90% knockdown and minimal material-derived cytotoxicity (Figure 2). Conclusion: Systematic rational design of a library of CSALs, a novel class of synthetic lipids, has elucidated SAR in properties governing effective siRNA delivery. This led to the discovery of lead CSAL materials that enable efficacious siRNA delivery to cancer cells. Cancer Prevention Research Institute of Texas (CPRIT) Training Grant RP140110; UT Southwestern Summer Undergraduate Research Fellowship Program

Independent Association of Postdoctoral Training with Subsequent Careers in Cancer Prevention.

The purpose of this study was to examine the career paths of alumni from the National Cancer Institute (NCI) Cancer Prevention Fellowship Program (CPFP), a structured in-house postdoctoral training program of 3–4 years duration, and specifically what proportion of the alumni were currently performing cancer prevention-related activities. The analyses here included 119 CPFP alumni and 85 unsuccessful CPFP applicants, all of whom completed postdoctoral training between 1987–2011 and are currently employed. Postdoctoral training experiences and current career outcomes data were collected via online surveys. Differences between groups were assessed using chi-square and Fisher’s exact test p-values and subsequent regression analyses adjusted for differences between the groups. Compared to 15.3% of unsuccessful CPFP applicants, 52.1% of CPFP alumni (odds ratio [OR] = 4.99, 95% confidence interval [95% CI): 1.91–13.0) were currently spending the majority of their time working in cancer prevention. Among those doing any cancer prevention-focused work, 54.3% of CPFP alumni spent the majority of their time performing cancer prevention research activities when compared to 25.5% of unsuccessful applicants (OR = 4.26, 95% CI: 1.38–13.2). In addition to the independent effect of the NCI CPFP, scientific discipline, and employment sector were also associated with currently working in cancer prevention and involvement in cancer prevention research-related activities. These results from a structured postdoctoral training program are relevant not only to the cancer prevention community but also to those interested in evaluating alignment of postdoctoral training programs with available and desired career paths more broadly.

Skin Cancer Risk in Gay and Bisexual Men: A Call to Action.

Skin Cancer Risk in Gay and Bisexual Men: A Call to Action.

Public Health Action Model for Cancer Survivorship.

Long-term objectives associated with cancer survivors have been suggested by Healthy People 2020, including increasing the proportion of survivors living beyond 5 years after diagnosis and improving survivors’ mental and physical health-related quality of life. Prior to reaching these objectives, several intermediate steps must be taken to improve the physical, social, emotional, and financial well-being of cancer survivors. Public health has a role in developing strategic, actionable, and measurable approaches to facilitate change at multiple levels to improve the lives of survivors and their families. The social ecological model has been used by the public health community as the foundation of multilevel intervention design and implementation, encouraging researchers and practitioners to explore methods that promote internal and external changes at the individual, interpersonal, organizational, community, and policy levels. The survivorship community, including public health professionals, providers, policymakers, survivors, advocates, and caregivers, must work collaboratively to identify, develop, and implement interventions that benefit cancer survivors. The National Action Plan for Cancer Survivorship highlights public health domains and associated strategies that can be the impetus for collaboration between and among the levels in the social ecological model and are integral to improving survivor outcomes. This paper describes the Public Health Action Model for Cancer Survivorship, an integrative framework that combines the National Action Plan for Cancer Survivorship with the social ecological model to demonstrate how interaction among the various levels may promote better outcomes for survivors.

Abstract B1-02: Correlation between oncogenic mutations, signaling pathways, and efficacy of platinum-based drugs against colorectal cancers

Abstract The purpose of this study is to correlate genetic mutations, amino-acid variants, signaling pathways with platiunum based drug activity to shed light on personalized treatment of cancer. Platinum anticancer drugs such as cisplatin, carboplatin, and oxalipaltin are widely used to treat a variety of cancers. Although DNA is the molecular target for these platinum therapies, their efficacies, toxicities, and resistance mechanisms vary widely among various categories and sub-categories of cancers. To comprehend this great variability, an integrated analysis was performed to determine the impact of somatic mutations on protein functions, signaling pathways, and drug activity (sensitivity or resistance) among the US National Cancer Institute (NCI) 60 human tumor cell lines based on Z-scores to predict a priori treatment outcome using CellMiner (http://discover.nci.nih.gov/cellminer). Specifically, somatic mutations of significantly mutated genes from the cancer genome atlas (TCGA) were analyzed along with the driver genes (oncogenes and tumor suppressor genes) from catalogue of somatic mutations in cancer (COSMIC) for total 188 genes that belong to more than 20 different signaling pathways. The functional impact of individual amino-acid variant for each gene and its correlation with the activity of carboplatin, cisplatin and oxaliplatin for each cancer cell line were explored. Particular attention was given to colon cancer for which nearly 40% of tumors are known to have mutated KRAS (Kirsten rat sarcoma viral oncogene homolog) gene. Resulting analysis revealed that colon cancer cell lines with KRAS mutations for codon 12 (G12V-mutant from SW620 cell line) and codon 13 (G13D-mutant from HCT116 and HCT15 cell lines) correlated with the sensitivity to oxaliplatin. Conversely, oxaliplatin resistant HCC2998 colon cancer cell line did not show any correlation with mutated KRAS for codon 146 (A146T-mutant). Notably, all the colon cancer cell lines were resistant to both carboplatin and cisplatin with no correlation to the KRAS mutants. Based on our integrated analysis we further predicted gene networks related to oxaliplatin activity for colon cancer. The network includes the epidermal growth factor (EGFR) signaling pathway that involves PIK3CA, PIK3CG and MTOR from the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) (PIK3/mTOR) pathway, and JAK3 from Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in addition to KRAS from Mitogen-activated protein kinases (MAPK) pathway. We conclude that instead of considering all mutations of a gene in the same way to assess their clinical significance, it may be beneficial to categorize them into different classes based on their functional impact and efficacies towards the anti-cancer drugs for personalized treatment. Similar analytical approach is being extended to non-small cell lung and ovarian cancers where platinum therapies are widely used. S. Tripathi gratefully acknowledges the support through a training fellowship from a grant by the Cancer Prevention Research Institute of Texas (Grant No. RP140113 to R.N.Bose). Citation Format: Swarnendu Tripathi, Louiza Belkacemi, Margaret S. Cheung, Rathindra N. Bose. Correlation between oncogenic mutations, signaling pathways, and efficacy of platinum-based drugs against colorectal cancers. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-02.

Abstract A2-48: Correlation between oncogenic mutations, signaling pathways and efficacy of platinum based drugs against colorectal cancers

Abstract The purpose of this study is to correlate genetic mutations, amino-acid variants, signaling pathways with platiunum based drug activity to shed light on personalized treatment of cancer. Platinum anticancer drugs such as cisplatin, carboplatin, and oxalipaltin are widely used to treat a variety of cancers. Although DNA is the molecular target for these platinum therapies, their efficacies, toxicities, and resistance mechanisms vary widely among various categories and sub-categories of cancers. To comprehend this great variability, an integrated analysis was performed to determine the impact of somatic mutations on protein functions, signaling pathways, and drug activity (sensitivity or resistance) among the US National Cancer Institute (NCI) 60 human tumor cell lines based on Z-scores to predict a priori treatment outcome using CellMiner (http://discover.nci.nih.gov/cellminer). Specifically, somatic mutations of significantly mutated genes from the cancer genome atlas (TCGA) were analyzed along with the driver genes (oncogenes and tumor suppressor genes) from catalogue of somatic mutations in cancer (COSMIC) for total 188 genes that belong to more than 20 different signaling pathways. The functional impact of individual amino-acid variant for each gene and its correlation with the activity of carboplatin, cisplatin and oxaliplatin for each cancer cell line were explored. Particular attention was given to colon cancer for which nearly 40% of tumors are known to have mutated KRAS (Kirsten rat sarcoma viral oncogene homolog) gene. Resulting analysis revealed that colon cancer cell lines with KRAS mutations for codon 12 (G12V-mutant from SW620 cell line) and codon 13 (G13D-mutant from HCT116 and HCT15 cell lines) correlated with the sensitivity to oxaliplatin. Conversely, oxaliplatin resistant HCC2998 colon cancer cell line did not show any correlation with mutated KRAS for codon 146 (A146T-mutant). Notably, all the colon cancer cell lines were resistant to both carboplatin and cisplatin with no correlation to the KRAS mutants. Based on our integrated analysis we further predicted gene networks related to oxaliplatin activity for colon cancer. The network includes the epidermal growth factor (EGFR) signaling pathway that involves PIK3CA, PIK3CG and MTOR from the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) (PIK3/mTOR) pathway, and JAK3 from Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in addition to KRAS from Mitogen-activated protein kinases (MAPK) pathway. We conclude that instead of considering all mutations of a gene in the same way to assess their clinical significance, it may be beneficial to categorize them into different classes based on their functional impact and efficacies towards the anti-cancer drugs for personalized treatment. Similar analytical approach is being extended to non-small cell lung and ovarian cancers where platinum therapies are widely used. S. Tripathi gratefully acknowledges the support through a training fellowship from a grant by the Cancer Prevention Research Institute of Texas (Grant No. RP140113 to R.N.Bose). Citation Format: Swarnendu Tripathi, Louiza Belkacemi, Margaret S. Cheung, Rathindra N. Bose. Correlation between oncogenic mutations, signaling pathways and efficacy of platinum based drugs against colorectal cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-48.

Enrolling Minority and Underserved Populations in Cancer Clinical Research.

Research suggests that community involvement is integral to solving public health problems, including involvement in clinical trials-a gold standard. Significant racial/ethnic disparities exist in the accrual of participants for clinical trials. Location and cultural aspects of clinical trials influence recruitment and accrual to clinical trials. It is increasingly necessary to be aware of defining characteristics, such as location and culture of the populations from which research participants are enrolled. Little research has examined the effect of location and cultural competency in adapting clinical trial research for minority and underserved communities on accrual for clinical trials. Utilizing embedded community academic sites, the authors applied cultural competency frameworks to adapt clinical trial research in order to increase minority participation in nontherapeutic cancer clinical trials. This strategy resulted in successful accrual of participants to new clinical research trials, specifically targeting participation from minority and underserved communities in metropolitan Washington, DC. From 2012 to 2014, a total of 559 participants enrolled across six nontherapeutic clinical trials, representing a 62% increase in the enrollment of blacks in clinical research. Embedding cancer prevention programs and research in the community was shown to be yet another important strategy in the arsenal of approaches that can potentially enhance clinical research enrollment and capacity. The analyses showed that the capacity to acquire cultural knowledge about patients-their physical locales, cultural values, and environments in which they live-is essential to recruiting culturally and ethnically diverse population samples.

Abstract PP01-01: A funny thing happened to me while trying to cure ovarian cancer; I became a cancer prevention research specialist

Abstract PP01-01: A funny thing happened to me while trying to cure ovarian cancer; I became a cancer prevention research specialist

Abstract A49: Meta-analysis of vitamin D-binding protein and cancer risk

Abstract Antiproliferative effects of 1,25-dihydroxyvitamin D, the biologically active form of vitamin D, are well established in various cell types, including normal and malignant cells, by influencing cell differentiation, cell growth and apoptosis. In addition meta-analyses of epidemiological studies showed that serum 25-hydroxyvitamin D (25OHD) and vitamin D receptors polymorphisms (VDRs) are associated with cancer risk. The biological effects of vitamin D are mediated by an abundance of the vitamin D binding protein (DBP) and VDRs. The gene for the vitamin D–binding protein, known as ‘‘group-specific component’’ (Gc), is also a logical candidate in the vitamin D pathway because its major function is to transport vitamin D metabolites in the blood to different target organs. Variants in this gene have been shown to alter plasma concentrations of 25OHD and several studies investigated Gc SNPs and DBP in association with cancer risk with controversial results. Thus we carried out a comprehensive literature search and meta-analysis to investigate these associations. A systematic literature search was performed following a pre-defined protocol and using validated search strategies up to April 2014. We included for 24 independent studies for a total of 38,331 cases and 25,050 controls, from several countries Australia, Canada and USA, Finland, Germany, the Netherlands, Spain, UK, China and Iran. Data collected concern the following cancer sites: skin (n. of estimates=1), bladder (n=2), breast (n=3), colon-rectum (n=5), endometrium (n=1), liver (n=1), esophagus (n=1), stomach (n=1), melanoma (n= 3), pancreas (n= 2), prostate (n= 5) and kidney (n=1). Through random effect models we calculated the Summary Odd Ratios (SORs) for serum DBP (n. of estimates=6) and the following polymorphisms: rs2282679 (n. of estimates=7), rs12512631 (n=4), rs7041 (n=17), rs4588 (n=12), rs1155563 (n=5) and rs1352844 (n=3). We found a significant 8% increase cancer risk at any site for rs4588 variant (dominant model) and a non significant decrease risk at increasing level of DBP: SOR= 0.94 (0.86-1.02) per an increase of 1000 nmol/L. We evaluated also departure from Hardy-Weinberg equilibrium (HWE) in controls and sensitivity analyses excluding studies that do not respect HWE did not show important changes in results. No indication of publication bias was found. In conclusion we found some interesting associations indicating a possible role of DBP in cancer etiology. Further studies should consider also the role of the ‘free’ unbound part of 25OHD, that drives many of the non-classical actions of vitamin D, and it is dependent on the concentration of DBP.

Abstract A38: Role of MC1R variants in childhood and adolescent melanoma

Abstract Cutaneous melanoma (CM) is rare in children, representing 1-3% of all paediatric malignancies and occurring at a frequency of 0.3-0.4% before puberty. MC1R is a key gene for skin pigmentation and is highly polymorphic in Caucasians. MC1R gene variants are associated with CM in different populations, and with congenital melanocytic naevi in children. The aim of this study is to evaluate whether the prevalence of MC1R variants differed among sporadic childhood and adolescent CM cases compared to adult patients. Data were gathered through the M-SKIP project, an international pooled-analysis on MC1R variants, skin cancer and phenotypic characteristics. CM cases with information on age at diagnosis were selected from the M-SKIP dataset and divided into three groups: childhood (age ≤14 years, N=13), adolescent (age 15 to 18 years, N=52) and adult (age > 18 years, N=7,696). The frequency of carrying specific MC1R variants as well as at least one MC1R variant were compared between childhood/adolescent and adult CM cases with Chi Square test. The prevalence of any MC1R variant was lower in children (≤14 years, 63%) than in adolescents (15-18 years, 71%) or adults (>18 years, 75%), although overall the difference was not statistically significant. A higher prevalence of the MC1R V92M variant was found in childhood and adolescent compared to adult CM cases (23% vs 5%, p=0.06). In contrast, the MC1R R151C variant was found less frequently in childhood and adolescent than in adult cases (9% vs 18%, p=0.06). Looking at rare variants in 5,983 cases with MC1R sequenced, 3 (9%) carriers of MC1R ins86A were found among 32 childhood and adolescent patients, while only 44 (1%) carriers of the same variant were found among 5,951 adult cases (p<0.0001). MC1R variants ins86A and V92M, but not R151C, may be specifically associated with childhood and adolescent melanoma. Further studies using a larger sample size is needed to validate the present findings. Citation Format: Sara Raimondi, Sara Gandini, Peter A. Kanetsky, Veronica Hoiom, Rajiv Kumar, Paola Ghiorzo, Tadeusz Debniak, Ricardo Fernandez de Misa, Giuseppe Palmieri, Jiali Han, Maria Teresa Landi, Terry Dwyer, Maria Concetta Fargnoli, Wojciech Branicki, Nelleke A. Gruis, Alexander Stratigos, Gloria Ribas, M. Laurin Council, Manfred Kayser, Philippe Autier, Jose Carlos García-Borrón, Julian Little, Julia Newton-Bishop, Francesco Sera, Eduardo Nagore. Role of MC1R variants in childhood and adolescent melanoma. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A38.

Abstract A46: Body mass index, waist circumference, and the risk of colorectal adenomas: Black Women's Health Study

Abstract Introduction: Overweight and obesity are independent risk factors for colorectal cancer among men and women. Associations of body mass index (BMI) with colorectal cancer risk are stronger among men than women. Evidence on the association of anthropometric factors with colorectal adenoma is more equivocal, especially among women. It has been suggested that the association of BMI with adenomas is weaker among postmenopausal women as compared to premenopausal women but data on this finding is limited. A recent study among participants in the PLCO trial failed to show an association of BMI with either colorectal adenoma or colorectal cancer risk among men and women. However, it is possible that BMI might not be the most relevant marker of obesity-associated colorectal neoplasia risk among women. A large cohort study of European Caucasian women showed a higher risk of colorectal cancer with waist circumference but not BMI. There are relatively few studies that have investigated multiple measures of obesity as risk factors for colorectal adenoma and cancer among women and none have been adequately powered for these analyses among African American women. We investigated the association of BMI and waist circumference as risk factors for colorectal adenoma among postmenopausal African American women in the Black Women's Health Study. Methods: We conducted a nested case-control study among participants in the Black Women's Health Study - a cohort study of 59,000 women followed biennially since 1995. Cases were defined as women diagnosed with incident colorectal adenoma between 1997 and 2011. Only those adenoma cases verified by medical record review were included. Controls were participants who also underwent lower gastrointestinal endoscopy and in whom no adenoma or other polyp was found. 3 controls were matched to each case based on age and follow-up period. Weight, height, and abdominal circumference were self-reported by participants at baseline. Weight and waist circumference were updated based on self-report every two years. BMI was categorized into 3 categories: 18-24.9 kg/m2 (normal BMI), 25-29.9 kg/ m2 (overweight), and ≥30 kg/ m2 (obese). Waist circumference was categorized in quintiles based on the distribution among controls. Using logistic regression models, we obtained odds ratios (OR) for colorectal adenoma in relation to BMI and waist circumference, adjusting for age, education, physical activity, fruit and vegetable intake, family history of colorectal cancer, smoking, alcohol intake, energy intake, aspirin use, menopausal status, and post-menopausal hormone therapy. Results: There were 915 adenoma cases and 2,745 controls. After adjusting for multiple covariates, neither overweight (OR: 1.10, 95% CI: 0.88-1.38) nor obese (OR: 1.09, 95% CI: 0.85-1.41) African-American women were at increased risk of colorectal adenomas than women with normal BMI. Although women in the fifth quintile of waist circumference were at higher risk of colorectal adenomas than those in the first quintile in age-adjusted models, the OR was no longer significant after multivariate adjustment (OR: 1.25, 95% CI: 0.94, 1.67) . Conclusions: We did not find an association of either BMI or waist circumference with colorectal adenomas among African-American women. Our results support the findings from other studies in primarily White women that showed no association of BMI with colorectal adenoma in women. Although the association of waist circumference with adenoma risk was stronger compared to BMI among African-American women in our study, it was not statistically significant. Further research is needed to confirm these findings, and explore the association of BMI and waist circumference with colorectal adenoma in African-American men. Citation Format: Chiranjeev Dash, Julie R. Palmer, Lynn Rosenberg, Jeffrey Yu, Lucile L. Adams-Campbell. Body mass index, waist circumference, and the risk of colorectal adenomas: Black Women's Health Study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A46.

Abstract B34: CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes

Abstract Introduction: CD56+ lymphocytes (a defining marker of natural killer cells) have a predominantly cytotoxic phenotype and a hypothetical role in breast tumor immunosurveillance. Here we investigate whether CD56+ staining density varies in nonmalignant breast lobules according to confirmed breast cancer risk factors- age, and histologic features of fibrocystic change and lobular involution. Methods: Archived breast tissue samples were obtained from 94 women with benign breast disease (BBD). The sample set was selected as a nested case-control study (47 cases, 47 controls) from within a large BBD cohort; cases were those who developed breast cancer subsequent to their benign breast biopsy; controls were matched to cases on age at biopsy, year of biopsy, and length of breast cancer free follow-up at least as long as the time-to-cancer in the matched case. Up to 10 representative lobules in each sample were characterized by H&E for fibrocystic changes and the degree of epithelial proliferation (normal, nonproliferative, proliferative, atypia) and for degree of lobular involution (none, partial, complete). Consecutive sections were immunostained for CD56 and hematoxylin. Using digital image analysis, CD56 staining was quantified on a per lobule basis by pixel ratio (PR) (positive stain:total lobule). Statistical analysis was performed using linear mixed effects regression on the rank transformed density to account for correlations among multiple lobules from the same patient in assessing the association of density with lobule characteristics and using conditional logistic regression for association with case-control status. Results: Among 94 women (median age 52, range 35-73), 876 lobules were evaluated: 431 in BBD cases and 445 in BBD controls. Overall, 391 lobules (45%) were normal and the remaining 485 (55%) demonstrated fibrocystic changes. Among fibrocystic lobules, 247 (51%) had nonproliferative changes, 218 (45%) had epithelial proliferation, and 20 (4%) had atypical hyperplasia. Among normal lobules, 61 (16%) had no involution, 139 (36%) had partial involution, and 191 (49%) had complete involution. The vast majority of lobules (861/876, 98%) demonstrated presence of CD56+ cells, while only 15 of 876 lobules in 11 patients had zero CD56+ cells [7 cases (15%) versus 4 controls (8.5%) OR 1.75, p = 0.37]. The median CD56+ PR was 0.55% overall. Fibrocystic lobules as a group showed significantly lower median CD56+ PR compared to normal lobules (0.37% vs 0.85%, p < 0.0001). Among subcategories of fibrocystic lobules, the median CD56+ PR was lower in proliferative lobules (0.29%) compared to non-proliferative (0.42%), but this difference was not statistically significant (p = 0.55). Older women (age > 55) showed the highest CD56+ PR (median of 0.92%), as compared to 0.38% in women 45-55 (p=0.02), and 0.52% in women age <45 (p = 0.26). Among normal lobules, median CD56+ PR was similar between lobules with no involution (0.55%) and partial involution (0.52%) but was considerably higher among lobules with complete involution (1.3%, p = 0.09 and p = 0.05, respectively). In a multivariable model, CD56+ PR differences between fibrocystic and normal lobules remained significant (p = 0.0002) and also remained significant between age groups of > 55 and 45-55 (p = 0.02), while involution was non-significant. Median CD56+ PR was lower in cases (0.43%) compared to controls (0.72%), but this was not statistically significant (p=0.19) in our sample of 47 case-control pairs. Conclusions: Breast lobules with fibrocystic changes show less CD56+ cells, raising a question of possible immune suppression induced by early epithelial abnormalities. These findings encourage further investigation to improve understanding of the immune microenvironment in premalignant breast tissues. Citation Format: Rushin D. Brahmbhatt, Daniel Kerekes, Tanya L. Hoskin, Alvaro Pena, Daniel W. Visscher, Melody L. Stallings-Mann, Derek C. Radisky, Linda M. Murphy, Vernon Shane Pankratz, Keith L. Knutson, Marlene Frost, Amy C. Degnim. CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B34.

Abstract A27: Association between diabetes pharmacotherapies and bladder cancer: A Medicare epidemiologic study

Abstract Background: Patients with type two diabetes mellitus (T2DM) have an increased risk of bladder cancer; they are also commonly treated with pioglitizone and angiotensin receptor blockers (ARBs), medications associated with an increased cancer risk in some studies. This study aimed to further explore the relationship between these medications and bladder cancer in an older population with higher baseline risk of this cancer and common exposure to these drugs. We examine the risk associated with exposure to the individual drug/drug class, and risk associated with exposure to both to assess for a potential cancer promoting interaction. Methods: Using a 40% Medicare random sample denominator and corresponding inpatient, outpatient (2004-2012) and prescription (2006-2012) claims, we studied fee-for-service beneficiaries age 67 and older. We identified pharmacotherapeutically treated diabetics (2006 to 2011) defined as patients filling one or more prescription for an oral hypoglycemic drug. Individual-level, time varying exposure to all oral and injectable hyopglycemics as well as ARBs and ACE-Is was calculated as count of drug-specific daily doses; daily doses were derived empirically as the median daily dose (MDDs) for this population. Cox proportional hazards models, adjusted for patient characteristics, comorbidities and diabetes complications, were used to examine the risk of incident bladder cancer associated with cumulative observed exposure to pioglitazone and ARBs. To address possible indication bias for the exposures of interest, we also estimated risk associated ACE-I exposure and non-pioglitazone TZD exposure, substitutes for the exposures of interest not suspected of increasing cancer risk. Interaction terms estimated the effect of exposure to ARBs with pioglitazone and ARBs with non-pioglitazone TZD. Secondary models repeated main models stratified on gender due to the higher baseline risk of bladder cancer in men. Results: Overall, we identified 1,161,443 diabetics, 62.5% female, 10.7% black, 9.8% Hispanic. Mean age at the beginning of follow-up was 75.1 years (SD 7.5); 18.9% had evidence of current or past tobacco use. Mean follow time was 42.2 months (SD 26.4). Overall, 20.2% of the cohort used some pioglitazone (mean exposure 642 MDDs); 31.7% used some ARB (Mean exposure 745 MDDs); 10.4% used some non-pioglitazone TZD (mean exposure 503 MDDs); 59.1% used some ACE-I (mean exposure 855 MDDs). 8.0% used both pioglitazone and ARBs; 13.2% used both pioglitazone and ACE-I; 4.1% used non-pioglitazone TZD and ARB; and 6.8% used non-pioglitazone TZD and ACE-I. In total, 5,874 bladder cancers were identified, 69% amongst men, an incidence of 0.28/1000 PY in men and 0.07/1000 PY in women. Compared to no observed exposure, the risk of bladder cancer associated with each additional year of exposure at median daily dose was: 0.97 (95% CI 0.89, 1.06) for pioglitazone, 1.04 (95% CI 0.97, 1.12) for ARBs; 0.99 (95% CI 0.95, 1.03) for ACE-Is and 0.98 (95% CI 0.86, 1.12) for non- pioglitizone TZDs. The risk of bladder cancer associated with each additional year of exposure to both pioglitizone and ARB was 0.97 (95% CI 0.91, 1.04); for pioglitazone and ACE-I, 1.01 (95% CI 0.98, 1.03); for non-pioglitazone TZD and ARB, 0.99 (95% CI 0.91, 1.08); and for non-pioglitazone TZD and ACE-I, 0.99 (95% CI 0.93, 1.04). Results did not differ when stratified by sex. Conclusions: We found no increased risk of bladder cancer associated with pioglitizone use, ARB use or exposure to both over an average observation time of 3.5 years. While the findings of this observational study should be confirmed in a prospective trial of longer duration, overall the results should reassure diabetics and their clinicians using these products to minimize the substantial health risks associated with diabetes. Citation Format: Jeremy Smith, Rebecca Zaha, Todd A. Mackenzie, Margaret R. Karagas, Nancy E. Morden. Association between diabetes pharmacotherapies and bladder cancer: A Medicare epidemiologic study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A27.

Abstract CN10-02: Rare disorders informing cancer biology: Lessons learned from dyskeratosis congenita

Abstract Dyskeratosis congenita (DC) is a cancer-prone inherited bone marrow failure syndrome (IBMFS) caused by germline defects in telomere biology. The classic triad of dysplastic nails, lacy reticular skin pigmentation, and oral leukoplakia is diagnostic but not always present. Individuals with DC are at very high risk of bone marrow failure, leukemia, myelodysplastic syndrome, and head/neck cancers. Esophageal or urethral stenosis, liver disease, pulmonary fibrosis, developmental delay, and other medical conditions may also be present. The clinical consequences manifest at variable ages and in different patterns, even within the same family. Approximately 70% of patients with DC have a germline mutation(s) in a key telomere biology gene. The inheritance of DC is variable with X-linked (DKC1), autosomal dominant (TERC, TERT, TINF2, or RTEL1), and autosomal recessive (NOP10, NHP2, TERT, WRAP53, CTC1, or RTEL1) inheritance patterns. Telomeres, tandem nucleotide repeats and a protein complex at chromosome ends, are vital in maintaining genomic integrity and function by keeping the chromosomes intact upon replication, preventing end-to-end fusion, and atypical recombination. They shorten with each cell division, and thus are a marker of cellular replicative capacity. When telomeres become critically short, cellular senescence or apoptosis are triggered. Cancer cells upregulate telomerase (TERT) and other pathways to continue cell division in the setting of telomere abnormalities and chromosomal instability. We previously demonstrated that telomere length <1st percentile for age, measured in leukocyte subsets by flow cytometry and fluorescent in situ hybridization (flow-FISH), was highly sensitive and specific for diagnosing DC. Numerous epidemiology studies suggest that short telomeres in blood or buccal cells may be associated with several diseases, including certain cancers. It is important to note that the telomere lengths in cases and controls from epidemiology studies may be statistically significantly different but they are still within the normal range for age whereas the telomeres of patients with DC are significantly shorter than expected for their age (<1st percentile) compared with controls. Genome-wide association studies have found single nucleotide polymorphisms in two DC-associated genes, TERT and RTEL1, associated with cancer risk, a finding that further connects DC and telomere biology with cancer etiology. We are conducting an IRB-approved longitudinal cohort study of DC nested within the NCI's IBMFS study (ClinicalTrials.gov Identifier: NCT00027274). This study includes comprehensive family history and individual history questionnaires, detailed medical record review, biospecimen collection, and evaluation at the NIH Clinical Center. In addition to the development of the diagnostic test, detailed clinical characterization of patients with DC and their families has led to improved understanding of the clinical consequences and management of DC and the spectrum of related telomere biology disorders. Through the use of genetic approaches ranging from linkage scans to whole exome sequencing, we have discovered three of the genetic causes of DC (TINF2, WRAP53, and RTEL1). Additional gene discovery efforts are underway. These clinical and molecular studies have led to improved understanding of key telomere proteins and formed the foundation for epidemiology studies of telomere biology and cancer in the general population. Citation Format: Sharon A. Savage. Rare disorders informing cancer biology: Lessons learned from dyskeratosis congenita. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN10-02.

Abstract CN03-03: Improving decision making for ductal carcinoma in situ

Abstract With greater use of screening mammography, the incidence of pre-invasive breast carcinoma or ductal carcinoma in situ (DCIS) has increased by 560% over the past 35 years. By the year 2020, more than 1 million women will be living with a DCIS diagnosis. Despite the large number of women affected, the optimal treatment strategy for DCIS is not known. DCIS does not spread to the lymph nodes or other sites in the body, but left untreated, can progress to invasive breast cancer. Mastectomy, or removal of the breast, had been the standard of care for treatment of DCIS and is curative in almost all patients; however, it is an extreme surgery for a diagnosis that may not progress to invasive breast cancer. Currently over 70% of women with DCIS receive breast-conserving surgery, but they then have a risk of being diagnosed with a second cancer in the same breast. To reduce this risk some women receive radiation therapy or tamoxifen therapy. Radiation therapy delivered to the breast after breast-conserving surgery to decrease the risk of another diagnosis in the affected breast. But if a woman undergoes radiation for DCIS and then has a 2nd diagnosis in the same breast, she will need a mastectomy since radiation can only be given once due to limits of normal tissue tolerance. Therefore, radiation therapy may also reduce the long-term likelihood of breast conservation. The important outcome of lifetime breast conservation with or without radiation has not been studied, resulting in patients and physicians choosing treatment without complete information about expected treatment outcomes. Across the United States, treatment patterns (type of surgery, use of radiation therapy or tamoxifen) for DCIS vary widely by region of the country. Instead, the choice of treatment should vary according to the values and preferences of each DCIS patient. To enable informed decision-making by DCIS patients, we seek to provide individualized data about outcomes– in terms of recurrence, disease-free and overall survival, and likelihood of long-term breast conservation. To present these data, we developed an online decision aid, www.onlineDeCISion.org through support from the Agency for Health Care Research and Quality (AHRQ). This web-based decision aid is informed by a disease simulation model and projects customized 10-year and lifetime outcomes following six different treatment strategies for DCIS: lumpectomy alone, lumpectomy with radiation, lumpectomy with radiation and tamoxifen, lumpectomy with tamoxifen, and mastectomy with and without breast reconstruction (Soeteman et al., JNCI 2013). Presented results are tailored to a patient's age at diagnosis. Default risks of recurrence are taken from randomized trials, however the tool allows for flexibility in terms of presenting outcomes for personalized risks of recurrence. The development of the decision tool used semi-structured interviews and incorporated results from usability testing with key stakeholders, including a diverse group of multidisciplinary clinicians and patient advocates. After further testing, we hope that our tool will help patients and clinicians choose treatment that is most aligned with a patient's preferences for the tailored outcomes. Citation Format: Rinaa Punglia. Improving decision making for ductal carcinoma in situ. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN03-03.

Abstract CN05-03: Cooperation between a rexinoid and EGFR-TKI for lung cancer prevention via Cyclin D1 destabilization

Abstract We previously reported that both nuclear retinoic acid receptor (RAR, retinoid) and retinoid X receptor (RXR, rexinoid) agonists can trigger proteasomal degradation of cyclins. This confers check point arrest and repair of carcinogenic DNA damage in bronchial epithelial cells. Mechanisms responsible for this induced degradation were discovered. These included ubiquitin-dependent as well as ISG15-dependent programs that independently destabilized expression of cyclin D1 and other G1 cyclin proteins. The critical receptor that confers this cyclin destabilization was RARβ. Yet, silencing of RARβ; and specifically of the previously unrecognized isoform that we cloned and designated as RARβ1 likely accounts for clinical resistance to classical retinoids (like 13-cis-retinoic acid and all-trans-retinoic acid) in lung carcinogenesis. We sought to learn whether RXR/RAR heterodimer complex activation with a rexinoid was able to trigger cyclin destabilization. This was found to be the case in in vitro studies. This finding implied that the same pathway would be engaged in the in vivo setting. To establish if this occurs, we engineered transgenic mice independently with human surfactant C-driven wild-type cyclin E or a proteasome-degradation resistant cyclin E species. This mouse model was developed because human pre-malignant and malignant lung lesions frequently deregulate cyclin expression. Intriguingly, these mice recapitulated many features of lung carcinogenesis found in patients. Neoplastic changes were enhanced by transgenic expression of the degradation-resistant cyclin E species. We built on this finding by showing that a rexinoid and an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) each chemoprevented lung cancers in vinyl carbamate-induced lung tumors within strain A/J mice. Notably, the rexinoid was more potent that the EGFR-TKI in conferring this chemoprevention. Both agents also reduced cyclin expression, but did so through distinct mechanisms. We sought to learn if a rexinoid (bexarotene) cooperated with an EGFR-TKI (erlotinib) in exerting anti-tumorigenic effects in lung cancer. Cooperation between these agents was found in both murine and human lung cancer cells and even in those cells that exhibited KRAS/p53 mutations. Over the past decade, we translated this work into the cancer clinic through a series of five clinical trials that moved this work through successive phase 0, phase I, and phase II trials of lung and aerodigestive tract cancers. In window of opportunity trials, pharmacodynamic responses (cyclin repression and induced necrosis and inflammatory responses) were seen when intratumoral levels of these drugs were comparable to those necessary to trigger in vitro effects. A phase II trial in heavily pre-treated stage IV non-small cell lung cancer (NSCLC) cases was performed. EGFR and cyclin expression profiles as well as KRAS mutations were searched for in these NSCLC cases. Findings revealed substantial cyclin repression and reduction of lung cancer growth by combined therapy with a rexinoid (bexarotene) and EGFR-TKI (erlotinib). Cyclins were repressed while necrosis and inflammation were induced in post-treatment versus pre-treatment lung tumor biopsies obtained in this window of opportunity trial. Objective anti-tumor responses occurred whether or not KRAS or activating EGFR mutations were detected. This refractory NSCLC trial had 3 major clinical responses (2 had KRAS or EGFR mutations) with prolonged survival (583, 665, and 1460+ days, respectively). Median survival was 22 weeks (16 weeks for controls). Hypertriglyceridemia or rash significantly increased median overall survival to 24 weeks. Thus, this combination regimen revealed substantial clinical anti-tumor activity against NSCLCs. Taken together, these findings indicate that cooperation between a rexinoid and EGFR-TKI can chemoprevent and treat lung cancers by causing cyclin destabilization. These agents are also useful tools to identify other antineoplastics that repress lung cancers by destabilizing cyclin expression or by inhibiting their associated kinases. Evidence for this will be presented in this session. Citation Format: Konstantin H. Dragnev, Vincent Memoli, Sarah J. Freemantle, Samuel Waxman, Ethan Dmitrovsky. Cooperation between a rexinoid and EGFR-TKI for lung cancer prevention via Cyclin D1 destabilization. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr CN05-03.